SIRT1–SIRT7 in Diabetic Kidney Disease: Biological Functions and Molecular Mechanisms

Abstract

Diabetic kidney disease (DKD) is a severe microvascular complication in patients with diabetes and is one of the main causes of renal failure. The current clinical treatment methods for DKD are not completely effective, and further exploration of the molecular mechanisms underlying the pathology of DKD is necessary to improve and promote the treatment strategy. Sirtuins are class III histone deacetylases, which play an important role in many biological functions, including DNA repair, apoptosis, cell cycle, oxidative stress, mitochondrial function, energy metabolism, lifespan, and aging. In the last decade, research on sirtuins and DKD has gained increasing attention, and it is important to summarize the relationship between DKD and sirtuins to increase the awareness of DKD and improve the cure rates. We have found that miRNAs, lncRNAs, compounds, or drugs that up-regulate the activity and expression of sirtuins play protective roles in renal function. Therefore, in this review, we summarize the biological functions, molecular targets, mechanisms, and signaling pathways of SIRT1–SIRT7 in DKD models. Existing research has shown that sirtuins have the potential as effective targets for the clinical treatment of DKD. This review aims to lay a solid foundation for clinical research and provide a theoretical basis to slow the development of DKD in patients.

1 Introduction

Diabetes mellitus (DM) is a metabolic disorder with chronic microvascular and macrovascular complications. DM is one of the most problematic health issues of the 21st century due to its severe complications. DM affects approximately 451 million people worldwide and is projected to reach 693 million by 2045 (1). NAD⁺ plays a key role in redox and energy metabolism. NAD⁺ acts as a co-substrate in the deacetylation reactions of sirtuins, and the regulation of the NAD⁺-sirtuins axis is a pivotal pathway for the new therapies of metabolic diseases (2). Moreover, in different renal disease models, such as diabetic kidney disease (DKD), sirtuins have been proven to regulate anti-fibrosis and anti-oxidative stress functions, and maintain the glomerular barrier integrity (3). DKD, diabetic retinopathy, and diabetic peripheral neuropathy are the main complications of DM, among which DKD has attracted worldwide attention due to its high incidence (20%–40% in diabetic patients) and poor prognosis (4, 5). DKD is a chronic disease that leads to renal failure; the treatments for rena0l failure are dialysis and kidney transplantation (6). However, once the disease progresses to end-stage renal disease, the course of this disease is both uncontrollable and irreversible ( (7). Although many researchers have studied the molecular mechanism of DKD and attempted to improve treatment strategies, DKD remains a clinically intractable complication of DM.

Histone deacetylases (HDACs) in eukaryotes are divided into IV classes, among which the I, II, and IV groups depend on Zn²⁺, whereas class III sirtuins depend on NAD⁺ to exert catalytic activity (8). The sirtuin family is classified into SIRT1–SIRT7 based on differences in the core structural domain, all of which catalyze the deacetylation of N^ℇ-acyl-lysine on histone and non-histone substrates ( (9, 10). SIRT1, SIRT6, and SIRT7 are mainly found in the nucleus, SIRT2 is localized in the cytoplasm, and SIRT3, SIRT4, and SIRT5 are found in mitochondria, and their positions are not fixed (11). Sirtuins are involved in the regulation of various biological activities, including DNA repair, apoptosis, cell cycle, oxidative stress, metabolism, lifespan, and aging (12, 13). Based on biological regulatory functions, many studies have shown that the sirtuin family has therapeutic effects in many diseases. Sirtuins are pharmacological targets in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease (14). Moreover, the regulation of sirtuins reveals a complex network of cellular metabolism and will provide clues for the diagnosis, treatment, and prevention of cancer (15). Additionally, as mitochondrial sirtuins affect many aspects of mitochondrial metabolism and signal transduction, targeting sirtuins may represent a potential therapeutic target to combat age-related mitochondrial recession (16). Through reviewing the literature, we found many studies on sirtuins and DKD, but a lack of systematic and detailed summaries. Therefore, in this review, we have first introduced the biological regulatory functions of SIRT1–SIRT7 in DKD animal and cell models. Subsequently, we have summarized the signaling pathways for treating DKD with various treatments, and finally, examined the differences and clinical implications of sirtuins in DKD studies.

2 Search Strategy

Data for this review were identified by searching PubMed and Web of Science using the search terms “histone deacetylase”, “sirtuins”, “SIRT”, “diabetic nephropathy”, “diabetic kidney disease”, and “diabetic complication” for collecting articles from 2004 to 2021, with the language limited to English.

3 Pathological Process of DKD

The pathogenesis of DKD is multifactorial, involving structural, physiological, hemodynamic, and inflammatory processes, which ultimately lead to a decreased glomerular filtration rate (17). Hyperglycemia and hypertension are critical factors in the development of DKD (17). Proteinuria is an important factor in the development of DKD, which is directly and predictably associated with kidney damage (18). Proteinuria results from an abnormal permeability function of the glomerular filtration barrier, which consists of three layers of glomerular endothelial cells, the glomerular basement membrane (GBM), and podocytes (19). DKD is a microvascular complication of DM that develops from micro-proteinuria to massive proteinuria, ultimately leading to end-stage renal disease (18). Importantly, metabolic and hemodynamic changes in DM cause ultrastructural changes in the glomerular filtration barrier, including podocyte foot process fusion and separation, GBM thickening, reduction of endothelial cell glycocalyx, accumulation of mesangial extracellular matrix, and glomerular sclerosis, all of which are directly related to the increase in proteinuria (20).

3.1 Relationship Between the Expression of SIRT1–SIRT7 and DKD

The important role of SIRT1 has been demonstrated by the enhanced mitochondrial damage in SIRT1 knockdown mice with DM, and its role in maintaining kidney cell homeostasis under mitochondrial stress or damage (21). Moreover, in advanced glycation end products (AGE)-treated rat primary glomerular mesangial cells (GMCs), investigators found that the overexpression of SIRT1 protected against reactive oxygen species (ROS) production and fibrosis by enhancing the Keap1/Nrf2/ARE pathway (22). Additionally, under the condition of HG-induced HK-2 cells, the deacetylase activity of SIRT1 decreased and resulted in renal tubular injury induced by the SIRT1/NF-κB/microR-29/Keap1 signaling pathway (23).

Furthermore, a reduction in the NAD⁺/NADH ratio has been shown to induce a decrease in SIRT3 activity and enhance mitochondrial oxidative stress in a DKD rat model (24). Another investigator found that the overexpression of SIRT3 antagonizes apoptosis in HG-induced HK-2 cells via the AKT/FOXO1 and AKT/FOXO3a signaling pathways (25). Similarly, in a streptozotocin (STZ)-induced mouse model, high expression of SIRT3 inhibited aberrant glycolysis and prevented fibrosis via the activation of PKM2 dimer formation and HIF-1α accumulation (26). Moreover, in HG-induced endothelial cells, the overexpression of SIRT3 activated the AMPK/SIRT3 pathway to sustain redox balance and alleviate vascular inflammation (27).

A previous report indicated that the overexpression of SIRT4 reduced the inflammatory effect and restrained apoptosis and the production of ROS in HG-induced mouse podocytes via the mitochondrial pathway (28).

In HG-induced podocytes, the overexpression of SIRT6 reduced mitochondrial dysfunction and apoptosis by activating the AMPK pathway (29). Another report illustrated that overexpression of SIRT6 promoted M2 macrophage transformation and alleviated kidney injury in in vivo and in vitro DKD models by upregulating the expression of Bcl−2 and CD206, and reducing the expression of Bax and CD86 (30). Additionally, another study demonstrated that in db/db mice and AGE/HG-induced human podocytes, overexpression of SIRT6 showed anti-apoptosis and anti-inflammatory effects by inhibiting the Notch pathway (31).

Taken together, these findings indicate that the overexpression of SIRT1, SIRT3, SIRT4, and SIRT6 reduces the biological impairment of kidney function in DKD models.

3.2 Gene Polymorphism and Clinical Research of Sirtuins in DKD

Human gene polymorphism plays an important role in elucidating the susceptibility and tolerance of the human body to diseases and poisons, the diversity of clinical manifestations of diseases, and the response to drug therapy (32–34). Studies have shown that SIRT1 and FOXO1 play important roles in the pathogenesis of DKD. Single nucleotide polymorphisms were analyzed by including 1066 patients with type 2 diabetes (T2DM) (413 without DKD and 653 with DKD), and the results indicated that the SIRT1 gene variant rs10823108 and the FoxO1 gene variant rs17446614 may be associated with DKD in patients with T2DM (35). Another study of gene polymorphisms suggested that, among 1016 patients with T2DM (388 without DKD and 628 with DKD), the transcriptional coactivator p300 rs20551 polymorphism is associated with the development of DKD, and the SIRT1 polymorphism is related to albumin-creatinine ratio progression (36). The researchers analyzed changes in serum vash-1 and other biomarkers in 692 patients with T2DM, and found that the UACR, VASH-1, HbA1c, ESR, CRP, VEGF, HIF-1α, TNF-α, and TGF-β1 levels in all patient groups were significantly higher, and the SIRT1 levels were lower compared to healthy controls. These findings indicated that serum VASH-1 may be associated with the expression of renal inflammation and fibrosis-related factors and have a potential connection with DKD (37). Another two-center, randomized study evaluated 117 patients with stage 2–4 DKD who were treated with sevelamer carbonate. The results showed that sevelamer carbonate increased anti-inflammatory defenses, including nuclear factor like-2, AGE receptor 1, and SIRT1, and decreased pro-inflammatory cytokines, such as TNF receptor 1 (38). In the latest clinical study, 313 patients with T2DM, 102 pre-diabetic patients, and 100 healthy volunteers were selected to study the relationship between SIRT6 and glucolipid metabolism and urinary protein. The clinical study results showed that SIRT6 increased with glucolipid metabolism and urinary protein markers, and is therefore expected to be a potential biomarker for the early prediction and diagnosis of glucolipid metabolism disorders and related nephropathy (39). The results of the above gene polymorphism and clinical studies indicate that sirtuins may represent a molecular target to explore new therapeutic approaches for DKD in the clinic.

