- 1The Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China
- 2Hebei Province Key Laboratory of Integrated Traditional and Western Medicine in Neurological Rehabilitation, Hebei Province Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Cangzhou, Hebei, China
Aquaporin-2 (AQP2) is a critical protein involved in water metabolism. It is primarily located in the renal collecting duct cells’ apical plasma membranes and intracellular vesicles and regulates the movement of water into and out of cells. It plays a pivotal role in maintaining fluid balance, and its dysregulation is associated with conditions such as hypertension and heart failure, which contribute to cardiovascular disease progression. AQP2 has garnered significant attention as an emerging therapeutic target. Traditional Chinese medicine (TCM) has demonstrated efficacy in treating water balance disorders, although its underlying mechanisms remain elusive. The discovery of AQP2 and its association with water metabolism provides an opportunity for TCM to explore these mechanisms more intuitively. This review integrates TCM formulas, single herbs, and active constituents, linking them to AQP2 regulation in the kidneys, heart, liver, inner ear, and uterus with an emphasis on the AVP–V2R–AQP2 axis, while distinguishing between short- and long-term regulation and highlighting cardiovascular applications. This review synthesizes the current evidence from experimental and limited clinical studies, highlights the regulatory effects of TCM on AQP2 in various organ systems, and identifies key research gaps to guide future translational and clinical investigations.
1 Introduction
Aquaporins (AQPs) are a family of membrane proteins that are specifically responsible for facilitating water transport across cellular membranes, with some subtypes permitting the passage of small molecules such as glycerol and urea (1). To date, at least 13 AQPs (AQP0–AQP12) have been identified in mammals. These proteins are distributed across various organs and tissues, significantly enhancing water permeability in the cellular membrane and performing critical physiological functions through their involvement in intracellular and extracellular water balance regulation (2). Among these, aquaporin-2 (AQP2) is predominantly localized in the apical plasma membrane and intracellular vesicles of renal collecting duct cells. AQP2 is uniquely responsive to arginine vasopressin (AVP), facilitating water transport in and out of renal cells, thereby enhancing water reabsorption from urine (3). Due to its critical role in renal water balance regulation, AQP2 dysfunction is closely associated with various kidney pathologies.
Recent studies have revealed that, beyond renal function, AQP2 is also involved in water metabolism disorders related to other organ systems, notably the cardiovascular system, liver, inner ear, and uterus (4). In particular, emerging evidence highlights the distinctive role of AQP2 in cardiovascular diseases through its modulation of fluid balance and blood pressure regulation, underscoring the importance of exploring its potential as a therapeutic target.
Traditional Chinese medicine (TCM) has historically provided comprehensive diagnostic and therapeutic approaches to managing conditions arising from abnormal water metabolism, such as pathological states involving water dampness and phlegm fluid retention (5). Clinical practice demonstrates that TCM interventions frequently yield substantial therapeutic effects when used to treat these disorders. At the molecular level, the function of AQP2 is primarily regulated through the vasopressin type 2 receptor (V2R) signaling pathway. In this classical pathway, AVP binds to V2R located on the basolateral membrane of renal collecting duct principal cells, leading to the activation of adenylate cyclase (AC) via Gs protein signaling (6). This activation increases intracellular cyclic adenosine monophosphate (cAMP) levels, which subsequently activate protein kinase A (PKA). Activated PKA then promotes the phosphorylation and trafficking of AQP2-bearing vesicles to the apical membrane, thereby increasing water reabsorption by enhancing membrane water permeability (6).
At present, TCM research is increasingly focused on this signaling pathway, providing novel insights and therapeutic targets for managing water metabolism disorders. This review aims to systematically summarize the current research regarding TCM interventions that modulate AQP2 expression and activity in diseases related to water metabolism. Moreover, we aim to elucidate the underlying molecular mechanisms, thereby providing robust theoretical support and guidance for future clinical applications of TCM in treating water metabolism disorders.
2 Literature search method
Relevant studies were identified through systematic searches of multiple databases, including PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang. The search terms used were combinations of “Aquaporin-2,” “AQP2,” “Traditional Chinese Medicine,” “TCM,” “water metabolism disorders,” “renal diseases,” “cardiovascular diseases,” “edema,” and the names of specific Chinese medicinal formulas and herbs known to regulate water metabolism. Articles published within the past 20 years were selected based on their relevance to the regulatory effects and mechanisms of TCM on AQP2 expression and activity. In addition, references from key articles were reviewed to ensure comprehensive coverage of the relevant literature.
Most of the included studies comprised in vivo animal models (primarily rats and mice) and explored the regulatory effects of TCM formulas or compounds on AQP2 and related aquaporins in pathological conditions such as heart failure, renal dysfunction, and edema.
3 Regulatory effects on kidney function and mechanisms
3.1 Zhenwu decoction
AQP2 is the most critical aquaporin in renal tubular epithelial cells, which play a crucial role in renal tubule concentration and reabsorption. In renal diseases, edema and oliguria are typical manifestations of fluid metabolism disorders according to TCM theory, and TCM treatment has the benefits of few side effects and remarkable curative effects (7). Zhenwu decoction, a classical formula for treating edema in TCM, has good clinical efficacy (8). Animal experiments have proved that Zhenwu decoction has an effect on the renal function of rats with renal failure and alleviates their water metabolism disorders by raising serum AVP levels, downregulating AQP2 protein expression in the renal tissues of spontaneously hypertensive rats (SHR), and lowering the level of AQP2 in urine (9). Scholars suggested that Zhenwu decoction may operate similar to AVP, which activates the “AVP-V2R-AQP2” pathway, and proposed that a drug-containing serum of Zhenwu decoction may increase the expression of V2R or prolong the time that V2R stays on the surface of the basement membrane, continuously binding to receptors and ultimately increasing the presentation of AQP2, thereby regulating the metabolism of water by improving the water permeability (10, 11).
