Role of gasdermins in chronic kidney disease

Abstract

Gasdermins (GSDMs), functioning as membrane perforating proteins, can be activated by canonical inflammasomes, noncanonical inflammasomes, as well as non-inflammasomes, leading to cell pyroptosis and the subsequent release of inflammatory mediators. Increasing evidence has implicated that GSDMs are associated with chronic kidney disease (CKD), including diabetes nephropathy, lupus nephritis, obstructive nephropathy, and crystalline nephropathy. This review centers on the role of GSDMs-mediated pyroptosis in the pathogenesis of CKD, providing novel ideas for enhancing the prognosis and therapeutic strategies of CKD.

1 Introduction

Chronic kidney disease (CKD), a pressing concern in global public health, imposes a considerable disease burden and poses a major challenge (1). CKD ranked as the 16th most common cause of death globally in 2016 and is expected to rise to 5th by 2040 (2). The global prevalence of CKD is about 9.1%, while awareness of CKD among the general population and high-risk groups, at just only 6% and 10% (3, 4). Currently, the definition of CKD is structural destruction or impaired function of the kidney lasting 3 months or more (4). Renal fibrosis, a common pathological manifestation of CKD, is characterized by glomerulosclerosis, tubular atrophy, interstitial fibrosis, and persistent inflammation (5, 6). With the continuous destruction of renal tissue, renal function progressively declines, and eventually it will develop into end stage renal disease. The ensuing need for renal replacement therapies, including peritoneal dialysis, hemodialysis, and kidney transplantation, undoubtedly further exacerbate the economic burden on patients.

Pyroptosis, a necrotic programmed cell death mediated by gasdermins (GSDMs), is characterized by cell membrane rupture and the release of inflammatory factors such as interleukin-1 (IL-1β) and interleukin-18 (IL-18) (7, 8). GSDMs were initially identified in macrophages in 1992 and subsequently named in 2001 (9, 10). Shao et al. characterized GSDMs as the executors of pyroptosis, and the in 2018, the definition was revised to cell death involving GSDMs-formed membrane pores (7, 11, 12). Pyroptosis primarily occurs in myeloid phagocytes, including macrophages, dendritic cells, and neutrophils, with evidence later confirming its presence in CD4⁺ T cells, keratinocytes, epithelial cells, and neurons as well (13, 14). Pyroptosis is involved in innate immunity by eliminating pathogens, including bacteria, fungi, and viruses, through the mediation of inflammatory response. However, uncontrolled pyroptosis has the potential to induce inflammation in adjacent cells and tissues, thereby contributing to the initiation and progression of diseases (15–17).

Recently, a wealth of evidence indicates that GSDMs-mediated pyroptosis plays a pivotal role in the pathogenesis and progression of CKD. This paper presents an overview of the fundamental characteristics of the GSDMs family and examines and summarizes their roles and potential mechanisms in CKD, providing novel insights for enhancing the prognosis and treatment of this condition.

2 Gasdermins

Gasdermins were initially discovered in the gastrointestinal tract and skin of mice, hence they were named “Gasdermins (GSDMs)” (18, 19). In humans, there are six GSDMs genes: GSDMA, GSDMB, GSDMC, GSDMD, GSDME (also known as DNFA5), and PJVK (pejvakin, also known as GSDMF, DFNB59). In mice, there are three Gsdma genes (Gsdma1-3), four Gsdmc genes (Gsdmc1-4), Gsdmd, Gsdme, and Pjvk, while the Gsdmb orthologs are lacking (20, 21) (Table 1). In kidney tissue, GSDMD was highly expressed, GSDMC and GSDME were moderately expressed, GSDMB was low, and GSDMA was not detected (21). Except for PJVK, members of the GSDMs protein family are composed of three parts, namely, the N-terminal pore-forming domain (PFD, NTD), the linker part, and the C-terminal inhibitory domain (RD, CTD) (22). When the body is exposed to various internal and external stimuli, GSDMs undergo cleavage by cysteinyl aspartate-specific protease (Caspases) or granzymes, and the dissociated N-terminal structural oligomers punch holes in the cell membrane, mediating the release of inflammatory factors, as well as the flux of water and electrolyte flow, ultimately leading to pyroptosis.