4 Biological Effects of SIRT1–SIRT7 in DKD Models

In the cell models of DKD, injury models are mostly induced by HG or AGE, while most kidney fibrosis models are induced by TGF-β1 or HG in podocytes, mesangial cells, renal tubular cells, and some endothelial cells (Table 1). In podocyte, proximal tubular cell, and mesangial cell models, SIRT1 and SIRT3 are involved in the mechanism by which therapeutic drugs restore mitochondrial biosynthesis. In podocyte and mesangial cell models, SIRT1 and SIRT6 play significant roles in reducing abnormal mitochondrial function. Moreover, SIRT1, SIRT3, and SIRT4 are involved in the anti-oxidative stress effect in podocytes, mesangial cells, and renal tubular cells. SIRT1, SIRT3, SIRT4, SIRT6, and SIRT7 all participate in reducing the apoptosis of podocytes, mesangial cells, and renal tubular cells in DKD models. In most DKD cell models, therapies targeting SIRT1, SIRT3, SIRT4, and SIRT6 have shown anti-inflammatory effects. In DKD tubular cell models, both SIRT1- and SIRT3-targeted therapies displayed anti-fibrosis effects and suppressed epithelial-mesenchymal transition (EMT). Targeting SIRT1 also enhanced autophagy in various DKD models. By summarizing the results of previous research, we found that SIRT1, SIRT3, SIRT4, SIRT6, and SIRT7 play different biological functions in DKD cell models. Notably, SIRT1 is the most widely investigated HDAC with the most diverse biological functions (Figure 1).

Figure 1

Animal models are valuable for studying the pathological origins of human diseases because they allow in-depth investigation of mechanisms, which cannot be explored in clinical studies. As DKD animal models, db/db mice or rats, STZ and/or HFD-induced mice or SD/Wistar rats, and some unique transgenic mouse models are often used as research objects. We summarized the research methods of SIRT1, SIRT3, SIRT4, SIRT6, and SIRT7 in different DKD animal models to understand the methods of animal models more intuitively (Tables 2–9).

Generally, these abnormal manifestations, such as inflammation, oxidative stress, abnormal mitochondrial function, renal fibrosis, podocyte loss and apoptosis, and impaired autophagy, are all likely to occur during the development of DKD. Meanwhile, SIRT1, SIRT3, SIRT4, SIRT6, and SIRT7 play diverse regulatory roles in these physiological processes.

5 The Role of SIRT1–SIRT7 in Signaling Pathways in DKD Models

5.1 AMPK/Sirtuins/PGC-1α Pathway

AMPK and SIRT1 are the two main energy sensors, which directly affect the activity of PGC-1α through phosphorylation and deacetylation, respectively (40). Studies have shown that impaired renal function under HG is directly related to the inactivation of the AMPK/SIRT1/PGC-1α signaling pathway (41). The study results showed that CL316, 243, glycyrrhizic acid, and a polysaccharide from okra (OP) all played antioxidant roles, reduced inflammation, and improved fibrosis through activation of the AMPK/SIRT1/PGC-1α pathway in STZ and/or HFD-induced db/db DKD mouse models (42–44). Resveratrol, pro-renin receptor shRNA, and grape seed procyanidin B2 (GSPB2) regained SIRT1 expression via the AMPK/SIRT1/PGC-1α signaling axis in DKD models, thus restoring mitochondrial biosynthesis and function, reducing oxidative stress, and inhibiting apoptosis (40, 41, 45–47). In DKD animal or cell models, FGF21, metformin, salidroside, and roflumilast increased or restored the expression level of SIRT1 and played anti-apoptotic and anti-oxidative roles by activating the AMPK/SIRT1 pathway (48–51). Moreover, catalpol and geniposide (GE) up-regulated the expression of SIRT1 in DKD models and inhibited oxidative stress and inflammation by activating the AMPK/SIRT1/NF-κB pathway (52, 53). Additionally, in HG-induced renal tubule cells, restoration of SIRT3 expression through stanniocalcin-1 activated the AMPK/SIRT3 pathway to produce antioxidant and anti-apoptotic activities (54). Furthermore, cocoa, metformin, glycyrrhizic acid, and probucol restored SIRT1 expression by activation of the AMPK/SIRT1 pathway, ultimately reducing oxidative stress, apoptosis, and enhancing autophagy in DKD models (26, 55–58). However, one particular study reported that resveratrol improved oxidative stress and enhanced mitochondrial biogenesis without altering SIRT1 expression, and is independent of the AMPK/SIRT1 pathway. The distinction is that they used H₂O₂-exposed proximal tubular cells as a DKD model, as opposed to HG or AGE, which are more commonly used (59). In HG-induced immortalized human mesangial cells (iHMCs), theobromine could activate SIRT1 and decrease kidney extracellular matrix (ECM) accumulation by activating the AMPK pathway (60). In BTBR ob/ob mice, honokiol protected mitochondrial health by activating mitochondrial SIRT3, which first revealed the renal protective effect of SIRT3 on diabetic glomerular disease (61). Moreover, in STZ-induced mouse models, salidroside and resveratrol restored SIRT1 expression via the SIRT1/PGC‐1α pathway, thus inhibiting fibrosis and reducing mitochondrial oxidative stress, respectively (61–63). BF175, as an activator of SIRT1, increased SIRT1 activity to acetylate PGC‐1α and activate PPARγ to reduce podocyte loss and oxidative stress (64). Furthermore, glucagon−like peptide−1, formononetin, and resveratrol enhanced SIRT1 expression in DKD models to attenuate apoptosis and oxidative stress by activating SIRT1 (65–67). Beyond this, in HG-induced podocytes or mesangial cells, overexpression of lncRNA SOX2OT, overexpression of lncRNA GAS5, or downregulation of miR-138 increased SIRT1 expression or activity to induce autophagy, inhibit fibrosis, and decrease inflammation, respectively, by regulating the miR-9/SIRT1, miR-221/SIRT1, and miR-138/SIRT1 axes (68–70). Through the studies reported above, we conclude that AMPK/Sirtuins/PGC-1α is a crucial pathway in regulating the pathological process of DKD (Table 2).

5.2 SIRT1/p53 Pathway

SIRT1 specifically associates with and acetylates the tumor suppressor protein p53, thereby negatively regulating p53-mediated transcriptional activation. More importantly, p53 deacetylation by SIRT1 prevents DNA damage and stress-induced cell senescence and apoptosis (71, 72). A previous study has shown that in HG-induced podocytes or HK-2 cells, inhibition of miR-150-5p or miR-155-5p, which could bind to the 3’-UTR of SIRT1, promoted autophagy by targeting the SIRT1/p53 pathway (73, 74). Moreover, in DKD animal and cell models, H₂S, resveratrol, and calcium dobesilate restored or enhanced SIRT1 expression to prevent apoptosis by activating the SIRT1/p53 pathway (75–77). These reports suggest that the SIRT1/p53 pathway reduces cellular stress in HG-induced cells or STZ-induced animals’ models (Table 3).

5.3 SIRT1/NF-κB-Related Pathway

Previous studies have demonstrated that the ability of SIRT1 deacetylation is critical to control the function of the transcription factor NF-κB, as SIRT1 modulates various biological responses by deacetylating NF-κB, including inflammation and autophagy (78, 79). In DKD models, isoliquiritigenin (ISLQ), baicalin, astragaloside IV, ligustilide, nicotinamide mononucleotide (NMN), and Tangshen formula have been shown to increase or activate SIRT1 through the SIRT1/NF-κB signaling pathway to improve inflammation, decrease apoptosis, and enhance autophagy (80–86). Moreover, in STZ-induced mouse models, BF175 decreased albuminuria and glomerular disease via the transcription factor NF-κB and p53 pathways (87). Additionally, panax notoginseng saponins (PNS) and baicalin have been found to up-regulate SIRT1 to inhibit inflammation, reactivate autophagy, and alleviate fibrosis via the NF-κB and TGF-β pathways in DKD models (88, 89). Furthermore, in HG-induced HK-2 cells, Na₂S₄ has been shown to directly sulfhydrate two conserved domains of SIRT1, leading to dephosphorylation and deacetylation of NF-κB and STAT3, which improves oxidative stress, apoptosis, and the inflammatory response (90). Thus, SIRT1 also has a protective effect on renal function by regulating downstream of NF-κB in DKD (Table 4).

5.4 Sirtuins and the TGF-β1/Smad3 Pathway

TGF-β superfamily members are critical in regulating fibrosis in most chronic kidney diseases, and the inhibition of TGF-β1 or its downstream signaling (e.g. Smad) has been shown to decrease renal fibrosis (91–94). It has also been reported that the reduction of miR-34a-5p targets the 3’UTR of SIRT1, which inhibits fibrosis by regulating TGF-β1 signaling in HG-induced HK-2 cells (95). Moreover, in AGE stimulated NRK-52E cells, oligo-fucoidan has been shown to improve renal fibrosis via restraint of the pro-fibrosis process caused by TGF-β1 activation (96). Additionally, tetrahydroxystilbene glucoside (TSG) restored SIRT1 expression to alleviate oxidative stress by targeting SIRT1 and TGF-β1 signaling both in vivo and in vitro (97). Moreover, the inhibition of miRNA−135a−5p increased SIRT1 expression and inhibited fibrosis by targeting the TGF-β1/Smad3 pathway in TGF-β1-induced HK-2 and HMC cells (98). As a unique example, FOXO3a binds to the SIRT6 promoter and promoted SIRT6 expression to reduce EMT and fibrosis through FOXO3a-mediated SIRT6/Smad3 pathway in DKD models (99). The above summary highlights the vital function of the TGF-β1/Smad3 pathway in the regulation of renal fibrosis by sirtuins in DKD (Table 5).

