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Sirtuin 6 protects against podocyte injury by blocking the renin-angiotensin system by inhibiting the Wnt1/β-catenin pathway

Acta Pharmacologica Sinica volume 45, pages 137–149 (2024)Cite this article

Abstract

Sirtuins (Sirts) are a family of nicotinamide adenine dinucleotide-dependent protein deacetylases that share diverse cellular functions. Increasing evidence shows that Sirts play a critical role in podocyte injury, which is a major determinant of proteinuria-associated renal disease. Membranous nephropathy (MN) is a typical glomerular disease in which podocyte damage mediates proteinuria development. In this study we investigated the molecular mechanisms underlying the regulatory roles of Sirt in podocyte injury in MN patients, rats with cationic bovine serum albumin (CBSA)-induced MN and zymosan activation serum (ZAS)-stimulated podocytes. Compared with healthy controls, MN patients showed significant reduction in intrarenal Sirt1 and Sirt6 protein expression. In CBSA-induced MN rats, significant reduction in intrarenal Sirt1, Sirt3 and Sirt6 protein expression was observed. However, only significant decrease in Sirt6 protein expression was found in ZAS-stimulated podocytes. MN patients showed significantly upregulated protein expression of Wnt1 and β-catenin and renin-angiotensin system (RAS) components in glomeruli. CBSA-induced MN rats exhibited significantly upregulated protein expression of intrarenal Wnt1 and β-catenin and their downstream gene products as well as RAS components. Similar results were observed in ZAS-stimulated podocytes. In ZAS-stimulated podocytes, treatment with a specific Sirt6 activator UBCS039 preserved the protein expression of podocin, nephrin and podocalyxin, accompanied by significant inhibition of the protein expression of β-catenin and its downstream gene products, including Snail1 and Twist; treatment with a β-catenin inhibitor ICG-001 significantly preserved the expression of podocyte-specific proteins and inhibited the upregulation of downstream β-catenin gene products accompanied by significant suppression of the protein expression of RAS components. Thus, we demonstrate that Sirt6 ameliorates podocyte injury by blocking RAS signalling via the Wnt1/β-catenin pathway. Sirt6 is a specific therapeutic target for the treatment of podocyte damage-associated renal disease.

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Fig. 1: Intrarenal Sirt deficiency, a hyperactive Wnt1/β-catenin pathway and RAS overexpression in MN patients.
Fig. 2: Renal function decline and renal injury in CBSA-induced rats.
Fig. 3: Podocyte injury and downregulated protein expression of Sirts in CBSA-induced rats.
Fig. 4: Activation of the Wnt1/β-catenin pathway and RAS signalling in CBSA-induced rats.
Fig. 5: Sirt6 deficiency exacerbated podocyte injury in ZAS-stimulated podocytes.
Fig. 6: Activation of the Wnt1/β-catenin pathway and RAS signalling in ZAS-stimulated podocytes.
Fig. 7: Sirt6 reduced podocyte injury by blocking RAS signalling via the Wnt1/β-catenin pathway.
Fig. 8: Summary of the underlying molecular mechanism of Sirt6 deficiency, the hyperactive Wnt1/β-catenin pathway and RAS overexpression in podocyte injury.

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Acknowledgements

This study was supported by the National Key Research & Development Program of China (No. 2019YFC1709405), the National Natural Science Foundation of China (No. 82274192, 82174366, 82074002, 82274079), the Shaanxi Key Research & Development Program (No. 2023-ZDLSF-26) and the Inheritance and Innovation of Traditional Chinese Medicine & Key Scientific Research on the Development of “Qin Medicine” of Shaanxi Administration of Traditional Chinese Medicine (No. 2021-03-22-005).

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Authors and Affiliations

  1. School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Hua Miao, Yan-ni Wang & Ying-yong Zhao

  2. Department of Nephrology, Baoji Central Hospital, Baoji, 721008, China

    Wei Su

  3. School of Food and Bioengineering, Chengdu University, Chengdu, 610106, China

    Liang Zou

  4. Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, 02903, USA

    Shou-gang Zhuang

  5. Department of Nephrology, Shaanxi Traditional Chinese Medicine Hospital, Xi’an, 710003, China

    Xiao-yong Yu

  6. Department of Urology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Fei Liu

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Contributions

YYZ conceived and designed the experiments. HM, YNW and YYZ conducted the experiments and analysed the data. HM and YYZ performed the statistical analysis. XYY and WS collected the clinical samples. YYZ wrote the initial draft of the paper. LZ, SGZ and FL revised the paper. All authors have critically revised the paper and approved the final version.

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Correspondence to Xiao-yong Yu, Fei Liu or Ying-yong Zhao.

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Miao, H., Wang, Yn., Su, W. et al. Sirtuin 6 protects against podocyte injury by blocking the renin-angiotensin system by inhibiting the Wnt1/β-catenin pathway. Acta Pharmacol Sin 45, 137–149 (2024). https://doi.org/10.1038/s41401-023-01148-w

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