2.1 GSDMA

Human GSDMA is located on chromosome 17 and is mainly expressed in epithelial cells of the skin and upper digestive tract (18). Gsdma1 is expressed specifically in the heart region, Gsdma2 is expressed in the fundus and pylorus, and Gsdma3 is mainly expressed in the skin (19). Overexpression of GSDMA is associated with glioma immune escape and poor prognosis in patients, while GSDMA knockdown increases T cell antitumor response via immunotherapy (23). GSDMA can promote the development of esophageal cancer and cisplatin resistance (24). In addition, GSDMA has been implicated in systemic sclerosis, asthma, intestinal bowel disease (IBD), and other immune-related diseases (25–27). However, the role of GSDMA in kidney disease has not been previously reported.

2.2 GSDMB

Human GSDMB is also located on chromosome 17 and is mainly expressed in the gastrointestinal tract, thyroid, skin, lungs, and kidneys (18, 28). Besides normal tissues, GSDMB is also highly expressed in tumor tissues, such as bladder cancer, clear cell renal cell carcinoma, gastric cancer, and non-small cell lung cancer (29–32). Furthermore, GSDMB is also associated with IBD, asthma, allergic rhinitis, psoriasis, and other diseases (33–36).

2.3 GSDMC

Human GSDMC is located on chromosome 8 (8q24.1), while mouse Gsdmc is located on chromosome 15, and is mainly expressed in skin, spleen, trachea, and gastrointestinal tract (37–39). Under hypoxic conditions, GSDMC transcription was enhanced in breast tumor cells, and GSDMC in turn converted TNF-α-induced apoptosis to pyroptosis (40). In addition, GSDMC is also associated with esophageal cancer, liver cancer, colorectal cancer, pancreatic cancer, and renal clear cell carcinoma (41–46).

2.4 GSDMD

Similar to GSDMC, human GSDMD is also located on chromosome 8 (8q24.3), and mouse Gsdmd is located on chromosome 15, and is predominantly expressed in tissues such as the gastrointestinal tract, kidney, and skin (47, 48). GSDMD is the first member of the GSDM family to be found to perform pyroptosis, and the mechanism is well understood (49). GSDMD is mainly cleaved by Caspases at the Asp275 or Asp276 site, Caspase-1/4/5 in humans and Caspase-1/11 in mice (47, 50). GSDMD is involved in a variety of inflammatory diseases such as non-alcoholic steatohepatitis, acute pancreatitis, colitis, sepsis, systemic lupus erythematosus, psoriasis (51–55), and is also associated with acute myocardial infarction, stroke, colon cancer, and other non-inflammatory diseases (56–58). In addition, GSDMD is associated with renal disease, which is described in detail below.

2.5 GSDME

GSDME, also known as deafness, autosomal dominant 5 (DFNA5), is localized on chromosome 7 in humans and chromosome 6 in mice, exhibiting ubiquitous expression across various normal tissues, notably including the gastrointestinal tract and kidney (59). In addition to tumors, GSDME is also involved in hearing loss, neurodegeneration, atherosclerosis, and many renal diseases, which are described in detail below (60–64).

2.6 PJVK

PJVK, situated on chromosome 2 in both humans and mice, is majored expresses in the inner ear and involved in auditory pathways (65). Mutations in PJVK can lead to hearing loss (66). The role of PJVK in renal diseases has not been described.

3 Molecular mechanism of pyroptosis

At present, there are two main types of pyroptosis pathways mediated by Gasdermins: inflammasome-dependent pathway (canonical pathway and non-canonical pathway) and non-inflammasome-dependent pathway (Figures 1, 2).

Figure 1

Figure 2

3.1 Canonical inflammasome-dependent pathway

In the canonical pathway, inflammasomes are intricate multi-molecular assemblies that encompass pattern recognition receptors (PRRs), apoptosis-associated speck like protein (ASC), and pro-Caspase-1 (67). As sensors that receive pathogen-associated molecular patterns (PAMP) or damage associated molecular patterns (DAMP) stimuli, PRRs mainly include NLR/NOD-like receptors (NLRP1, NLRP3, NLRP6, NLRP9, NLRC4), Pyrin, and AIM2-like receptor (68). NLRP1 can be activated by Anthrax lethal toxin (LeTx), bacterial muramyl dipeptide, T. gondii, and ATP depletion (69). NLRP3 senses a variety of stimuli, including microbial toxins, viral RNA, ATP, ROS, uric acid crystals, cholesterol, and particulate matter (70–72). Microbial RNA, metabolites, Lipoteichoic acid, and LPS can be used as NLRP6 activation signals (73–75). NLRP9 and AIM2 inflammasomes can recognize pathogen dsDNA (76, 77). Bacterial flagellin can induce the activation of NLRC4 inflammasome (78). Pyrin cannot directly recognize PAMP or DAMP but can be activated when bacterial toxins induce GTPase inactivation (79). PAMP or DAMP activates TLRs/MyD88/NF-κB signaling pathway, leading to transcriptional upregulation of NLRP3, ASC, pro-Caspase-1, pro-IL-1β, and pro-IL-18 (80, 81). After inflammasome assembly, activated Caspase-1 cleaves pro-IL-1β and pro-IL-18 to mature IL-1β and IL-18, and simultaneously cleaves GSDMD to release the N terminus of GSDMD (7, 82). GSDMD-NTs oligomerize in the cell membrane to form transmembrane pores to release IL-1β and IL-18 as well as lead to pyroptosis (15, 83).