5.5 PI3K/AKT/FOXO Pathway

The PI3K/AKT pathway plays a crucial role in cell physiology, which participates in glucose homeostasis, lipid metabolism, protein synthesis, and cell proliferation and survival (100, 101). FOXO1 and FOXO3a, as important substrates of AKT, are regulated by the PI3K/AKT pathway (102). Researchers have found that resveratrol restored SIRT1 expression to attenuate oxidative stress damage in STZ-induced rat models through the SIRT1/FOXO3a or SIRT1/FOXO1 pathway (103–105). Furthermore, fucoxanthin and angiotensin 1–7 restored SIRT1 expression in response to antioxidative stress via the AKT/SIRT1/FOXO3α and SIRT1/FOXO1/ATGL signaling pathways in DKD models, separately (106, 107). Moreover, in STZ- and HFD-induced mouse models, purinergic receptor (P2Y2R) deficiency enhanced autophagy and the expression of SIRT1 by AKT/FOXO3a and SIRT1 signaling pathways (108). Additionally, pyrroloquinoline quinine increased the expression of SIRT3 to antagonize oxidative stress and apoptosis in HG-induced HK-2 cells via the PI3K/AKT/FOXO3a signaling pathway (109). Moreover, it has been reported that progranulin (PGRN) restored both SIRT1 and SIRT3 to maintain mitochondrial biogenesis and mitophagy via SIRT1/PGC-1α/FOXO1 signaling in HG-treated podocytes (110). These findings suggest that the PI3K/AKT/FOXO pathway performs important biological functions in improving DKD by targeting sirtuins (Table 6).

5.6 Keap1/Nrf2/ARE Pathway

Dysregulation of Nrf2 transcriptional activity has been described in the pathogenesis of various diseases, and the Nrf2/Keap1 axis is a key regulator of cell homeostasis (111). It has been reported that formononetin, resveratrol, and polydatin up-regulate the expression of SIRT1 to anti-oxidative stress and fibrosis by activating the Nrf2/ARE pathway in HG/AGE-induced GMCs (112–114). Investigators have also found that SRT2104 (SIRT1 activators) protect against oxidative stress, inflammation, and fibrosis via the SIRT1/p53/Nrf2 pathway in DKD models (115). Moreover, in HG-induced NRK-52E cells, ISLQ treatment reduced inflammation and oxidative stress by inhibiting MAPK activation and the induction of Nrf2 signaling (116). These findings demonstrate that SIRT1 regulates the transcription factor Nrf2 in DKD models (Table 7).

5.7 STAT and HIF-1α-Related Pathway

It has been reported that connexin 43, LincRNA 1700020I14Rik, and silencing of miR-217 restrain inflammation and fibrosis in both in vivo and in vitro DKD models through SIRT1/HIF-1α signaling (117–119). Additionally, in AGE-induced human podocytes, PYR as an AGE inhibitor, restored SIRT1 expression to reduce kidney injury by decreasing p65 and STAT3 acetylation (120). In one study in HFD-diet DM rats, EX-527, as a SIRT1 inhibitor, reduced SIRT1 expression and increased SIRT3 expression to lessen fibrosis and inflammation by blocking the phosphorylation of EGFR and PDGFR, blocking STAT3 signaling (121). In another study, glucagon-like peptide-1 decreased SIRT1 expression to improve the inflammatory changes in db/db mice by inhibiting JAK/STAT signaling (122). Thus, STAT and HIF-1α-related pathways reduce negative effects in DKD models by targeting sirtuins (Table 8).

5.8 Other Pathways Involved in the Regulation of Sirtuins in DKD

5.8.1 Pathways Associated With SIRT1 in DKD

Researchers have shown that both 1α, 25-Dihydroxyvitamin D3 and puerarin activate and increase SIRT1 expression to achieve anti-oxidative effects by suppressing NOX4 expression in DKD models (123, 124). Carnosine upregulated SIRT1 expression to decrease glycative and lipoperoxidative stress in HG-induced podocytes via the Hsp70/HO-1 pathway. Another report showed that anserine revealed anti-oxidant and glycative stress in HG-induced HK-2 cells via the Hsp70/HO-1 defense system, but did not affect SIRT1 expression (125, 126). Several other studies have shown that aerobic exercise training, inhibition of HIC1, INT-767 (FXR/TGR5 dual agonist), and SGLT2 restored SIRT1 expression under DKD animal and cell models, which improve mitochondrial function, reduce ROS, anti-inflammation, and prevent glucose entry (127–130). These results suggest that SIRT1 largely exhibits anti-inflammatory and anti-oxidant effects through different signaling pathways in DKD models.

5.8.2 Pathways Associated With SIRT3 in DKD

Apigenin (CD38 inhibitor) and empagliflozin (SGLT2 inhibitor) have been shown to increase SIRT3 levels in HG-induced HK-2 cells to relieve mitochondrial oxidative stress and restore aberrant functions; this is mediated by restoring the NAD⁺/NADH ratio and inhibiting glucose uptake into the proximal tubules, respectively (131, 132). Liraglutide (glucagon−like peptide−1 agonist) has also been shown to increase SIRT3 expression to prevent the activation of mitochondrial apoptosis by activating the ERK−Yap signaling pathway in HG-induced HRMCs (133). It has been reported that INT-777 (TGR5-agonist) increased the activity of both SIRT1 and SIRT3 to improve mitochondrial biogenesis, and reduce oxidative stress and fibrosis via the TGR5 pathway in db/db diabetic mice (134). Moreover, in the C57BL/KsJ db/db mouse model, the overexpression of SIRT3 reduced apoptosis and fibrosis through modulation of mitophagy (135). It can be seen from the above results that high expression of SIRT3 reduced mitochondrial stress response, including oxidative stress and apoptosis.

5.8.3 Pathways Associated With SIRT6 in DKD

SIRT6-knockout male mice have been shown to exhibit an enhanced fibrotic phenotype, which was controlled by the Nampt-SIRT6 axis to regulate extracellular matrix remodeling, and the authors found that SIRT1 is not the controller of SIRT6 expression (136). The results of this article show that SIRT6 plays an important regulatory role in ECM remodeling.

5.8.4 Pathways Associated With SIRT7 in DKD

In HG-treated podocytes, the increase in SIRT7 has been shown to inhibit podocyte apoptosis, while the suppression of microRNA-20b promotes SIRT7 expression to decrease apoptosis (137) (Table 9). This research demonstrated that increasing the expression of SIRT7 reduced the occurrence of apoptosis in podocytes.

5.9 Summary of SIRT1–SIRT7

SIRT1 was the first sirtuin discovered in mammals, and remains the most extensively and deeply studied so far (138). Resveratrol is the most recognized and studied activator of SIRT1 (139). SIRT1 has been extensively studied in DKD models, including podocytes, mesangial cells, and tubular cells. SIRT2 is the only cytoplasmic sirtuin, but its role in treating DKD has not been reported yet so far, nor has that of SIRT5. SIRT3 is normally located in the mitochondria, but under cellular stress, it can translocate into the nucleus (140). Some studies have reported that increased expression of SIRT3 is beneficial to DKD, mainly through AMPK or PI3K pathways (25, 27, 54, 109, 110). However, we found one article that reported that the overexpression of SIRT4 reduced inflammatory effects, and inhibited ROS production and apoptosis in HG-induced podocytes (28). SIRT6 is a nuclear HDAC that plays an important role in the pathological processes of inflammation, aging, cancer, and neurodegenerative diseases (141). However, only a few studies on SIRT6 have been reported, mainly in podocyte and tubular cell models of DKD. Additionally, the catalytic activity of SIRT7 is weak, and a previous report indicated that the suppression of microRNA-20b increased SIRT7 expression and reduced HG-induced podocyte apoptosis (137) (Figure 2).

Figure 2

6 Conclusions and Perspectives

Many researchers are working to investigate the etiology of DKD and explore new treatment methods. In our conventional view, sirtuins are a class of HDACs involved in the regulation of longevity and maintaining the stability of nucleosomes by balancing with histone acetylases (13). However, in addition to deacetylate histones, we discovered that sirtuins also regulate many transcription factors, including FOXO1, FOXO3a, STAT3, Smad2/3, NF-κB, p53, and Nrf-2. These transcription factors are involved in regulating many biological processes, including autophagy, oxidative stress, apoptosis, inflammation, EMT, and fibrosis (Figure 3). We found that in DKD studies, the high expression of SIRT1–SIRT7 alleviated or reduced kidney injury through different mechanisms or molecular pathways, of which SIRT1 is the most widely explored. However, an exception was found in db/db mice, which showed that treatment with glucagon-like peptide-1 reduced SIRT1 expression, while in HUVEC cells, glucagon-like peptide-1 had no significant effect on the SIRT1 expression level. The authors explained that the in vivo results were due to a reduced inflammatory environment that did not stimulate SIRT1, while the in vitro results were due to SIRT1 only participating in transcriptional responses (122). Resveratrol is a recognized activator of SIRT1, but in db/db mice, treatment with resveratrol failed to cause changes in SIRT1 expression, and it still improved oxidative stress and enhanced mitochondrial biogenesis in the AMPK/SIRT1-independent pathway (59). Furthermore, the expression of SIRT1, SIRT2, SIRT3, and SIRT6 was higher than SIRT4, SIRT5, and SIRT7 in the kidney; therefore, the study of SIRT1, SIRT2, SIRT3, and SIRT6 in DKD models is both reasonable and credible (136).

Figure 3

In light of the above, to better illuminate the roles of SIRT1–SIRT7 in DKD and the research progress, we have summarized the therapeutics, targets, and signaling pathways involved in in vitro and in vivo models of DKD (Figure 3). Our aim is that this review will serve as a valuable reference for future studies of sirtuins and DKD, and provide a theoretical foundation for delaying the pathological process of DKD in the clinic.

Funding

This work was supported by the National Natural Science Foundation of China (U19A2013), the National Key Research and Development Program of China (2017YFC1702103), and the Science and Technology Development Plan Project of Jilin Province (202002053JC).