As the main component of Zhenwu decoction, Poria cocos (Fuling) has been found harbor total triterpene, water-soluble polysaccharides, and water-insoluble polysaccharides, which increased the expression of AC and PKA, and decreased the expressions of antidiuretic hormone (ADH), V2R, AQP1, and AQP2 in edema in lower energizer model rats with renal deficiencies in recent studies (12, 13). It is speculated that the increase in serum ADH content initiates V2R and inhibits the action of AC. Thus, the intracellular concentrations of cAMP and PKA decrease, leading to an increase in AQP2, which improves renal water reabsorption (14). This conclusion supported the previous speculation that the chief components of Poria cocos resemble aldosterone (ALD) receptor antagonists.
3.2 Shenqi Wan
Shenqi Wan also contains Poria cocos, which can rectify water metabolism disorders in renal deficiency. In consideration of the “multi-component, multi-target” action characteristic of compound formulae in TCM, scholars utilized the relevant inhibitors and agonists to intervene in each link of the “V2R-cAMP-AQP2” pathway and confirmed that Shenqi Wan may have an effect similar to AVP, which activates the AVP-V2R-AQP2 pathway through V2R (15). In addition, PKA is also one of the significant targets of Shenqi Wan, adjusting AQP2 expression. Compared with Zhenwu decoction, Shenqi Wan has more complex components and combinations. It has been previously demonstrated that Rhizoma alismatis (Zexie), another fundamental component of Shenqi Wan, has the effect of inhibiting the expression of AQP2 in the renal medulla of normal rats (16).
3.3 Zhuling decoction
Zhuling decoction, which also contains Poria cocos and Rhizoma alismati, was found to downregulate AQP2 mRNA and protein expression, increase urine volume in rats with adriamycin nephropathy (AN), and improve water and sodium metabolism in nephrotic syndrome (17). Ergosterol, the index component of Polyporus umbellatus (Zhuling), has also been found to have a critical diuretic effect and markedly downregulate the mRNA and protein expressions of AQP1, AQP2, and AQP4 (18, 19).
3.4 Er Shen Wan
Er Shen Wan has been found to diminish polyuria symptoms through hormone regulation (20). Moreover, Er Shen Wan has been found to improve renal water absorption and increase AQP2 and arginine vasopressin receptor 2 (AVPR2) expression levels (21). However, these studies were limited by experimental conditions and time; thus, the effects of Er Shen Wan on AVPR2 and AQP2 protein expression should be further confirmed, and more detailed analyses of the regulatory mechanism are needed. The composition of the TCM compound is complicated, so it is essential to conduct an in-depth study on its composition and the principles of its combination and compatibility in order to clarify the internal mechanism and material basis of its therapeutic effect.
4 Application of single Chinese herbs in water metabolism disorders
Studies have demonstrated that a single Chinese herb can also be effective in treating water metabolism-related diseases. Urine production is regulated by renal autoregulation and humoral regulation, and urine volume chiefly depends on the amount of water reabsorbed by distal convoluted tubules and the renal collecting duct. This is affected by changes in the aquaporin expression in this segment. The humoral factors involved in the regulation of urine production are manifold, among which ADH, ALD, and atrial natriuretic peptide (ANP) are the most significant.
4.1 Phytolacca acinosa (Shanglu)
A study discovered that Phytolacca acinosa Roxb (Shanglu), when processed with vinegar, can significantly decrease the AQP2 expression in rat kidneys, act as a vasopressin-sensitive water channel, significantly decrease serum ADH and ALD, and increase the content of ANP (22). There is speculation that the regulating effect may be associated with further changes in the regulation of water channel protein expression levels by kidney hormones.
4.2 Lagopsis supina
Lagopsis supina and its four soluble parts were found to have potential diuretic activity in salt-loaded rats and significantly inhibited renin angiotensin aldosterone system (RAAS) activity, including lowering serum angiotensin II (Ang II), ADH, and ALD levels and increasing serum ANP levels (23). In particular, two components of Lagopsis supina, stachysoside A and acteoside, have practical diuretic effects through the inhibition of AQPs and RAAS and upregulation of atriopeptin expression in salt-loaded rats, which strongly supports the potential use of Lagopsis supina as a new diuretic (24). Previous studies have revealed that Ang II may play a meaningful role during AQP2 transport to chief cells of the medullary collecting duct (25). Further quantitative research needs to be explicit about whether AQP-2 is directly related to RAAS in regulating urine volume.
4.3 Quercetin
In chronic renal failure (CRF), TCM can also play an adjunctive role by regulating AQP2. Researchers have shown that quercetin, the main component of Shengqing Jiangzhuo capsule, may regulate AQP1 and AQP2 in the kidneys of rats with chronic renal failure, thereby moderating water retention and toxin accumulation to relieve CRF (26).
4.4 Ephedra (Mahuang)
Ephedra (Mahuang), a water-draining and swelling-dispersing medicinal herb, has a therapeutic effect in renal edema. Experts found that a water extract of Ephedra and its alkaloid components can inhibit the expression of AQP1 and AQP2 in rat kidneys. They speculate that Ephedra and its alkaloid fractions may lower the expression of AQP1 and AQP2 to achieve the effect of inducing diuresis to alleviate edema (27). In further research, a water extract of Ephedra and its alkaloid components increased the urine volume of rats and reduced the plasma ADH level and the expression of AQP2 protein in the kidneys. This research concluded that its diuretic effect may be related to the level of ADH. However, a different result was observed in another experiment, as a water extract of Ephedra and its alkaloid components had no effect on AQP1 and AQP2 in the kidneys of a rat model with a water retention pattern in the upper energizer (28). This contradiction with previous research results may be attributed to the differences in the models, as they focused on the kidneys that belonged to the lower energizer and the upper energizer, respectively.