3.2 Non-canonical inflammasome-dependent pathway

In the non-canonical pathway, inflammasomes, human Caspase-4/5 and mouse Caspase-11, specifically recognize the lipopolysaccharide (LPS) by N-terminal CARD (84). The cleavage of GSDMD by Caspase-4/5/11 triggers the process of pyroptosis (47, 50). Caspase-11 fails to cleave pro-IL-1β and pro-IL-18 like Caspase-4/5, but instead activates Pannexin-1 and releases ATP. Subsequently, ATP binds to the P2X7 receptor (P2X7R), causing K⁺ efflux and further activating NLRP3 inflammasome to indirectly cleave pro-IL-1β and pro-IL-18 (85).

3.3 Non-inflammasome-dependent pathway

The human pathogen Group A Streptococcus (GAS) secretes the cysteine protein streptococcal exotoxin B (SpeB), which cleaves GSDMA at the junction area of Gln246 and triggers pyroptosis of skin epithelial cells and keratinocytes, independent of Caspase (86, 87). In HEK293T cells, Caspase-3/4/7 are able to cleave GSDMA to induce pyroptosis (88). Granzyme A (GZMA), secreted by natural killer cells and cytotoxic T lymphocytes, cleaves GSDMB at the K244 site of the junction and targets phospholipids on the membrane of Gram-negative bacteria to directly kill bacteria (89, 90). GSDMB can bind to Caspase-1/3/4/6/7 and promote pyroptosis (91, 92). It has also been reported that activated Caspase-7 cuts GSDMB at the D91 site to block GSDMB-mediated pyroptosis (93). α-Ketoglutarate (α-KG) contributes to pyroptosis by enabling Caspase-8 to cleave GSDMC at the Asp240 site, with a similar cleavage occurring at the Asp233 site in mouse GSDMC4 (94). In addition, GSDMC is also cleaved by Caspase-6 to induce pyroptosis (40). Under hypoxia conditions, the increased expression of GSDMC can transform the apoptosis induced by Caspase-8 into pyroptosis (95). Besides Caspase-1/4/5/11, neutrophil elastase (ELANE) and cathepsin G (CatG) can also activate GSDMD (96, 97). Caspase-8 activated by Yersinia can cleave GSDMD and GSDME to trigger pyroptosis (98). GSDME can also be specifically cleaved by Caspase-3 at the Asp270 site to induce pyroptosis, which is transformed into apoptosis after GSDME knockout or promoter demethylation (11, 95, 99, 100).

4 Gasdermins and CKD

Inflammation and fibrosis are prevalent pathological characteristics in all forms of CKD, and persistent inflammation can drive fibrosis progression, leading to the pathogenesis of CKD (5, 101). Damaged cells secrete pro-inflammatory cytokines to recruit inflammatory cells for infiltration, and release pro-fibrotic mediators to promote proliferation of myofibroblasts, resulting in the production and deposition of a large amount of extracellular matrix, ultimately causing pathological changes and impaired renal function (101, 102). Recently, a great number of studies has demonstrated that GSDMs-mediate pyroptosis, a pro-inflammatory form of cell death, which is associated with the pathogenesis of various CKD, including diabetic nephropathy, lupus nephritis, obstructive nephropathy, and crystal nephropathy (Table 2, Figure 3).

Figure 3

4.1 Diabetic nephropathy

Diabetic nephropathy (DN) is a prevalent microvascular complication of diabetes mellitus, emerging as a major type of CKD (103). Pathological changes of diabetic nephropathy include cells damage (podocytes, renal tubular epithelial cells (RTECs), endothelial cells), glomerular sclerosis, glomerular basement membrane thickening, mesangial matrix increase, tubular interstitial inflammation, and fibrosis (104).