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

• 1

  WangAJWangSWangBJXiaoMGuoYTangYet al. Epigenetic Regulation Associated With Sirtuin 1 in Complications of Diabetes Mellitus. Front Endocrinol (Lausanne) (2020) 11:598012. doi: 10.3389/fendo.2020.598012

  • CrossRef
  • Google Scholar

• 2

  HershbergerKAMartinASHirscheyMD. Role of NAD(+) and Mitochondrial Sirtuins in Cardiac and Renal Diseases. Nat Rev Nephrol (2017) 13(4):213–25. doi: 10.1038/nrneph.2017.5

  • CrossRef
  • Google Scholar

• 3

  WakinoSHasegawaKItohH. Sirtuin and Metabolic Kidney Disease. Kidney Int (2015) 88(4):691–8. doi: 10.1038/ki.2015.157

  • CrossRef
  • Google Scholar

• 4

  Navarro-GonzalezJFMora-FernandezCMuros de FuentesMGarcia-PerezJ. Inflammatory Molecules and Pathways in the Pathogenesis of Diabetic Nephropathy. Nat Rev Nephrol (2011) 7(6):327–40. doi: 10.1038/nrneph.2011.51

  • CrossRef
  • Google Scholar

• 5

  GheithOFaroukNNampooryNHalimMAAl-OtaibiT. Diabetic Kidney Disease: World Wide Difference of Prevalence and Risk Factors. J Nephropharmacol (2016) 5(1):49–56. doi: 10.4103/1110-9165.197379

  • CrossRef
  • Google Scholar

• 6

  KoyeDNMaglianoDJNelsonRGPavkovME. The Global Epidemiology of Diabetes and Kidney Disease. Adv Chronic Kidney Dis (2018) 25(2):121–32. doi: 10.1053/j.ackd.2017.10.011

  • CrossRef
  • Google Scholar

• 7

  WangWSunWChengYXuZCaiL. Role of Sirtuin-1 in Diabetic Nephropathy. J Mol Med (Berl) (2019) 97(3):291–309. doi: 10.1007/s00109-019-01743-7

  • CrossRef
  • Google Scholar

• 8

  LiXZhangJXieYJiangYYingjieZXuW. Progress of HDAC Inhibitor Panobinostat in the Treatment of Cancer. Curr Drug Targets (2014) 15(6):622–34. doi: 10.2174/1389450115666140306152642

  • CrossRef
  • Google Scholar

• 9

  ChenBZangWWangJHuangYHeYYanLet al. The Chemical Biology of Sirtuins. Chem Soc Rev (2015) 44(15):5246–64. doi: 10.1039/c4cs00373j

  • CrossRef
  • Google Scholar

• 10

  MorigiMPericoLBenigniA. Sirtuins in Renal Health and Disease. J Am Soc Nephrol (2018) 29(7):1799–809. doi: 10.1681/ASN.2017111218

  • CrossRef
  • Google Scholar

• 11

  WangYHeJLiaoMHuMLiWOuyangHet al. An Overview of Sirtuins as Potential Therapeutic Target: Structure, Function and Modulators. Eur J Med Chem (2019) 161:48–77. doi: 10.1016/j.ejmech.2018.10.028

  • CrossRef
  • Google Scholar

• 12

  YoonYKOonCE. Sirtuin Inhibitors: An Overview From Medicinal Chemistry Perspective. Anticancer Agents Med Chem (2016) 16(8):1003–16. doi: 10.2174/1871520616666160310141622

  • CrossRef
  • Google Scholar

• 13

  WatrobaMDudekISkodaMStangretARzodkiewiczPSzukiewiczD. Sirtuins, Epigenetics and Longevity. Ageing Res Rev (2017) 40:11–9. doi: 10.1016/j.arr.2017.08.001

  • CrossRef
  • Google Scholar

• 14

  LeiteJAGhirottoBTarghettaVPde LimaJCamaraNOS. Sirtuins as Pharmacological Targets in Neurodegenerative and Neuropsychiatric Disorders. Br J Pharmacol (2021) 179(8):1496–511. doi: 10.1111/bph.15570

  • CrossRef
  • Google Scholar

• 15

  ZhuSDongZKeXHouJZhaoEZhangKet al. The Roles of Sirtuins Family in Cell Metabolism During Tumor Development. Semin Cancer Biol (2019) 57:59–71. doi: 10.1016/j.semcancer.2018.11.003

  • CrossRef
  • Google Scholar

• 16

  van de VenRAHSantosDHaigisMC. Mitochondrial Sirtuins and Molecular Mechanisms of Aging. Trends Mol Med (2017) 23(4):320–31. doi: 10.1016/j.molmed.2017.02.005

  • CrossRef
  • Google Scholar

• 17

  DeFronzoRAReevesWBAwadAS. Pathophysiology of Diabetic Kidney Disease: Impact of SGLT2 Inhibitors. Nat Rev Nephrol (2021) 17(5):319–34. doi: 10.1038/s41581-021-00393-8

  • CrossRef
  • Google Scholar

• 18

  ZojaCXinarisCMacconiD. Diabetic Nephropathy: Novel Molecular Mechanisms and Therapeutic Targets. Front Pharmacol (2020) 11:586892. doi: 10.3389/fphar.2020.586892

  • CrossRef
  • Google Scholar

• 19

  GnudiLCowardRJMLongDA. Diabetic Nephropathy: Perspective on Novel Molecular Mechanisms. Trends Endocrinol Metab (2016) 27(11):820–30. doi: 10.1016/j.tem.2016.07.002

  • CrossRef
  • Google Scholar

• 20

  LiuSYuanYXueYXingCZhangB. Podocyte Injury in Diabetic Kidney Disease: A Focus on Mitochondrial Dysfunction. Front Cell Dev Biol (2022) 10:832887. doi: 10.3389/fcell.2022.832887

  • CrossRef
  • Google Scholar

• 21

  ChuangPYXuJDaiYJiaFMallipattuSKYacoubRet al. In Vivo RNA Interference Models of Inducible and Reversible Sirt1 Knockdown in Kidney Cells. Am J Pathol (2014) 184(7):1940–56. doi: 10.1016/j.ajpath.2014.03.016

  • CrossRef
  • Google Scholar

• 22

  HuangKGaoXWeiW. The Crosstalk Between Sirt1 and Keap1/Nrf2/ARE Anti-Oxidative Pathway Forms a Positive Feedback Loop to Inhibit FN and TGF-Beta1 Expressions in Rat Glomerular Mesangial Cells. Exp Cell Res (2017) 361(1):63–72. doi: 10.1016/j.yexcr.2017.09.042

  • CrossRef
  • Google Scholar

• 23

  ZhouLXuDYShaWGShenLLuGYYinXet al. High Glucose Induces Renal Tubular Epithelial Injury via Sirt1/NF-Kappab/microR-29/Keap1 Signal Pathway. J Transl Med (2015) 13:352. doi: 10.1186/s12967-015-0710-y

  • CrossRef
  • Google Scholar

• 24

  OguraYKitadaMMonnoIKanasakiKWatanabeAKoyaD. Renal Mitochondrial Oxidative Stress is Enhanced by the Reduction of Sirt3 Activity, in Zucker Diabetic Fatty Rats. Redox Rep (2018) 23(1):153–9. doi: 10.1080/13510002.2018.1487174

  • CrossRef
  • Google Scholar

• 25

  JiaoXLiYZhangTLiuMChiY. Role of Sirtuin3 in High Glucose-Induced Apoptosis in Renal Tubular Epithelial Cells. Biochem Biophys Res Commun (2016) 480(3):387–93. doi: 10.1016/j.bbrc.2016.10.060

  • CrossRef
  • Google Scholar

• 26

  SrivastavaSPLiJKitadaMFujitaHYamadaYGoodwinJEet al. SIRT3 Deficiency Leads to Induction of Abnormal Glycolysis in Diabetic Kidney With Fibrosis. Cell Death Dis (2018) 9(10):997. doi: 10.1038/s41419-018-1057-0

  • CrossRef
  • Google Scholar

• 27

  WangYZhangXWangPShenYYuanKLiMet al. Sirt3 Overexpression Alleviates Hyperglycemia-Induced Vascular Inflammation Through Regulating Redox Balance, Cell Survival, and AMPK-Mediated Mitochondrial Homeostasis. J Recept Signal Transduct Res (2019) 39(4):341–9. doi: 10.1080/10799893.2019.1684521

  • CrossRef
  • Google Scholar

• 28

  ShiJXWangQJLiHHuangQ. SIRT4 Overexpression Protects Against Diabetic Nephropathy by Inhibiting Podocyte Apoptosis. Exp Ther Med (2017) 13(1):342–8. doi: 10.3892/etm.2016.3938

  • CrossRef
  • Google Scholar

• 29

  FanYYangQYangYGaoZMaYZhangLet al. Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes Through AMPK Activation. Int J Biol Sci (2019) 15(3):701–13. doi: 10.7150/ijbs.29323

  • CrossRef
  • Google Scholar

• 30

  JiLChenYWangHZhangWHeLWuJet al. Overexpression of Sirt6 Promotes M2 Macrophage Transformation, Alleviating Renal Injury in Diabetic Nephropathy. Int J Oncol (2019) 55(1):103–15. doi: 10.3892/ijo.2019.4800

  • CrossRef
  • Google Scholar

• 31

  LiuMLiangKZhenJZhouMWangXWangZet al. Sirt6 Deficiency Exacerbates Podocyte Injury and Proteinuria Through Targeting Notch Signaling. Nat Commun (2017) 8(1):413. doi: 10.1038/s41467-017-00498-4

  • CrossRef
  • Google Scholar

• 32

  AbbasSRazaSTAhmedFAhmadARizviSMahdiF. Association of Genetic Polymorphism of PPARgamma-2, ACE, MTHFR, FABP-2 and FTO Genes in Risk Prediction of Type 2 Diabetes Mellitus. J BioMed Sci (2013) 20:80. doi: 10.1186/1423-0127-20-80

  • CrossRef
  • Google Scholar

• 33

  LiYY. ENPP1 K121Q Polymorphism and Type 2 Diabetes Mellitus in the Chinese Population: A Meta-Analysis Including 11,855 Subjects. Metabolism (2012) 61(5):625–33. doi: 10.1016/j.metabol.2011.10.002

  • CrossRef
  • Google Scholar

• 34

  DobignyGBritton-DavidianJRobinsonTJ. Chromosomal Polymorphism in Mammals: An Evolutionary Perspective. Biol Rev Camb Philos Soc (2017) 92(1):1–21. doi: 10.1111/brv.12213

  • CrossRef
  • Google Scholar

• 35

  ZhaoYWeiJHouXLiuHGuoFZhouYet al. SIRT1 Rs10823108 and FOXO1 Rs17446614 Responsible for Genetic Susceptibility to Diabetic Nephropathy. Sci Rep (2017) 7(1):10285. doi: 10.1038/s41598-017-10612-7