4.5 Epimedium (Yinyanghuo)
In addition to renal AQP2, Ephedra and Epimedium (Yinyanghuo) can suppress the expression of AQP3 in the lungs for the treatment of edema, while a high dose of Epimedium alone can significantly reduce the levels of AQP2 in the kidneys (29, 30), regulating the secretion of relevant body fluids from various organs of rats under water load to induce diuresis. This conclusion is consistent with the theory that Ephedra enters the lung meridian and Epimedium enters the kidney meridian, which may explain the insignificant effect of Ephedra on renal AQP2 in some specific disease models. This series of studies indicated that the regulatory effect of traditional Chinese medicine on AQP2 may be related to medicinal meridian tropism and pattern identification, including visceral pattern identification, triple energizer pattern identification, and six-meridian pattern identification in TCM, which may guide studies on Chinese medicinal targets in the future.
5 Regulatory effects of traditional Chinese medicine on water metabolism in various organ systems
5.1 Regulating effects on hypertension
Water and sodium metabolism disorders in the kidneys are the leading mechanisms of salt-sensitive hypertension. Wulingsan has a great effect when used to treat hypertension resulting from water metabolic disorders in the kidneys. Researchers have shown that Wulingsan can significantly relieve water reabsorption by decreasing the expression of AQP2 protein and AVP-V2R in kidney tissue from rats with hypertension, preliminarily illustrating the hypotensive mechanism of Wulingsan on a molecular level (31). Containing Polyporus umbellatus, Poria cocos, and Rhizoma alismatis, Wulingsan has a similar regulation mechanism to Zhuling decoction, proving the reliability of the study (32). Scholars have demonstrated that acupuncture with Zusanli (ST36) and Quchi (LI11), combined with acupoint application on Pishu (BL20), regulates the abnormal expression of AQP1 and AQP2 in the kidneys, thus correcting the water metabolism disorder to decrease blood pressure and control the occurrence and progression of hypertension (33). Studies on AQP1 and AQP2 will provide new ideas for elucidating the pathogenesis of salt-sensitive hypertension. Acupuncture combined with acupoint application can modulate the expression of AQP1 and AQP2, which may be one of the mechanisms by which acupuncture lowers blood pressure, with great significance for the prevention and treatment of hypertension.
5.2 Regulating effects in chronic heart failure
Vasopressin is considered the main mechanism of water retention in chronic heart failure (CHF) (34). During heart failure, the sensitivity of the atrial stretch receptors decreases, giving rise to a weakened inhibition effect on AVP, which increases the concentration of AVP in circulating blood. AQP2 is then transferred from the cytoplasm to the membrane through the AVP-V2R-AQP2 pathway, resulting in water retention in the body by increasing water reabsorption (35). The water retention resulting from the abnormal increase in AQP2 is a fundamental cause of the poor prognosis of CHF. Therefore, AQP2 has attracted attention as an emerging target in research into water metabolism imbalance and has become an entry point for the treatment of cardiac edema (Table 1).

Table 1. Regulation of aquaporin expression by traditional Chinese medicine in cardiovascular diseases.
There are two regulatory mechanisms of AQP2, namely short-term and long-term regulation. According to the differences in their principles, scholars have carried out studies on the effects of drugs on AQP2. It has been reported that the Yiqi Huoxue formula inhibits the increase in AQP2 protein expression induced by long-term continuous elevated AVP levels, in which cAMP/exchange protein is directly activated by the cyclic adenosine monophosphate (Epac)/extracellular signal-regulated protein kinase (ERK) signaling pathway involved in long-term regulation (47). Experiments have shown that the short-term application of water-draining medicinal herbs [Poria cocos, plantain seeds (Cheqianzi), and pepperweed seeds (Tinglizi)] decreases AQP2 expression in the urine of rats with heart failure, and the conclusion is consistent with previous studies (48). However, the effect of blood-activating medicinal herbs [Radix salviae miltiorrhizae (Danshen), Carthamus tinctorius (Honghua), and Radix paeoniae rubra (Chishao)], qi-tonifying medicinal herbs [Radix ginseng rubra (Renshen) and Radix astragali (Huangqi)], and interior-warming medicinal herbs [Cassia twig (Guizhi) and Aconite (Fuzi)] was not obvious under the same conditions. With increasing administration time, the effects of the latter three sorts of drugs on AQP2 continuously increased, while the impact of water-draining medicinal herbs did not change significantly. R. salviae miltiorrhizae is associated with a reduction of AQP2, leading to a redistribution of AQP2 in renal collecting ducts (49). Moreover, the therapeutic effect of R. astragali on heart failure was partly related to an improvement in the AVP system and the abnormal expression of AQP2 in rats. The difference in the results may be related to the short-term and long-term regulatory mechanisms of different drugs, which are worthy of further study.
In addition, the Bushen Huoxue recipe was found to decrease the level of BNP in serum and AQP2 expression in renal tissue of CHF model rats, and its regulatory effect was similar to captopril tablets (38). Therefore, it can be inferred that the Bushen Huoxue recipe may be used to treat CHF by lessening the expression of AQP2 in the kidneys, but this needs to be confirmed by further experimental data (Figure 1).

Figure 1. Mechanisms by which traditional Chinese medicine regulates AQP2 in water metabolism disorders. AQP2-mediated regulation of renal water balance is intimately linked to the development and progression of heart failure. Angiotensin II (Ang II) engages AT1 receptors to trigger the ENaC/NHE3 pathway, leading to VP release and increased aldosterone production. These hormonal signals synergistically elevate AQP2 expression in renal collecting duct cells, resulting in fluid retention and hyponatremia that worsen heart failure symptoms. In contrast, the serine protease Corin converts pro-ANP into its active form, ANP, which suppresses AQP2 expression, and ultimately improving the clinical manifestations of heart failure.