Recent studies have revealed a correlation between GSDMs-mediated pyroptosis and DN, suggesting a potential mechanistic link between the two processes. In a recent study, high glucose (HG) or streptozotocin (STZ) stimulated pyroptosis in renal cells (podocytes, renal tubules, human glomerular endothelial cells, and mouse glomerular endothelial cells) though the Caspase-11/GSDMD pathway, resulting in impaired renal function, manifested by significant increases in serum nitrogen, serum creatinine, and urinary albumin levels (105). After knocking down the Gsdmd gene in DN mice, pyroptosis and IL-18 were markedly reduced, resulting in improved renal function (105).An et al. showed that punicalagin effectively inhibit NLRP3/Caspase-1/GSDMD/IL-1β pathway, and significantly ameliorates renal function, glomerular sclerosis, renal interstitial fibrosis and other pathological changes in diabetic mice (106). Cheng et al. also demonstrated that the expression levels of Caspase-4/11, GSDMD-N, IL-1β, and IL-18 were markedly elevated in HG-treated podocytes or podocytes from diabetic mice, and the deficiency of Caspase-11 or Gsdmd alleviated inflammation and podocytes loss in diabetic mice (107). Immunohistochemistry staining showed that the levels of fibronectin, alpha-smooth muscle actin, and the number of F4/80⁺ macrophages in DN mice were higher than the control group (108). Western blotting results indicated that the expressions of GSDMD-FL, GSDMD-NT, IL-1β, IL-18, and α-SMA were increased in DN mice, suggesting that pyroptosis was associated with renal tubule injury and interstitial inflammation (108). In the rat DN model and HG-treated human kidney proximal tubular epithelial cells (HK-2 cells), Caspase-1/3, GSDME, GSDME-NT, and IL-1β were significantly upregulated. In rats that underwent renal cortical injection of AAV9-shGSDME to knockdown Gsdme in the kidney, reduced renal injury and pyroptosis were observed, demonstrating that Caspase-3/GSDME promotes pyroptosis and contributes to renal injury in DN (109).

In addition, pyroptosis was also detected in renal biopsy tissues obtained from DN patients. When compared with patients with glomerular minor lesion, the expressions of Caspase-1 and GSDMD in renal tubular cells were increased in DN patients (108). Increased expression of GSDMD in DN patients was positively correlated with renal tubulointerstitial fibrosis and negatively correlated with renal function (110). Additionally, the expression of NLRP3 was upregulated in DN patients, and demonstrating a positive association with tubulointerstitial injury (111).

These studies indicate that GSDMD and GSDME are activated in DN, and GSDMD or GSMDE mediated-pyroptosis promotes the pathogenesis of DN.

4.2 Lupus nephritis

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by autoantibody formation, immune complex deposition, and chronic inflammation (112). Kidneys are the affected organs in SLE, with up to 60% of patients developing lupus nephritis (LN) (113). The pathological mechanism of LN involves the deposition of immune complexes, infiltration of inflammatory cells, and injury or death of glomerular and tubular cell (114).

Studies have shown that characteristic autoantibodies and typical clinical and renal pathological changes of SLE can be produced after intraperitoneal injection of pristane (115, 116). Increased expressions of pyroptosis related proteins (NLRP3, GSDMD, and Caspase-1) and inflammatory factors (TNF-α and IL-1β) were observed in pristane-induced LN mice models (117). Cao et al. treated LN patients and MRL/lpr mice with a combination of mycophenolate mortiate, calcineurin inhibitors, and steroids, resulting in significant inhibition of Caspase-1/GSDMD-mediated pyroptosis and alleviation of disease progression (118). GSDME was observed to be highly expressed in the renal tubules of SLE patients and pristane-induced lupus mice, while Caspase-3/GSDME-mediated pyroptosis, autoantibody, glomerular IgG deposition and renal lesions were ameliorated in Gsdme^-/- lupus mice (119).

4.3 Obstructive nephropathy

The causes of obstructive nephropathy (ON) include urinary calculi, congenital stenosis, and tumor masses. The main characteristics of ON include renal dysfunction, inflammation, and renal interstitial fibrosis, which may progress to CKD with the progression of the disease (120, 121).

