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Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis
Published on: April 25, 2025
Blocking sirtuin 1 and 2 inhibits renal interstitial fibroblast activation and attenuates renal interstitial fibrosis
Murugavel Ponnusamy1, Xiaoxu Zhou1, Yanli Yan1
1Department of Medicine, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island (M.P., X.Z., Y.Y., E.T., R.G., S.Z.); First Affiliated Hospital of Harbin Medical University, Harbin, China (X.Z.); Departments of Nephrology (J.T., S.Z.) and Emergency Medicine (Y.Y.), Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; and Department of Surgery, Roger William Medical Center, Boston University Medical School, Providence, Rhode Island (T.C.Z.).
Abstract:
Our recent studies revealed that blocking class I/II histone deacetylases (HDACs) inhibits renal interstitial fibroblast activation and proliferation and alleviates development of renal fibrosis. However, the effect of class III HDAC, particularly sirtuin 1 and 2 (SIRT1 and SIRT2), inhibition on renal fibrogenesis remains elusive. Here, we demonstrate that both SIRT1 and SIRT2 were expressed in cultured renal interstitial fibroblasts (NRK-49F). Exposure of NRK-49F to sirtinol, a selective inhibitor of SIRT1/2, or EX527 (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide), an inhibitor for SIRT1, resulted in reduced expression of fibroblast activation markers (α-smooth muscle actin, fibronectin, and collagen I) as well as proliferation markers (proliferating cell nuclear antigen, cyclin D1, cyclin E) in dose- and time-dependent manners. Treatment with a SIRT2 inhibitor, AGK2 (2-cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide), also dose- and time-dependently inhibited renal fibroblast activation and, to a lesser extent, cell proliferation. Furthermore, silencing of either SIRT1 or SIRT2 by small interfering RNA exhibited similar inhibitory effects. In a mouse model of obstructive nephropathy, administration of sirtinol attenuated deposition of collagen fibrils as well as reduced expression of α-smooth muscle actin, collagen I, and fibronectin in the injured kidney. SIRT1/2 inhibition-mediated antifibrotic effects are associated with dephosphorylation of epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor-β (PDGFRβ), and signal transducer and activator of transcription 3. Thus, SIRT1/2 activity may contribute to renal fibroblast activation and proliferation as well as renal fibrogenesis through activation of at least EGFR and PDGFRβ signaling. Blocking SIRT1/2 activation may have therapeutic potential for the treatment of chronic kidney disease.
Insights
Blocking class III histone deacetylases (SIRT1 and SIRT2) inhibits renal fibroblast activation and proliferation, offering potential therapeutic strategies for kidney fibrosis. This study highlights SIRT1/2 as key contributors to fibrogenesis.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Class I/II histone deacetylases (HDACs) inhibition mitigates renal fibrosis.
- The role of class III HDACs, specifically sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2), in renal fibrogenesis remains unclear.
Purpose of the Study:
- To investigate the effects of SIRT1 and SIRT2 inhibition on renal interstitial fibroblast activation, proliferation, and fibrogenesis.
- To explore the underlying molecular mechanisms and therapeutic potential of targeting SIRT1/2 in kidney disease.
Main Methods:
- Utilized cultured renal interstitial fibroblasts (NRK-49F) and selective SIRT1/2 inhibitors (sirtinol, EX527, AGK2).
- Employed small interfering RNA (siRNA) for SIRT1 and SIRT2 gene silencing.
- Assessed fibroblast activation and proliferation markers (e.g., α-smooth muscle actin, fibronectin, collagen I, PCNA, cyclins).
- Utilized a mouse model of obstructive nephropathy to evaluate in vivo efficacy.
Main Results:
- Sirtinol and EX527 significantly reduced fibroblast activation and proliferation markers in a dose- and time-dependent manner.
- AGK2 inhibited renal fibroblast activation and, to a lesser extent, proliferation.
- siRNA-mediated silencing of SIRT1 or SIRT2 mimicked the inhibitory effects of pharmacological inhibitors.
- In vivo, sirtinol administration attenuated collagen deposition and reduced fibrotic markers in a mouse model of kidney injury.
- SIRT1/2 inhibition led to dephosphorylation of EGFR, PDGFRβ, and STAT3.
Conclusions:
- SIRT1 and SIRT2 activity promotes renal fibroblast activation, proliferation, and fibrogenesis, at least partly through EGFR and PDGFRβ signaling pathways.
- Inhibition of SIRT1/2 exhibits significant antifibrotic effects in both in vitro and in vivo models of kidney disease.
- Targeting SIRT1/2 represents a promising therapeutic strategy for treating chronic kidney disease and other fibrotic conditions.
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