5.3 Regulating effects on the liver
Ascites is one of the complications of liver cirrhosis and hepatocellular carcinoma. In decompensated cirrhosis, increased portal venous pressure leads to renal insufficiency and water retention, resulting in ascites that seriously affects the patient's quality of life (50). AVP and AQP2 are thought to play an essential role in ascites formation. It has been proven that when the expression of AQP2 and V2R is downregulated, liver ascites in mice with hepatocellular carcinoma is significantly alleviated and ascites symptoms are relieved. Danggui Shaoyao San may decrease the expression of AQP2 to treat ascites by inhibiting the release of AVP and the binding of AVP and V2R (51). Scholars found that the protein expression levels of AQP2 and V2R were considerably increased in a hepatocellular carcinoma rat model with ascites after 12 days of ascites inoculation, while Euphorbia pekinensis (Daji) decoction effectively moderated abnormally elevated AQP2 and V2R expression levels (52). The inhibitory effect of E. pekinensis was further enhanced when combined with twice the amount of Glycyrrhiza (Gancao). Preliminary mechanism exploration verified that Glycyrrhiza combined with E. pekinensis, when used to treat ascites in hepatocellular carcinoma, may regulate renal AQP2 and V2R (53). Researchers have found that 3-O-(2'E,4'Z-decadienoyl)-20-O-acetylingenol (3-O-EZ), a major diterpenoid of EK, exhibits a specific therapeutic effect on ascites in mice with hepatoma (54). In conclusion, AQP2 inhibition may be a therapeutic strategy for treating ascites in hepatoma.
5.4 Regulating effects on the inner ear
In a study on water metabolism-related diseases of the inner ear, all the downstream factors of AVP in the AVP-V2R-AQP2 system that regulate AQP2 expression were found to be present in the inner ear. The AQP2 protein is mainly distributed in the stria vascularis, Corti's organ, and spiral ganglion cells (55). Previous animal experiments showed that the classical Linggui Zhu Gan decoction and Zexie decoction formulae lower the degree of endolymphatic hydrops induced by intraperitoneal injections of desmopressin acetate in guinea pigs (56). One of the mechanisms may be the downregulation of AQP2 expression in the vestibular membrane. Electroacupuncture may modulate the AVP-V2R-AQP2 system and lower the expression of AQP2 in the whole body, which in turn decreases the opening of water channels to weaken endolymphatic hydrops symptoms. However, electroacupuncture at GV20 can reverse the decrease in V2R expression caused by AVP (57). Whether the effect of electroacupuncture on V2R expression is directly caused by electroacupuncture or due to the decrease in plasma AVP still needs to be studied further.
5.5 Regulating effects on the uterus
AQP2 expression is periodic as it is upregulated in the endometrial epithelium during the secretory phase and plays a vital role in the periodic changes of the endometrium (58). Shaofu zhuyu decoction was found to decrease the AQP1 and AQP5 mRNA levels and upregulate the AQP2mRNA expression level in the abdominal fluid of rats with endometriosis (EM), thus affecting the disease course (59). In this case, the drug works by restraining the promotion of AQP2 to endometrial debris infiltration, which may be a function of AQP2. AQP2 expression in the vaginal epithelium at different stages of fertility may play a role in regulating the production and quantity of vaginal secretions. Clinical research indicates that the use of TCM treatment after cervical columnar epithelium ectopic physical therapy can alleviate an increase in postoperative vaginal secretions and abnormal water drainage and shorten the vaginal drainage duration (60). Moreover, scholars found that AQP2 expression diminished simultaneously after TCM treatment, indicating that there was an apparent connection between the decreasing expression of AQP2 and the decrease in vagina drainage.
6 Impact of traditional medicines on the metabolism of cardiovascular drugs
In addition to modulating AQP2 expression to regulate water metabolism, TCM can also influence the pharmacokinetics and pharmacodynamics of conventional cardiovascular drugs, including diuretics and antihypertensive agents. Several TCM formulations and single herbs possess active compounds that interact with key regulatory pathways, such as the renin-angiotensin-aldosterone system (61) and the sympathetic nervous system, both of which are critical in blood pressure regulation and fluid balance. For instance, herbs such as Ephedra and Glycyrrhiza have been shown to affect not only water reabsorption mechanisms via AQP modulation but also the activity of cytochrome P450 enzymes involved in drug metabolism (62). Such interactions alter the bioavailability or efficacy of diuretics and hypertensive medications, potentially leading to synergistic effects. When TCMs are used in conjunction with diuretics, by targeting different points (such as AQP2 expression and ion channels/pumps), they can enhance the excretion of water and electrolytes, potentially increasing the diuretic effect and aiding in the alleviation of edema or hypertension caused by sodium and water retention (63–65). However, combined use, if not properly matched in dose or formula, can increase risks such as electrolyte disturbances and dehydration, necessitating close monitoring of patient electrolyte levels. However, some TCMs that have tonic effects or regulate kidney yang may promote water reabsorption under certain stages or specific pathogenic conditions, which could theoretically reduce the efficacy of diuretics if combined inappropriately. Thus, a comprehensive consideration of patient diagnosis and pharmacological properties is required.
Moreover, by modulating neurohormonal pathways, TCM enhances the therapeutic outcomes of conventional therapies or reduces their side effects, offering a complementary approach in managing complex conditions such as heart failure and hypertension (66). Given these possibilities, further research is warranted to systematically explore the molecular mechanisms behind these interactions, which may ultimately facilitate the rational design of integrated treatment regimens that combine TCM with standard cardiovascular drugs for optimized patient care.