  • CrossRef
  • Google Scholar

• 36

  TangKSunMShenJZhouB. Transcriptional Coactivator P300 and Silent Information Regulator 1 (SIRT1) Gene Polymorphism Associated With Diabetic Kidney Disease in a Chinese Cohort. Exp Clin Endocrinol Diabetes (2017) 125(8):530–7. doi: 10.1055/s-0043-103966

  • CrossRef
  • Google Scholar

• 37

  RenHShaoYMaXYangMLiuYWangQ. Expression Levels of Serum Vasohibin-1 and Other Biomarkers in Type 2 Diabetes Mellitus Patients With Different Urinary Albumin to Creatinine Ratios. J Diabetes Complications (2019) 33(7):477–84. doi: 10.1016/j.jdiacomp.2019.04.008

  • CrossRef
  • Google Scholar

• 38

  Yubero-SerranoEMWoodwardMPoretskyLVlassaraHStrikerGEGroup AG-lS. Effects of Sevelamer Carbonate on Advanced Glycation End Products and Antioxidant/Pro-Oxidant Status in Patients With Diabetic Kidney Disease. Clin J Am Soc Nephrol (2015) 10(5):759–66. doi: 10.2215/CJN.07750814

  • CrossRef
  • Google Scholar

• 39

  BianCGaoJWangYLiJLuanZLuHet al. Association of SIRT6 Circulating Levels With Urinary and Glycometabolic Markers in Pre-Diabetes and Diabetes. Acta Diabetol (2021) 58(11):1551–62. doi: 10.1007/s00592-021-01759-x

  • CrossRef
  • Google Scholar

• 40

  AkhtarSSiragyHM. Pro-Renin Receptor Suppresses Mitochondrial Biogenesis and Function via AMPK/SIRT-1/ PGC-1alpha Pathway in Diabetic Kidney. PloS One (2019) 14(12):e0225728. doi: 10.1371/journal.pone.0225728

  • CrossRef
  • Google Scholar

• 41

  KimMYLimJHYounHHHongYAYangKSParkHSet al. Resveratrol Prevents Renal Lipotoxicity and Inhibits Mesangial Cell Glucotoxicity in a Manner Dependent on the AMPK-SIRT1-PGC1alpha Axis in Db/Db Mice. Diabetologia (2013) 56(1):204–17. doi: 10.1007/s00125-012-2747-2

  • CrossRef
  • Google Scholar

• 42

  LiaoZZhangJWangJYanTXuFWuBet al. The Anti-Nephritic Activity of a Polysaccharide From Okra (Abelmoschus Esculentus (L.) Moench) via Modulation of AMPK-Sirt1-PGC-1alpha Signaling Axis Mediated Anti-Oxidative in Type 2 Diabetes Model Mice. Int J Biol Macromol (2019) 140:568–76. doi: 10.1016/j.ijbiomac.2019.08.149

  • CrossRef
  • Google Scholar

• 43

  CaiYYZhangHBFanCXZengYMZouSZWuCYet al. Renoprotective Effects of Brown Adipose Tissue Activation in Diabetic Mice. J Diabetes (2019) 11(12):958–70. doi: 10.1111/1753-0407.12938

  • CrossRef
  • Google Scholar

• 44

  HouSZhangTLiYGuoFJinX. Glycyrrhizic Acid Prevents Diabetic Nephropathy by Activating AMPK/SIRT1/PGC-1alpha Signaling in Db/Db Mice. J Diabetes Res (2017) 2017:2865912. doi: 10.1155/2017/2865912

  • CrossRef
  • Google Scholar

• 45

  ParkHSLimJHKimMYKimYHongYAChoiSRet al. Resveratrol Increases AdipoR1 and AdipoR2 Expression in Type 2 Diabetic Nephropathy. J Transl Med (2016) 14(1):176. doi: 10.1186/s12967-016-0922-9

  • CrossRef
  • Google Scholar

• 46

  CaiXBaoLRenJLiYZhangZ. Grape Seed Procyanidin B2 Protects Podocytes From High Glucose-Induced Mitochondrial Dysfunction and Apoptosis via the AMPK-SIRT1-PGC-1alpha Axis In Vitro. Food Funct (2016) 7(2):805–15. doi: 10.1039/c5fo01062d

  • CrossRef
  • Google Scholar

• 47

  BaoLCaiXZhangZLiY. Grape Seed Procyanidin B2 Ameliorates Mitochondrial Dysfunction and Inhibits Apoptosis via the AMP-Activated Protein Kinase-Silent Mating Type Information Regulation 2 Homologue 1-PPARgamma Co-Activator-1alpha Axis in Rat Mesangial Cells Under High-Dose Glucosamine. Br J Nutr (2015) 113(1):35–44. doi: 10.1017/S000711451400347X

  • CrossRef
  • Google Scholar

• 48

  WengWGeTWangYHeLLiuTWangWet al. Therapeutic Effects of Fibroblast Growth Factor-21 on Diabetic Nephropathy and the Possible Mechanism in Type 1 Diabetes Mellitus Mice. Diabetes Metab J (2020) 44(4):566–80. doi: 10.4093/dmj.2019.0089

  • CrossRef
  • Google Scholar

• 49

  RogackaDAudzeyenkaIRychlowskiMRachubikPSzrejderMAngielskiSet al. Metformin Overcomes High Glucose-Induced Insulin Resistance of Podocytes by Pleiotropic Effects on SIRT1 and AMPK. Biochim Biophys Acta Mol Basis Dis (2018) 1864(1):115–25. doi: 10.1016/j.bbadis.2017.10.014

  • CrossRef
  • Google Scholar

• 50

  ShatiAA. Salidroside Ameliorates Diabetic Nephropathy in Rats by Activating Renal AMPK/SIRT1 Signaling Pathway. J Food Biochem (2020) 44(4):e13158. doi: 10.1111/jfbc.13158

  • CrossRef
  • Google Scholar

• 51

  TikooKLodeaSKarpePAKumarS. Calorie Restriction Mimicking Effects of Roflumilast Prevents Diabetic Nephropathy. Biochem Biophys Res Commun (2014) 450(4):1581–6. doi: 10.1016/j.bbrc.2014.07.039

  • CrossRef
  • Google Scholar

• 52

  ChenJYangYLvZShuADuQWangWet al. Study on the Inhibitive Effect of Catalpol on Diabetic Nephropathy. Life Sci (2020) 257:118120. doi: 10.1016/j.lfs.2020.118120

  • CrossRef
  • Google Scholar

• 53

  LiFChenYLiYHuangMZhaoW. Geniposide Alleviates Diabetic Nephropathy of Mice Through AMPK/SIRT1/NF-kappaB Pathway. Eur J Pharmacol (2020) 886:173449. doi: 10.1016/j.ejphar.2020.173449

  • CrossRef
  • Google Scholar

• 54

  LiuZLiuHXiaoLLiuGSunLHeL. STC-1 Ameliorates Renal Injury in Diabetic Nephropathy by Inhibiting the Expression of BNIP3 Through the AMPK/SIRT3 Pathway. Lab Invest (2019) 99(5):684–97. doi: 10.1038/s41374-018-0176-7

  • CrossRef
  • Google Scholar

• 55

  RenHShaoYWuCMaXLvCWangQ. Metformin Alleviates Oxidative Stress and Enhances Autophagy in Diabetic Kidney Disease via AMPK/SIRT1-FoxO1 Pathway. Mol Cell Endocrinol (2020) 500:110628. doi: 10.1016/j.mce.2019.110628

  • CrossRef
  • Google Scholar

• 56

  Alvarez-CillerosDLopez-OlivaMEMartinMARamosS. Cocoa Ameliorates Renal Injury in Zucker Diabetic Fatty Rats by Preventing Oxidative Stress, Apoptosis and Inactivation of Autophagy. Food Funct (2019) 10(12):7926–39. doi: 10.1039/c9fo01806a

  • CrossRef
  • Google Scholar

• 57

  YangSZhaoLHanYLiuYChenCZhanMet al. Probucol Ameliorates Renal Injury in Diabetic Nephropathy by Inhibiting the Expression of the Redox Enzyme p66Shc. Redox Biol (2017) 13:482–97. doi: 10.1016/j.redox.2017.07.002

  • CrossRef
  • Google Scholar

• 58

  HouSZhengFLiYGaoLZhangJ. The Protective Effect of Glycyrrhizic Acid on Renal Tubular Epithelial Cell Injury Induced by High Glucose. Int J Mol Sci (2014) 15(9):15026–43. doi: 10.3390/ijms150915026

  • CrossRef
  • Google Scholar

• 59

  KitadaMKumeSImaizumiNKoyaD. Resveratrol Improves Oxidative Stress and Protects Against Diabetic Nephropathy Through Normalization of Mn-SOD Dysfunction in AMPK/SIRT1-Independent Pathway. Diabetes (2011) 60(2):634–43. doi: 10.2337/db10-0386

  • CrossRef
  • Google Scholar

• 60

  PapadimitriouASilvaKCPeixotoEBBorgesCMLopes de FariaJMLopes de FariaJB. Theobromine Increases NAD(+)/Sirt-1 Activity and Protects the Kidney Under Diabetic Conditions. Am J Physiol Renal Physiol (2015) 308(3):F209–25. doi: 10.1152/ajprenal.00252.2014

  • CrossRef
  • Google Scholar

• 61

  LocatelliMZojaCZanchiCCornaDVillaSBologniniSet al. Manipulating Sirtuin 3 Pathway Ameliorates Renal Damage in Experimental Diabetes. Sci Rep (2020) 10(1):8418. doi: 10.1038/s41598-020-65423-0

  • CrossRef
  • Google Scholar

• 62

  ZhangTChiYKangYLuHNiuHLiuWet al. Resveratrol Ameliorates Podocyte Damage in Diabetic Mice via SIRT1/PGC-1alpha Mediated Attenuation of Mitochondrial Oxidative Stress. J Cell Physiol (2019) 234(4):5033–43. doi: 10.1002/jcp.27306

  • CrossRef
  • Google Scholar

• 63

  XueHLiPLuoYWuCLiuYQinXet al. Salidroside Stimulates the Sirt1/PGC-1alpha Axis and Ameliorates Diabetic Nephropathy in Mice. Phytomedicine (2019) 54:240–7. doi: 10.1016/j.phymed.2018.10.031