Several studies have used the unilateral ureteral obstruction (UUO) model to investigate the role of GSDMs in ON. In UUO model, Caspase-11 was activated to cleave GSDMD to mediate pyroptosis, which induced the formation neutrophil extracellular trap and the transformation of macrophage to myofibroblast, promoting inflammation and renal fibrosis (122). Furthermore, Li et al.’s research suggested that Caspase3/GSDME-mediated pyroptosis of renal tubular cells promoted the progression of renal injury and fibrosis induced by ureteral obstruction (63). In the UUO mice model, inhibition of Caspase-3 or loss of Gsdme was found to alleviate renal fibrosis (123). Disulfiram has been reported to directly inhibit GSDMD cleavage, thereby suppressing pyroptosis and cell fibrosis; however, it is ineffective in inhibiting pyroptosis once the process has already been initiated (124). Furthermore, Tongluo Yishen Detection has been proven to effectively inhibit pyroptosis and improve renal function and fibrosis by targeting NLRP3/Caspase-1/GSDMD pathway (125). YiShen HuoXue decoction can also inhibit this pathway to improve renal fibrosis and inflammation (126).

4.4 Crystalline nephropathy

Crystals, including calcium oxalate (CaOx) and uric acid (UA), that deposit in the renal tubules and interstitium induce ischemia, tubule fibrosis, and inflammation through mechanisms involving tubular obstruction and cytotoxicity, ultimately leading to crystalline nephropathy (CN) (127, 128).

Oxalate nephropathy, although rare, has a poor prognosis and often develops into the final stage of CKD (129, 130). Studies have shown that CaOx induced RTECs and HK-2 cells injury through NLRP3/Caspase-1/GSDMD pathway (131, 132). H3 relaxin, with its anti-inflammatory and antioxidant properties, exerted a protective effect against oxalate nephropathy in rats by targeting the NLRP3/Caspase-1/GSDMD axis (133). Melatonin alleviated RTECs damage and renal CaOx crystal deposition by inhibiting non-canocial inflammasome mediated pyroptosis by NLRP3/Caspase-11/GSDMD (134).

Recent studies have shown that hyperuricemia plays a pathogenic role in the progression of kidney disease, leading to CKD (hyperuricemic nephropathy, HN) (135–137). GSDMD was significantly upregulated in renal tissue of experimental HN mice, and the loss of renal function and renal tubule fibrosis were improved after Gsdmd knockout (138). A study has shown that UA activated autophagy through the p53 pathway and released cathepsin B, which subsequently activated the NLRP3/Caspase-1,11/GSDMD pathway to participate in the development of experimental HN (139). A. manihot L. flower mitigates UA-induced RTECs damage by inhibiting Caspase-8/Caspase-3/NLRP3/GSDME-mediated pyroptosis (140).

Current studies have shown that GSDMs-mediated pyroptosis is involved in experimental CN, but its role in human CN remains to be determined.

4.5 Other experimental CKD

Animal models of CKD provide powerful experimental basis for further exploring the pathogenesis of CKD, verifying the effectiveness of treatment methods. 5/6 nephrectomy (5/6Nx), by removing one whole kidney and two-thirds of the opposite kidney, simulates human CKD manifestations including renal fibrosis and decreased kidney function (141, 142). It is shown that Gsdme deletion significantly improves renal function and renal interstitial fibrosis in mice underwent 5/6Nx (123). Adenine-induced renal injury is also commonly used to mimic human CKD. Data indicated that pyroptosis-related proteins such as GSDMD were upregulated in adenine-induced CKD mice, and pyroptosis was significantly alleviated after butyrate intervention (143).

5 Conclusion

Here, we provide an overview indicating that GSDMD/GSDME-mediated pyroptosis is an important factor in the pathogenesis of CKD. However, several issues remain to be explored and elucidated through further research. First, it has been established that GSDMD and GSDME are associated with multiple types of CKD; however, the role of GSDMDA, GSDMB, GSDMC, and PJVK in CKD remains unclear. Second, in addition to being activated by Caspases to trigger pyroptosis, GSDMs can convert apoptosis to pyroptosis in some cases, so whether there is mutual conversion or interaction between pyroptosis and apoptosis in CKD. Third, at present, in animal and cellular experiments, some drugs and knocking out/down GSDMs can improve CKD; however, clinical trials are needed to verify. Therefore, we hope that future studies will focus on the design and development of drugs that specifically target GSDMD/GSDME, with the aim of improving the quality of life of CKD patients and will also further explore the functional roles by other members of GSDMs.

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