7 Limitations and future prospects
This study primarily focused on the regulation of AQP2 by traditional Chinese medicine and its application in diseases related to water metabolism. However, there are still limitations that warrant further exploration and improvement. First, most current research on the regulation of AQP2 by TCM primarily involves in vitro cellular studies and animal experiments and lacks large-scale, high-quality randomized controlled clinical trial data. Due to differences between in vivo environments and actual clinical conditions, the extrapolation and reproducibility of experimental results in clinical settings still require further validation. Second, compound traditional Chinese medicines often contain multiple herbs, characterized by their multicomponent and multitarget synergistic effects. Although existing studies suggest that these effects may be mediated through the AVP-V2R-AQP2 signaling pathway or other AQP subtypes, the specific drug–receptor binding modes, downstream signaling networks, and the mechanisms of interaction between components lack systematic and in-depth elucidation. AQP2's regulation is distinguished into short-term and long-term mechanisms at the molecular level; for example, short-term regulation primarily involves the trafficking and localization of AQP2, whereas long-term regulation is associated with gene transcription and protein synthesis. Current research on the effects of TCM over different durations on AQP2 is insufficient, making it difficult to comprehensively assess the optimal timing for intervention and the sustainability of effects at various stages of disease. Although this article focuses on the pivotal role of AQP2 in water metabolism, other AQPs (such as AQP1, AQP3, and AQP4) also play significant roles in fluid balance across various tissues and organs. Whether interventions with TCM synergistically or adversely affect the expression or function of other AQPs has been minimally studied and warrants further exploration. The application of TCM emphasizes individualized treatment based on differential diagnosis; coupled with the fact that the quality of Chinese medicinal materials, preparation techniques, and methods of administration have not yet been completely standardized, this may lead to variations in clinical efficacy and safety across different studies or regions. Future efforts are required to continually improve the quality control of Chinese medicines and standardize clinical dosing. Although there are some exploratory studies suggesting potential synergistic or antagonistic interactions when TCM is used with diuretics and antihypertensive drugs, the current research is not systematic and lacks rigorously designed pharmacokinetic and pharmacodynamic trials and conclusive clinical evidence.
8 Conclusions
As can be seen from the above studies, AQP2 is a critical protein in the regulation of water metabolism and has become a valuable target in the study of TCM treatment of water metabolism imbalance. However, as AQPs are widely distributed in the body, it should be considered whether TCM affects the expression of other aquaporins while regulating AQP2. At the same time, the relationship between the effect of TCM on AQP2 expression and neural and humoral regulation requires further research. Moreover, TCM has fewer side effects and can be used for a long duration. However, due to the lack of detailed research on long-term and short-term regulation of AQP2, the limits of its effect are not clear, and the specific role of TCM still requires further study. In conclusion, an in-depth study on the mechanism of AQP2 and its influence on diseases may provide new ideas for TCM treatment of related diseases (Supplementary Table S1).
Author contributions
YC: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. LL: Data curation, Methodology, Software, Writing – review & editing. XX: Data curation, Investigation, Methodology, Resources, Visualization, Writing – review & editing. SZ: Conceptualization, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This study was supported by the Hebei Provincial Administration of Traditional Chinese Medicine Research Program [Grant No. 2025562].
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcvm.2025.1506190/full#supplementary-material
References
1. Li C, Wang W. Molecular biology of aquaporins. Adv Exp Med Biol. (2017) 969:1–34. doi: 10.1007/978-94-024-1057-0_1
2. Galli M, Hameed A, Żbikowski A, Zabielski P. Aquaporins in insulin resistance and diabetes: more than channels!. Redox Biol. (2021) 44:102027. doi: 10.1016/j.redox.2021.102027
3. Kakeshita K, Koike T, Imamura T, Fujioka H, Yamazaki H, Kinugawa K. Altered arginine vasopressin-cyclic AMP-Aquaporin 2 pathway in patients with chronic kidney disease. Clin Exp Nephrol. (2022) 26(8):788–96. doi: 10.1007/s10157-022-02220-1
4. Huang Y, Yan S, Su Z, Xia L, Xie J, Zhang F, et al. Aquaporins: a new target for traditional Chinese medicine in the treatment of digestive system diseases. Front Pharmacol. (2022) 13:1069310. doi: 10.3389/fphar.2022.1069310
5. Wei X-H, Liu W-J, Jiang W, Lan T-H, Pan HE, Ma M-Y, et al. Xinli formula, a traditional Chinese decoction, alleviates chronic heart failure via regulating the interaction of Agtr1 and Aqp1. Phytomedicine. (2023) 113:154722. doi: 10.1016/j.phymed.2023.154722
6. Olesen ETB, Fenton RA. Aquaporin 2 regulation: implications for water balance and polycystic kidney diseases. Nat Rev Nephrol. (2021) 17(11):765–81. doi: 10.1038/s41581-021-00447-x
7. Liu X-J, Hu X-K, Yang H, Gui L-M, Cai Z-X, Qi M-S, et al. A review of traditional Chinese medicine on treatment of diabetic nephropathy and the involved mechanisms. Am J Chin Med. (2022) 50(7):1739–79. doi: 10.1142/S0192415X22500744
8. Li S, Xiao X, Han L, Wang Y, Luo G. Renoprotective effect of Zhenwu decoction against renal fibrosis by regulation of oxidative damage and energy metabolism disorder. Sci Rep. (2018) 8(1):14627. doi: 10.1038/s41598-018-32115-9
9. Liu Z, Shang Q, Li H, Fang D, Li Z, Huang Y, et al. Exploring the possible mechanism(S) underlying the nephroprotective effect of Zhenwu decoction in diabetic kidney disease: an integrated analysis. Phytomedicine. (2023) 119:154988. doi: 10.1016/j.phymed.2023.154988
10. Zhou X-J, Bao Y-T, Chen H-S, Xuan L, Chen X-M, Zhang J-Y, et al. Effect of Zhenwu Tang on regulating of “Avp-V2r-Aqp2” pathway in Nrk-52e cells. Zhongguo Zhong Yao Za Zhi. (2018) 43(3):603–8. doi: 10.19540/j.cnki.cjcmm.20171113.007
11. Cheung PW, Ueberdiek L, Day J, Bouley R, Brown D. Protein phosphatase 2c is responsible for Vp-induced dephosphorylation of Aqp2 Serine 261. Am J Physiol Renal Physiol. (2017) 313(2):F404–13. doi: 10.1152/ajprenal.00004.2017
12. Huang Y, Liu Q, Liu M, Xu L, Li Y, Chen Q, et al. System pharmacology-based determination of the functional components and mechanisms in chronic heart failure treatment: an example of Zhenwu decoction. J Biomol Struct Dyn. (2023) 42(23):12935–53. doi: 10.1080/07391102.2023.2274515
13. Li H, Wang T, You P, Xia H, Zhang D, Han S. Clearing damp and promoting diuresis effect of Poria Cocos from different origins on lower energizer edema of rat with kidney-Yang deficiency. Traditional Chin Drug Res Clin Pharmacol. (2021) 32:632–8.