  • CrossRef
  • Google Scholar

• 64

  HongQZhangLDasBLiZLiuBCaiGet al. Increased Podocyte Sirtuin-1 Function Attenuates Diabetic Kidney Injury. Kidney Int (2018) 93(6):1330–43. doi: 10.1016/j.kint.2017.12.008

  • CrossRef
  • Google Scholar

• 65

  OzaMJKulkarniYA. Formononetin Attenuates Kidney Damage in Type 2 Diabetic Rats. Life Sci (2019) 219:109–21. doi: 10.1016/j.lfs.2019.01.013

  • CrossRef
  • Google Scholar

• 66

  ShiJXHuangQ. Glucagonlike Peptide1 Protects Mouse Podocytes Against High Glucoseinduced Apoptosis, and Suppresses Reactive Oxygen Species Production and Proinflammatory Cytokine Secretion, Through Sirtuin 1 Activation In Vitro. Mol Med Rep (2018) 18(2):1789–97. doi: 10.3892/mmr.2018.9085

  • CrossRef
  • Google Scholar

• 67

  MaLFuRDuanZLuJGaoJTianLet al. Sirt1 is Essential for Resveratrol Enhancement of Hypoxia-Induced Autophagy in the Type 2 Diabetic Nephropathy Rat. Pathol Res Pract (2016) 212(4):310–8. doi: 10.1016/j.prp.2016.02.001

  • CrossRef
  • Google Scholar

• 68

  GeXXuBXuWXiaLXuZShenLet al. Long Noncoding RNA GAS5 Inhibits Cell Proliferation and Fibrosis in Diabetic Nephropathy by Sponging miR-221 and Modulating SIRT1 Expression. Aging (Albany NY) (2019) 11(20):8745–59. doi: 10.18632/aging.102249

  • CrossRef
  • Google Scholar

• 69

  ZhangYChangBZhangJWuX. LncRNA SOX2OT Alleviates the High Glucose-Induced Podocytes Injury Through Autophagy Induction by the miR-9/SIRT1 Axis. Exp Mol Pathol (2019) 110:104283. doi: 10.1016/j.yexmp.2019.104283

  • CrossRef
  • Google Scholar

• 70

  LiuFGuoJQiaoYPanSDuanJLiuDet al. MiR-138 Plays an Important Role in Diabetic Nephropathy Through SIRT1-P38-TTP Regulatory Axis. J Cell Physiol (2021) 236(9):6607–18. doi: 10.1002/jcp.30238

  • CrossRef
  • Google Scholar

• 71

  SmithJ. Human Sir2 and the 'Silencing' of P53 Activity. Trends Cell Biol (2002) 12(9):404–6. doi: 10.1016/s0962-8924(02)02342-5

  • CrossRef
  • Google Scholar

• 72

  CohenHYMillerCBittermanKJWallNRHekkingBKesslerBet al. Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase. Science (2004) 305(5682):390–2. doi: 10.1126/science.1099196

  • CrossRef
  • Google Scholar

• 73

  WangYZhengZJJiaYJYangYLXueYM. Role of P53/miR-155-5p/Sirt1 Loop in Renal Tubular Injury of Diabetic Kidney Disease. J Transl Med (2018) 16(1):146. doi: 10.1186/s12967-018-1486-7

  • CrossRef
  • Google Scholar

• 74

  DongWZhangHZhaoCLuoYChenY. Silencing of miR-150-5p Ameliorates Diabetic Nephropathy by Targeting SIRT1/p53/AMPK Pathway. Front Physiol (2021) 12:624989. doi: 10.3389/fphys.2021.624989

  • CrossRef
  • Google Scholar

• 75

  AhmedHHTahaFMOmarHSElwiHMAbdelnasserM. Hydrogen Sulfide Modulates SIRT1 and Suppresses Oxidative Stress in Diabetic Nephropathy. Mol Cell Biochem (2019) 457(1-2):1–9. doi: 10.1007/s11010-019-03506-x

  • CrossRef
  • Google Scholar

• 76

  WangXLWuLYZhaoLSunLNLiuHYLiuGet al. SIRT1 Activator Ameliorates the Renal Tubular Injury Induced by Hyperglycemia In Vivo and In Vitro via Inhibiting Apoptosis. BioMed Pharmacother (2016) 83:41–50. doi: 10.1016/j.biopha.2016.06.009

  • CrossRef
  • Google Scholar

• 77

  WangYZuoBWangNLiSLiuCSunD. Calcium Dobesilate Mediates Renal Interstitial Fibrosis and Delay Renal Peritubular Capillary Loss Through Sirt1/p53 Signaling Pathway. BioMed Pharmacother (2020) 132:110798. doi: 10.1016/j.biopha.2020.110798

  • CrossRef
  • Google Scholar

• 78

  DengZJinJWangZWangYGaoQZhaoJ. The Metal Nanoparticle-Induced Inflammatory Response is Regulated by SIRT1 Through NF-kappaB Deacetylation in Aseptic Loosening. Int J Nanomed (2017) 12:3617–36. doi: 10.2147/IJN.S124661

  • CrossRef
  • Google Scholar

• 79

  NopparatCSinjanakhomPGovitrapongP. Melatonin Reverses H2 O2 -Induced Senescence in SH-SY5Y Cells by Enhancing Autophagy via Sirtuin 1 Deacetylation of the RelA/p65 Subunit of NF-Kappab. J Pineal Res (2017) 63(1):1–13. doi: 10.1111/jpi.12407

  • CrossRef
  • Google Scholar

• 80

  LiJLingYYinSYangSKongMLiZ. Baicalin Serves a Protective Role in Diabetic Nephropathy Through Preventing High Glucose-Induced Podocyte Apoptosis. Exp Ther Med (2020) 20(1):367–74. doi: 10.3892/etm.2020.8701

  • CrossRef
  • Google Scholar

• 81

  AlzahraniSZaitoneSASaidEEl-SherbinyMAjwahSAlsharifSYet al. Protective Effect of Isoliquiritigenin on Experimental Diabetic Nephropathy in Rats: Impact on Sirt-1/NFkappaB Balance and NLRP3 Expression. Int Immunopharmacol (2020) 87:106813. doi: 10.1016/j.intimp.2020.106813

  • CrossRef
  • Google Scholar

• 82

  WangXGaoYTianNWangTShiYXuJet al. Astragaloside IV Inhibits Glucose-Induced Epithelial-Mesenchymal Transition of Podocytes Through Autophagy Enhancement via the SIRT-NF-kappaB P65 Axis. Sci Rep (2019) 9(1):323. doi: 10.1038/s41598-018-36911-1

  • CrossRef
  • Google Scholar

• 83

  DuYGZhangKNGaoZLDaiFWuXXChaiKF. Tangshen Formula Improves Inflammation in Renal Tissue of Diabetic Nephropathy Through SIRT1/NF-kappaB Pathway. Exp Ther Med (2018) 15(2):2156–64. doi: 10.3892/etm.2017.5621

  • CrossRef
  • Google Scholar

• 84

  ChenYLiangYHuTWeiRCaiCWangPet al. Endogenous Nampt Upregulation is Associated With Diabetic Nephropathy Inflammatory-Fibrosis Through the NF-kappaB P65 and Sirt1 Pathway; NMN Alleviates Diabetic Nephropathy Inflammatory-Fibrosis by Inhibiting Endogenous Nampt. Exp Ther Med (2017) 14(5):4181–93. doi: 10.3892/etm.2017.5098

  • CrossRef
  • Google Scholar

• 85

  WangXGaoYTianNZhuZWangTXuJet al. Astragaloside IV Represses High Glucose-Induced Mesangial Cells Activation by Enhancing Autophagy via SIRT1 Deacetylation of NF-kappaB P65 Subunit. Drug Des Devel Ther (2018) 12:2971–80. doi: 10.2147/DDDT.S174058

  • CrossRef
  • Google Scholar

• 86

  XuFYeZTaoSLiuWSuJFangXet al. Ligustilide Alleviates Podocyte Injury via Suppressing the SIRT1/NF-kappaB Signaling Pathways in Rats With Diabetic Nephropathy. Ann Transl Med (2020) 8(18):1154. doi: 10.21037/atm-20-5811

  • CrossRef
  • Google Scholar

• 87

  FengJBaoLWangXLiHChenYXiaoWet al. Low Expression of HIV Genes in Podocytes Accelerates the Progression of Diabetic Kidney Disease in Mice. Kidney Int (2021) 99(4):914–25. doi: 10.1016/j.kint.2020.12.012

  • CrossRef
  • Google Scholar

• 88

  ZhengXPNieQFengJFanXYJinYLChenGet al. Kidney-Targeted Baicalin-Lysozyme Conjugate Ameliorates Renal Fibrosis in Rats With Diabetic Nephropathy Induced by Streptozotocin. BMC Nephrol (2020) 21(1):174. doi: 10.1186/s12882-020-01833-6

  • CrossRef
  • Google Scholar

• 89

  DuYGWangLPQianJWZhangKNChaiKF. Panax Notoginseng Saponins Protect Kidney From Diabetes by Up-Regulating Silent Information Regulator 1 and Activating Antioxidant Proteins in Rats. Chin J Integr Med (2016) 22(12):910–7. doi: 10.1007/s11655-015-2446-1

  • CrossRef
  • Google Scholar

• 90

  SunHJXiongSPCaoXCaoLZhuMYWuZYet al. Polysulfide-Mediated Sulfhydration of SIRT1 Prevents Diabetic Nephropathy by Suppressing Phosphorylation and Acetylation of P65 NF-kappaB and STAT3. Redox Biol (2021) 38:101813. doi: 10.1016/j.redox.2020.101813

  • CrossRef
  • Google Scholar

• 91

  Munoz-FelixJMGonzalez-NunezMMartinez-SalgadoCLopez-NovoaJM. TGF-Beta/BMP Proteins as Therapeutic Targets in Renal Fibrosis. Where Have We Arrived After 25 Years of Trials and Tribulations? Pharmacol Ther (2015) 156:44–58. doi: 10.1016/j.pharmthera.2015.10.003

