SIRT1 Restores Autophagic Flux to Attenuate Podocyte Injury in Experimental Membranous Nephropathy

<title>Abstract</title> <p> Background Membranous nephropathy (MN), characterized by subepithelial immune deposits and podocyte injury, lacks targeted therapies addressing non-immunological injury mechanisms. SIRT1, a NAD⁺-dependent deacetylase, regulates autophagy and cellular homeostasis, but its role in MN remains undefined. Methods We combined passive Heymann nephritis (PHN) rats and complement-injured podocytes to investigate SIRT1’s function. Pharmacological activation (resveratrol/SRT1720) or SIRT1 ^ΔPod models were employed. Assessments included proteinuria, histopathology, autophagic flux, and SIRT1 activity. Results SIRT1 activation in PHN rats reduced proteinuria and glomerular IgG and C5b-9 deposition, restored podocyte integrity and SIRT1 activity, resolved autophagic flux blockade. In podocytes, SIRT1 agonists attenuated complement-induced LDH release and cytoskeletal disruption, enhanced autophagosome-lysosome fusion. SIRT1 ^ΔPod mice exhibited mild proteinuria without structural damage, implicating SIRT1 in functional maintenance. Conclusion SIRT1 protects podocytes in MN by restoring autophagic flux specifically through promoting autophagosome-lysosome fusion. </p>