14. Chen L, Yu D, Ling S, Xu J-W. Mechanism of tonifying-kidney Chinese herbal medicine in the treatment of chronic heart failure. Front Cardiovasc Med. (2022) 9:988360. doi: 10.3389/fcvm.2022.988360
15. He JW B, Ji L, Zhou X, Chen H, Chen Y, Yang Y, et al. Study on mechanism of Shenqi Pills up-regulating Aqp2 expression in Nrk cells based on ‘V2r-Camp-Pka’ pathway. Chin J Tradit Chin Med Pharm. (2019) 34(6):2412–6.
16. Yan L, Ou ZM, Wang YJ, Zhang Y, Cheng Y, Wang ZC, et al. Mechanism of Alisma orientale and its processed products on water retention model in kidney Yin deficiency rats. Chin J Exp Tradit Med Formulae. (2022) 28(24):42–9. doi: 10.13422/j.cnki.syfjx.20222280
17. Chen N, Chu Y, Su S, Zhang Q, Zhang L. Network pharmacology and molecular docking validation to explore the pharmacological mechanism of Zhuling decoction against nephrotic syndrome. Curr Pharm Des. (2024) 30(28):2244–56. doi: 10.2174/0113816128305808240529115047
18. Kong M. Clinical observation of the therapeutic effect of water-dampness pattern differentiation-based treatment on cardiorenal syndrome with volume overload and the method of nourishing Yin and promoting diuresis (master's thesis). China Academy of Chinese Medical Sciences, Beijing, China (2023).
19. Wang Y-N, Wu X-Q, Zhang D-D, Hu H-H, Liu J-L, Vaziri ND, et al. Polyporus umbellatus protects against renal fibrosis by regulating intrarenal fatty Acyl metabolites. Front Pharmacol. (2021) 12:633566. doi: 10.3389/fphar.2021.633566
20. Xiong R, Li W, Li Y, Zheng K, Zhang T, Gao M, et al. Er Shen Wan extract reduces diarrhea and regulates Aqp 4 and Nhe 3 in a rat model of spleen-kidney Yang deficiency-induced diarrhea. Biomed Pharmacother. (2018) 98:834–46. doi: 10.1016/j.biopha.2018.01.023
21. Xiong R, Li Y, Zheng K, Zhang T, Gao M, Li Y, et al. Er shen wan extract alleviates polyuria and regulates Aqp 2 and Avpr 2 in a rat model of spleen-kidney Yang deficiency-induced diarrhea. Biomed Pharmacother. (2019) 110:302–11. doi: 10.1016/j.biopha.2018.11.147
22. Sun W-x, Sheng Y-h, Huang JJ, Wei S-t, Tang L-m. Study on pharmacodynamics and pharmacokinetics of Phytolacca acinosa roxb. And its mechanism. Chin Pharmacol Bull. (2022) 38(9):1429–34.
23. He J, Zeng L, Wei R, Zhong G, Zhu Y, Xu T, et al. Lagopsis supina exerts its diuretic effect via inhibition of Aquaporin-1, 2 and 3 expression in a rat model of traumatic blood stasis. J Ethnopharmacol. (2019) 231:446–52. doi: 10.1016/j.jep.2018.10.034
24. Yang L, He Z-W, He J-W. The chemical profiling of aqueous soluble fraction from Lagopsis supina and its diuretic effects via suppression of AQP and RAAS pathways in saline-loaded rats. J Ethnopharmacol. (2021) 272:113951. doi: 10.1016/j.jep.2021.113951
25. He J, Yang L. Diuretic effect of Lagopsis supina fraction in saline-loaded rats is mediated through inhibition of aquaporin and renin-angiotensin-aldosterone systems and up-regulation of atriopeptin. Biomed Pharmacother. (2021) 139:111554. doi: 10.1016/j.biopha.2021.111554
26. Tu H, Ma D, Luo Y, Tang S, Li Y, Chen G, et al. Quercetin alleviates chronic renal failure by targeting the Pi3k/Akt pathway. Bioengineered. (2021) 12(1):6538–58. doi: 10.1080/21655979.2021.1973877
27. Li M, Zeng M, Zhang B, Fan H, Wu G, Feng W, et al. Effect of ephedrae herba decoction and its splitting fractions in rats with Kidney-Yang deficiency and edema. Chin J Exp Tradit Med Form. (2017) 23:91–6.
28. Yang SL, Sun YP, Si YP, Han DW, Zheng XK, Feng WS. Effect of nature and flavor subdivision of ephedrae herba on rats model of harmful fluid retention in upper Jiao. Chin J Exp Tradit Med Formulae. (2019) 25(03):1–7.