  • CrossRef
  • Google Scholar

• 92

  MengXMNikolic-PatersonDJLanHY. TGF-Beta: The Master Regulator of Fibrosis. Nat Rev Nephrol (2016) 12(6):325–38. doi: 10.1038/nrneph.2016.48

  • CrossRef
  • Google Scholar

• 93

  SutariyaBJhonsaDSarafMN. TGF-Beta: The Connecting Link Between Nephropathy and Fibrosis. Immunopharmacol Immunotoxicol (2016) 38(1):39–49. doi: 10.3109/08923973.2015.1127382

  • CrossRef
  • Google Scholar

• 94

  FrangogiannisN. Transforming Growth Factor-Beta in Tissue Fibrosis. J Exp Med (2020) 217(3):e20190103. doi: 10.1084/jem.20190103

  • CrossRef
  • Google Scholar

• 95

  XueMLiYHuFJiaYJZhengZJWangLet al. High Glucose Up-Regulates microRNA-34a-5p to Aggravate Fibrosis by Targeting SIRT1 in HK-2cells. Biochem Biophys Res Commun (2018) 498(1):38–44. doi: 10.1016/j.bbrc.2017.12.048

  • CrossRef
  • Google Scholar

• 96

  YuWCHuangRYChouTC. Oligo-Fucoidan Improves Diabetes-Induced Renal Fibrosis via Activation of Sirt-1, GLP-1R, and Nrf2/HO-1: An In Vitro and In Vivo Study. Nutrients (2020) 12(10):1–15. doi: 10.3390/nu12103068

  • CrossRef
  • Google Scholar

• 97

  LiCCaiFYangYZhaoXWangCLiJet al. Tetrahydroxystilbene Glucoside Ameliorates Diabetic Nephropathy in Rats: Involvement of SIRT1 and TGF-Beta1 Pathway. Eur J Pharmacol (2010) 649(1-3):382–9. doi: 10.1016/j.ejphar.2010.09.004

  • CrossRef
  • Google Scholar

• 98

  ZhangJZhangLZhaDWuX. Inhibition of Mirna135a5p Ameliorates TGFbeta1induced Human Renal Fibrosis by Targeting SIRT1 in Diabetic Nephropathy. Int J Mol Med (2020) 46(3):1063–73. doi: 10.3892/ijmm.2020.4647

  • CrossRef
  • Google Scholar

• 99

  WangXJiTLiXQuXBaiS. FOXO3a Protects Against Kidney Injury in Type II Diabetic Nephropathy by Promoting Sirt6 Expression and Inhibiting Smad3 Acetylation. Oxid Med Cell Longev (2021) 2021:5565761. doi: 10.1155/2021/5565761

  • CrossRef
  • Google Scholar

• 100

  HuangXFChenJZ. Obesity, the PI3K/Akt Signal Pathway and Colon Cancer. Obes Rev (2009) 10(6):610–6. doi: 10.1111/j.1467-789X.2009.00607.x

  • CrossRef
  • Google Scholar

• 101

  du RusquecPBlonzCFrenelJSCamponeM. Targeting the PI3K/Akt/mTOR Pathway in Estrogen-Receptor Positive HER2 Negative Advanced Breast Cancer. Ther Adv Med Oncol (2020) 12:1758835920940939. doi: 10.1177/1758835920940939

  • CrossRef
  • Google Scholar

• 102

  BurgeringBMKopsGJ. Cell Cycle and Death Control: Long Live Forkheads. Trends Biochem Sci (2002) 27(7):352–60. doi: 10.1016/s0968-0004(02)02113-8

  • CrossRef
  • Google Scholar

• 103

  HusseinMMMahfouzMK. Effect of Resveratrol and Rosuvastatin on Experimental Diabetic Nephropathy in Rats. BioMed Pharmacother (2016) 82:685–92. doi: 10.1016/j.biopha.2016.06.004

  • CrossRef
  • Google Scholar

• 104

  WangXMengLZhaoLWangZLiuHLiuGet al. Resveratrol Ameliorates Hyperglycemia-Induced Renal Tubular Oxidative Stress Damage via Modulating the SIRT1/FOXO3a Pathway. Diabetes Res Clin Pract (2017) 126:172–81. doi: 10.1016/j.diabres.2016.12.005

  • CrossRef
  • Google Scholar

• 105

  WuLZhangYMaXZhangNQinG. The Effect of Resveratrol on FoxO1 Expression in Kidneys of Diabetic Nephropathy Rats. Mol Biol Rep (2012) 39(9):9085–93. doi: 10.1007/s11033-012-1780-z

  • CrossRef
  • Google Scholar

• 106

  YangGJinLZhengDTangXYangJFanLet al. Fucoxanthin Alleviates Oxidative Stress Through Akt/Sirt1/FoxO3alpha Signaling to Inhibit HG-Induced Renal Fibrosis in GMCs. Mar Drugs (2019) 17(12):1–16. doi: 10.3390/md17120702

  • CrossRef
  • Google Scholar

• 107

  MoriJPatelVBRamprasathTAlrobOADesAulniersJScholeyJWet al. Angiotensin 1-7 Mediates Renoprotection Against Diabetic Nephropathy by Reducing Oxidative Stress, Inflammation, and Lipotoxicity. Am J Physiol Renal Physiol (2014) 306(8):F812–21. doi: 10.1152/ajprenal.00655.2013

  • CrossRef
  • Google Scholar

• 108

  DusabimanaTKimSRParkEJJeJJeongKYunSPet al. P2Y2R Contributes to the Development of Diabetic Nephropathy by Inhibiting Autophagy Response. Mol Metab (2020) 42:101089. doi: 10.1016/j.molmet.2020.101089

  • CrossRef
  • Google Scholar

• 109

  WangZLiYWangYZhaoKChiYWangB. Pyrroloquinoline Quinine Protects HK-2cells Against High Glucose-Induced Oxidative Stress and Apoptosis Through Sirt3 and PI3K/Akt/FoxO3a Signaling Pathway. Biochem Biophys Res Commun (2019) 508(2):398–404. doi: 10.1016/j.bbrc.2018.11.140

  • CrossRef
  • Google Scholar

• 110

  ZhouDZhouMWangZFuYJiaMWangXet al. PGRN Acts as a Novel Regulator of Mitochondrial Homeostasis by Facilitating Mitophagy and Mitochondrial Biogenesis to Prevent Podocyte Injury in Diabetic Nephropathy. Cell Death Dis (2019) 10(7):524. doi: 10.1038/s41419-019-1754-3

  • CrossRef
  • Google Scholar

• 111

  KopaczAKloskaDFormanHJJozkowiczAGrochot-PrzeczekA. Beyond Repression of Nrf2: An Update on Keap1. Free Radic Biol Med (2020) 157:63–74. doi: 10.1016/j.freeradbiomed.2020.03.023

  • CrossRef
  • Google Scholar

• 112

  HuangKChenCHaoJHuangJWangSLiuPet al. Polydatin Promotes Nrf2-ARE Anti-Oxidative Pathway Through Activating Sirt1 to Resist AGEs-Induced Upregulation of Fibronetin and Transforming Growth Factor-Beta1 in Rat Glomerular Messangial Cells. Mol Cell Endocrinol (2015) 399:178–89. doi: 10.1016/j.mce.2014.08.014

  • CrossRef
  • Google Scholar

• 113

  ZhuangKJiangXLiuRYeCWangYWangYet al. Formononetin Activates the Nrf2/ARE Signaling Pathway Via Sirt1 to Improve Diabetic Renal Fibrosis. Front Pharmacol (2020) 11:616378. doi: 10.3389/fphar.2020.616378

  • CrossRef
  • Google Scholar

• 114

  HuangKHuangJXieXWangSChenCShenXet al. Sirt1 Resists Advanced Glycation End Products-Induced Expressions of Fibronectin and TGF-Beta1 by Activating the Nrf2/ARE Pathway in Glomerular Mesangial Cells. Free Radic Biol Med (2013) 65:528–40. doi: 10.1016/j.freeradbiomed.2013.07.029

  • CrossRef
  • Google Scholar

• 115

  MaFWuJJiangZHuangWJiaYSunWet al. P53/NRF2 Mediates SIRT1's Protective Effect on Diabetic Nephropathy. Biochim Biophys Acta Mol Cell Res (2019) 1866(8):1272–81. doi: 10.1016/j.bbamcr.2019.04.006

  • CrossRef
  • Google Scholar

• 116

  HuangXShiYChenHLeRGongXXuKet al. Isoliquiritigenin Prevents Hyperglycemia-Induced Renal Injuries by Inhibiting Inflammation and Oxidative Stress via SIRT1-Dependent Mechanism. Cell Death Dis (2020) 11(12):1040. doi: 10.1038/s41419-020-03260-9

  • CrossRef
  • Google Scholar

• 117

  ShaoYLvCWuCZhouYWangQ. Mir-217 Promotes Inflammation and Fibrosis in High Glucose Cultured Rat Glomerular Mesangial Cells via Sirt1/HIF-1alpha Signaling Pathway. Diabetes Metab Res Rev (2016) 32(6):534–43. doi: 10.1002/dmrr.2788

  • CrossRef
  • Google Scholar

• 118

  LiAPengRSunYLiuHPengHZhangZ. LincRNA 1700020I14Rik Alleviates Cell Proliferation and Fibrosis in Diabetic Nephropathy via miR-34a-5p/Sirt1/HIF-1alpha Signaling. Cell Death Dis (2018) 9(5):461. doi: 10.1038/s41419-018-0527-8

  • CrossRef
  • Google Scholar

• 119

  SunXHuangKHaimingXLinZYangYZhangMet al. Connexin 43 Prevents the Progression of Diabetic Renal Tubulointerstitial Fibrosis by Regulating the SIRT1-HIF-1alpha Signaling Pathway. Clin Sci (Lond) (2020) 134(13):1573–92. doi: 10.1042/CS20200171

  • CrossRef
  • Google Scholar

• 120

  LiuRZhongYLiXChenHJimBZhouMMet al. Role of Transcription Factor Acetylation in Diabetic Kidney Disease. Diabetes (2014) 63(7):2440–53. doi: 10.2337/db13-1810