29. Sun X, Li Y, Li J, Liang H, Zhang J, Chen X, et al. Bioactive metabolites reveal the therapeutic consistency of epimedii folium from multi-plant sources for the treatment of Kidney-Yang deficiency. J Ethnopharmacol. (2024) 319(Pt 2):117215. doi: 10.1016/j.jep.2023.117215
30. Zheng X, Li S, Wang K, Wang Z, Li J, Yang Q, et al. Comparing the pharmacological effects of the prepared folium of epimedium brevicornu maxim. And epimedium sagittatum maxim. On Kidney-Yang deficiency syndrome and liver injury complications. Fitoterapia. (2024) 176:106006. doi: 10.1016/j.fitote.2024.106006
31. Lee HS, Kim HY, Ahn YM, Cho KW. Herbal medicine oryeongsan (Wulingsan): cardio-renal effects via modulation of renin-angiotensin system and atrial natriuretic peptide system. Integr Med Res. (2024) 13(3):101066. doi: 10.1016/j.imr.2024.101066
32. Kim MG, Lee YJ, Choi ES, Yoon JJ, Han BH, Kang DG, et al. Wiryeongtang regulates hypertonicity-induced expression of Aquaporin-2 water channels in mimcd-3 cells. Mol Med Rep. (2017) 15(5):2665–72. doi: 10.3892/mmr.2017.6296
33. Wei X, Wang J, Qiao Y, Zhang L, Zhou H. Effect of electroacupuncture combined with acupoint application on kidney Aqp1 and Aqp2 in prehypertensive rats. Mod Tradit Chin Med Mater Med-World Sci Technol. (2022) 23(11):4351–8.
34. Bao LZ, Shen M, Qudirat H, Shi JB, Su T, Song JW, et al. Obestatin ameliorates water retention in chronic heart failure by downregulating renal aquaporin 2 through GPR39, V2R and PPARG signaling. Life Sci (2019) 231:116493. doi: 10.1016/j.lfs.2019.05.049
35. Yang C-R, Park E, Chen L, Datta A, Chou C-L, Knepper MA. Proteomics and Aqp2 regulation. J Physiol. (2024) 602(13):3011–23. doi: 10.1113/JP283899
36. Zhang C, Cai T, Pan H, Zeng X, Zhao Z, Liu Y, et al. Therapeutic mechanism of BA-MA mini-pig with spleen deficiency type coronary heart disease by modified Yiqi Jianpi formula. Chin J Tradit Chin Med Pharm. (2018) 33(6):2300–4.
37. He Z, Zhao Y, Zhang Y, Li D, Zhang F, Yang H. Mechanisms and components identification of naoxintong intestinal absorption liquid protecting cardiac injury induced by H2O2. Chin J Exp Tradit Med Formulae. (2019) 25(4):29–35.
38. Kong F, Zhang Y, Zhu A, Zhang Y, Kang Y. Effects of bushen huoxue recipe on cardiac function and Aquaporin-2 in renal tissue of chronic heart failure model rats. J Tradit Chin Med. (2019) 60(6):522–6.
39. Ke Y, Wang M, Li Y, Shan Z, Mi W, Yuan P, et al. Oligosaccharides composition of Descurainiae sophia exerts anti-heart failure by improving heart function and water-liquid metabolism in rats with heart failure. Biomed Pharmacother. (2020) 129:110487. doi: 10.1016/j.biopha.2020.110487
40. Xu J, Zhang Q, Yang Z, Luo C, Li L, Ren X, et al. Effects of TCM therapy method of yang-warming and fluid retention-resolving on expression of Aquaporin-2 in kidney of rats with congestive heart failure. J Beijing Univ Tradit Chin Med. (2015) 38(11):749–52.
41. Oztopuz O, Coskun O, Buyuk B. Alterations in aquaporin gene expression level on cyclophosphamide-induced cardiac injury and possible protective role of Ganoderma lucidum. Biologia. (2021) 76:3081–90. doi: 10.1007/s11756-021-00817
42. He XP, Chen DF, Zheng JH, Du S, Deng B, Zhang S. Effect of jianxin pinglu pill on arrhythmia and aquaporin 4 expression in rats with myocardial ischemia/reperfusion injury. Chin J Integr Tradit West Med. (2004) 24(9):823–6.
43. Yang J, Ma Q, Zhang Y. Effect of invigorating Qi, warming Yang, promoting blood circulation and inducing diuresis on aquaporin 4 expression in rats with chronic pulmonary heart disease and its mechanisms. Chin J Immunol. (2019) 35(21):2599–603.
44. Li XD, Yang YJ, Geng YJ, Cheng YT, Zhang HT, Zhao JL, et al. The cardioprotection of simvastatin in reperfused swine hearts relates to the inhibition of myocardial edema by modulating aquaporins via the PKA pathway. Int J Cardiol. (2013) 167(6):2657–66. doi: 10.1016/j.ijcard.2012.06.121
45. Chen Y, Lin K, Li X, Han Y, Huang G, Li J. Study on effect and mechanism of Yiqi Wenyang Zhushui decoction on improving heart failure by regulating aquaporin and myocardial energy metabolism. Chin Arch Tradit Chin Med. (2023) 41(10):48–52, +263–264.
46. Tan C, Zeng J, Wu G, Zheng L, Huang M, Huang X. Xinshuitong capsule extract attenuates doxorubicin-induced myocardial edema via regulation of cardiac aquaporins in the chronic heart failure rats. Biomed Pharmacother. (2021) 144:112261. doi: 10.1016/j.biopha.2021.112261
47. Zhang B, Wu J, Han A, Zhang D, Cui X. Mechanism research on effect of Yiqi Huoxue formula on the expression of Aqp2 in Imcd3 cells inducted by Ddavp. China J Tradit Chin Med Pharm. (2019) 34(7):3277–81.
48. Zeng MN, Li M, Zhang BB, Wu GC, Feng WS, Kuang HX, et al. Comparison of the diuretic effects of descurainiae semen, coicis semen and plantaginis semen. Chin Tradit Patent Med. (2018) 40(1): 40–6.
49. Guo Q, Zhou SN. Clinical efficacy of modified Chai-Ting-Danshen-Yin in treating coronary heart disease and heart failure with Qi stagnation, blood stasis, and water retention pattern, and its effect on 24 h urine volume and AVP. Sichuan J Tradit Chin Med. (2021) 39(6):64–8.