  • CrossRef
  • Google Scholar

• 121

  KunduARichaSDeyPKimKSSonJYKimHRet al. Protective Effect of EX-527 Against High-Fat Diet-Induced Diabetic Nephropathy in Zucker Rats. Toxicol Appl Pharmacol (2020) 390:114899. doi: 10.1016/j.taap.2020.114899

  • CrossRef
  • Google Scholar

• 122

  Zitman-GalTEinbinderYOhanaMKatzavAKartawyABenchetritS. Effect of Liraglutide on the Janus Kinase/Signal Transducer and Transcription Activator (JAK/STAT) Pathway in Diabetic Kidney Disease in Db/Db Mice and in Cultured Endothelial Cells. J Diabetes (2019) 11(8):656–64. doi: 10.1111/1753-0407.12891

  • CrossRef
  • Google Scholar

• 123

  WangDLiYWangNLuoGWangJLuoCet al. 1alpha,25-Dihydroxyvitamin D3 Prevents Renal Oxidative Damage via the PARP1/SIRT1/NOX4 Pathway in Zucker Diabetic Fatty Rats. Am J Physiol Endocrinol Metab (2020) 318(3):E343–E56. doi: 10.1152/ajpendo.00270.2019

  • CrossRef
  • Google Scholar

• 124

  LiXCaiWLeeKLiuBDengYChenYet al. Puerarin Attenuates Diabetic Kidney Injury Through the Suppression of NOX4 Expression in Podocytes. Sci Rep (2017) 7(1):14603. doi: 10.1038/s41598-017-14906-8

  • CrossRef
  • Google Scholar

• 125

  ScutoMTrovato SalinaroAModafferiSPolimeniAPfefferTWeigandTet al. Carnosine Activates Cellular Stress Response in Podocytes and Reduces Glycative and Lipoperoxidative Stress. Biomedicines (2020) 8(6):1–14. doi: 10.3390/biomedicines8060177

  • CrossRef
  • Google Scholar

• 126

  PetersVCalabreseVForsbergEVolkNFlemingTBaeldeHet al. Protective Actions of Anserine Under Diabetic Conditions. Int J Mol Sci (2018) 19(9):1–12. doi: 10.3390/ijms19092751

  • CrossRef
  • Google Scholar

• 127

  ZengSWuXChenXXuHZhangTXuY. Hypermethylated in Cancer 1 (HIC1) Mediates High Glucose Induced ROS Accumulation in Renal Tubular Epithelial Cells by Epigenetically Repressing SIRT1 Transcription. Biochim Biophys Acta Gene Regul Mech (2018) 1861(10):917–27. doi: 10.1016/j.bbagrm.2018.08.002

  • CrossRef
  • Google Scholar

• 128

  WangXXWangDLuoYMyakalaKDobrinskikhERosenbergAZet al. FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity. J Am Soc Nephrol (2018) 29(1):118–37. doi: 10.1681/ASN.2017020222

  • CrossRef
  • Google Scholar

• 129

  UminoHHasegawaKMinakuchiHMuraokaHKawaguchiTKandaTet al. High Basolateral Glucose Increases Sodium-Glucose Cotransporter 2 and Reduces Sirtuin-1 in Renal Tubules Through Glucose Transporter-2 Detection. Sci Rep (2018) 8(1):6791. doi: 10.1038/s41598-018-25054-y

  • CrossRef
  • Google Scholar

• 130

  TangLXWangBWuZK. Aerobic Exercise Training Alleviates Renal Injury by Interfering With Mitochondrial Function in Type-1 Diabetic Mice. Med Sci Monit (2018) 24:9081–9. doi: 10.12659/MSM.912877

  • CrossRef
  • Google Scholar

• 131

  OguraYKitadaMXuJMonnoIKoyaD. CD38 Inhibition by Apigenin Ameliorates Mitochondrial Oxidative Stress Through Restoration of the Intracellular NAD(+)/NADH Ratio and Sirt3 Activity in Renal Tubular Cells in Diabetic Rats. Aging (Albany NY) (2020) 12(12):11325–36. doi: 10.18632/aging.103410

  • CrossRef
  • Google Scholar

• 132

  LiJLiuHTakagiSNittaKKitadaMSrivastavaSPet al. Renal Protective Effects of Empagliflozin via Inhibition of EMT and Aberrant Glycolysis in Proximal Tubules. JCI Insight (2020) 5(6):1–17. doi: 10.1172/jci.insight.129034

  • CrossRef
  • Google Scholar

• 133

  LiJLiNYanSLuYMiaoXGuZet al. Liraglutide Protects Renal Mesangial Cells Against Hyperglycemiamediated Mitochondrial Apoptosis by Activating the ERKYap Signaling Pathway and Upregulating Sirt3 Expression. Mol Med Rep (2019) 19(4):2849–60. doi: 10.3892/mmr.2019.9946

  • CrossRef
  • Google Scholar

• 134

  WangXXEdelsteinMHGafterUQiuLLuoYDobrinskikhEet al. G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes. J Am Soc Nephrol (2016) 27(5):1362–78. doi: 10.1681/ASN.2014121271

  • CrossRef
  • Google Scholar

• 135

  FengJLuCDaiQShengJXuM. SIRT3 Facilitates Amniotic Fluid Stem Cells to Repair Diabetic Nephropathy Through Protecting Mitochondrial Homeostasis by Modulation of Mitophagy. Cell Physiol Biochem (2018) 46(4):1508–24. doi: 10.1159/000489194

  • CrossRef
  • Google Scholar

• 136

  MuraokaHHasegawaKSakamakiYMinakuchiHKawaguchiTYasudaIet al. Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy. Cell Rep (2019) 27(1):199–212.e5. doi: 10.1016/j.celrep.2019.03.024

  • CrossRef
  • Google Scholar

• 137

  WangXLinBNieLLiP. microRNA-20b Contributes to High Glucose-Induced Podocyte Apoptosis by Targeting SIRT7. Mol Med Rep (2017) 16(4):5667–74. doi: 10.3892/mmr.2017.7224

  • CrossRef
  • Google Scholar

• 138

  HowitzKTBittermanKJCohenHYLammingDWLavuSWoodJGet al. Small Molecule Activators of Sirtuins Extend Saccharomyces Cerevisiae Lifespan. Nature (2003) 425(6954):191–6. doi: 10.1038/nature01960

  • CrossRef
  • Google Scholar

• 139

  DomiEHoxhaMPrendiEZappacostaB. A Systematic Review on the Role of SIRT1 in Duchenne Muscular Dystrophy. Cells (2021) 10(6):1–28. doi: 10.3390/cells10061380

  • CrossRef
  • Google Scholar

• 140

  ScherMBVaqueroAReinbergD. SirT3 is a Nuclear NAD+-Dependent Histone Deacetylase That Translocates to the Mitochondria Upon Cellular Stress. Genes Dev (2007) 21(8):920–8. doi: 10.1101/gad.1527307

  • CrossRef
  • Google Scholar

• 141

  AkterRAfroseARahmanMRChowdhuryRNirzhorSSRKhanRIet al. A Comprehensive Analysis Into the Therapeutic Application of Natural Products as SIRT6 Modulators in Alzheimer's Disease, Aging, Cancer, Inflammation, and Diabetes. Int J Mol Sci (2021) 22(8):1–23. doi: 10.3390/ijms22084180

  • CrossRef
  • Google Scholar

• 142

  GuJYangMQiNMeiSChenJSongSet al. Olmesartan Prevents Microalbuminuria in db/db Diabetic Mice Through Inhibition of Angiotensin II/p38/SIRT1-Induced Podocyte Apoptosis. Kidney Blood Press Res (2016) 41(6):848–64. doi: 10.1159/000452588

  • CrossRef
  • Google Scholar

• 143

  KumarGSKulkarniAKhuranaAKaurJTikooK. Selenium Nanoparticles Involve HSP-70 and SIRT1 in Preventing the Progression of Type 1 Diabetic Nephropathy. Chem Biol Interact (2014) 223:125–33. doi: 10.1016/j.cbi.2014.09.017

  • CrossRef
  • Google Scholar

• 144

  LoCSShiYChenierIGhoshAWuCHCailhierJFet al. Heterogeneous Nuclear Ribonucleoprotein F Stimulates Sirtuin-1 Gene Expression and Attenuates Nephropathy Progression in Diabetic Mice. Diabetes (2017) 66(7):1964–78. doi: 10.2337/db16-1588

  • CrossRef
  • Google Scholar

• 145

  SunZMaYChenFWangSChenBShiJ. miR-133b and miR-199b Knockdown Attenuate TGF-beta1-iIduced Epithelial to Mesenchymal Transition and Renal Fibrosis By Targeting SIRT1 in Diabetic Nephropathy. Eur J Pharmacol (2014) 223:125–33. doi: 10.1016/j.cbi.2014.09.017

  • CrossRef
  • Google Scholar

• 146

  ZhuHFangZChenJYangYGanJLuoLet al. PARP-1 and SIRT-1 Are Interacted in Diabetic Nephropathy By Activating AMPK/PGC-1alpha Signaling Pathway. Diabetes Metab Syndr Obes (2021) 14:355–66. doi: 10.2147/DMSO.S291314

  • CrossRef
  • Google Scholar

• 147

  ZhouLXuDYShaWGShenLLuGY. Long Non-Coding RNA MALAT1 Interacts With Transcription Factor Foxo1 to Regulate SIRT1 Transcription in High Glucose-Induced HK-2 Cells Injury. Biochem Biophys Res Commun (2018) 503(2):849–55. doi: 10.1016/j.bbrc.2018.06.086

  • CrossRef
  • Google Scholar

• 148

  HuangKPChenCHaoJHuangJYLiuPQHuangHQ. AGEs-RAGE System Down-Regulates Sirt1 Through the Ubiquitin-Proteasome Pathway to Promote FN and TGF-Beta1 Expression in Male Rat Glomerular Mesangial Cells. Endocrinology (2015) 156(1):268–79. doi: 10.1210/en.2014-1381

  • CrossRef
  • Google Scholar

• 149

  WenDHuangXZhangMZhangLChenJGuYet al. Resveratrol Attenuates Diabetic Nephropathy via Modulating Angiogenesis. PLoS One (2013) 8(12):1–12. doi: 10.1371/journal.pone.0082336

  • CrossRef
  • Google Scholar