50. Xu X, Duan Z, Ding H, Li W, Jia J, Wei L, et al. Chinese guidelines on the management of ascites and its related complications in cirrhosis. Hepatol Int. (2019) 13(1):1–21. doi: 10.1007/s12072-018-09923-2
51. Lin WY, Qiu YL. Clinical observation of Zhenwu decoction combined with Danggui-Shaoyao-San in treating edema in diabetic nephropathy (G4A3 stage) and its effect on urinary AQP2. Asia-Pac Tradit Med. (2024) 20(10):65–9.
52. Yan C, Li Y, Guo X, Guo Q, Zhang Y, Lin N. Effect of combination of glycyrrhizae radix Et rhizoma and euphorbia pekinensis radix in resisting hepatocellular carcinoma ascites in mice. J Nanjing Univ Tradit Chinese Med. (2017) 33(3):279–83. doi: 10.14148/j.issn.1672-0482.2017.0279
53. Zhang Y, Liu D, Xue F, Yu H, Wu H, Cui X, et al. Anti-malignant ascites effect of total diterpenoids from Euphorbiae ebracteolatae radix is attributable to alterations of aquaporins via inhibiting Pkc activity in the kidney. Molecules. (2021) 26(4), 942. doi: 10.3390/molecules26040942
54. Zhang Q, Ju Y-H, Zhang Y, Wang K, Zhang M, Chen P-D, et al. The water expelling effect evaluation of 3-O-(2′e,4′z-decadienoyl)-20-O-acetylingenol and ingenol on H22 mouse hepatoma ascites model and their content differences analysis in Euphorbia Kansui before and after stir-fried with vinegar by UPLC. J Ethnopharmacol. (2021) 267:113507. doi: 10.1016/j.jep.2020.113507
55. Takumida M, Kakigi A, Egami N, Nishioka R, Anniko M. Localization of Aquaporins 1, 2, and 3 and vasopressin type 2 receptor in the mouse inner ear. Acta Otolaryngol. (2012) 132(8):807–13. doi: 10.3109/00016489.2012.662718
56. Luo ChiQiong LC, Li Qian LQ, Zhang Qi ZQ. Effects of Linggui Zhugan decoction combined with Zexie decoction on the expression of Aqp2 in vestibular membrane of guinea pig with membranous labyrinth hydrops. Chin J Tradit Chin Med Pharm. (2015) 30(02):578–80.
57. Jiang L-y, He J-j, Chen X-x, Sun X-j, Wang X-z, Zhong S, et al. Arginine vasopressin-aquaporin-2 pathway-mediated dehydration effects of electroacupuncture in Guinea pig model of Avp-induced eendolymphatic hydrops. Chin J Integr Med. (2019) 25:763–9. doi: 10.1007/s11655-017-2411-2
58. Zhang H, Yang B. Aquaporins in reproductive system. Adv Exp Med Biol. (2023) 1398:179–94. doi: 10.1007/978-981-19-7415-1_12
59. Wang N, Wu X, Jiang Z, Wang X, Yang D. Study on the effect of Shaofu Zhuyu decoction on hydro-channel protein in abdominal cavity fluid in rats with internal disease caused by cold coagulation and blood stasis. Lishizhen Med Mater Med Res. (2021) 32(8):1840–3.
60. Peng Q, Zhang Y, Yang L. Observation of clinical effect of herbal promote wound repair in patients with cervical columnar ectopy after physical treatment and exploration of mechanism from Aqp2. Lishizhen Med Mater Med Res. (2017) 28(7):1683–5.
61. Li BX, Zhao JF, Zhang S, Liu L, Peng YZ, Zhou H. Multi-target mechanism of warming Yang and eliminating fluid formula against adriamycin-induced chronic heart failure in mice via liver X receptor-mediated NF-κB/AVP-AQP2 axis. Chin J Exp Tradit Med Formulae. (2025):1–12.
62. He J, Huo M, Chen SH, Xiu LL, Li W, Wang X, et al. Effects of modified Gansui-Banxia decoction and Gansui-Gancao antagonistic pair on CYP450 enzymes in rats with ascites. Chin J Exp Tradit Med Formulae. (2022) 28(23):10–8. doi: 10.13422/j.cnki.syfjx.20221428
63. Yang XQ, Wang X. Clinical study of Luofengning formula no. 2 in patients with chronic heart failure and diuretic resistance. World J Tradit Chin Med. (2023) 18(8):1126–30.
64. Ren DZ, Wei GC, Zhang JR, Li F, Gao A. Effect of Yangxin mixture on the expression of AVP and AQP2 in patients with chronic heart failure and diuretic resistance. J Integr Tradit West Med Cardiovasc Cerebrovasc Dis. (2018) 16(19):2833–5.
65. Zhang MM, Zhao FC, Ren WH, Sun Q, Liu CL, Jia K. Meta-analysis of the treatment of chronic heart failure with diuretic resistance using the methods of tonifying Qi, activating blood circulation, warming Yang, and promoting urination. Chin J Tradit Med Res. (2024) 37(12):79–86.
Keywords: Aquaporin-2, traditional Chinese medicine, water balance disorders, cardiovascular diseases, Zhenwu decoction
Citation: Chang Y, Liu L, Xu X and Zhang S (2025) Regulation of aquaporin-2 using traditional Chinese medicine in water balance disorders: a literature review. Front. Cardiovasc. Med. 12:1506190. doi: 10.3389/fcvm.2025.1506190
Received: 4 October 2024; Accepted: 29 August 2025;
Published: 23 September 2025.
Edited by:
Hendrik Tevaearai Stahel, University Hospital of Bern, SwitzerlandReviewed by:
Youhua Wang, Shanghai University of Traditional Chinese Medicine, ChinaAsma Tchakal-Mesbahi, Harvard Medical School, United States
Copyright: © 2025 Chang, Liu, Xu and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Shiqiang Zhang, emhhbmdzaGlxaWFuZzA4MTFAMTYzLmNvbQ==