Sarsasapogenin Preserves Podocyte Integrity and Attenuates Renal Injury in Experimental IgA Nephropathy

ABSTRACT IgA nephropathy (IgAN) is a progressive glomerular disease marked by mesangial IgA deposition, inflammation, podocyte injury, and fibrogenesis. Although understanding of its pathophysiology has advanced, effective disease‐modifying therapies are still limited. Sarsasapogenin (SAR), a natural steroidal sapogenin, demonstrates anti‐inflammatory, antioxidant, and antifibrotic properties by modulating signaling pathways such as NF‐κB and TGF‐β. The present study investigated the renoprotective effects of SAR in an experimental model of IgAN. IgAN was induced in Sprague–Dawley rats using bovine serum albumin (BSA), carbon tetrachloride (CCl 4 ), and lipopolysaccharide (LPS). SAR was administered at 60 mg/kg/day from week 7 through week 12. Renal function, histopathological changes (Oxford MEST‐C classification), and immunohistochemical, ultrastructural, and molecular alterations were assessed. Induction of IgAN resulted in significant proteinuria, renal dysfunction, mesangial IgA deposition, and podocyte alterations, accompanied by increased expression of IL‐6, TGF‐β1, SMAD3, fibronectin, and α‐SMA. Masson's trichrome staining did not reveal excessive collagen deposition, indicating early fibrogenic activity rather than established fibrosis. SAR treatment significantly reduced proteinuria and improved renal function, accompanied by decreased IL‐6‐mediated inflammation and reduced activation of the TGF‐β1/SMAD3 pathway. SAR also preserved podocyte‐associated proteins, including nephrin and podocin, and lowered pre‐fibrotic markers. Ultrastructural analysis confirmed preservation of podocyte architecture, with reduced foot process fusion and mesangial matrix expansion. Overall, sarsasapogenin modulated multiple targets in experimental IgAN by reducing inflammation and early fibrogenesis while supporting podocyte integrity. These findings indicate that SAR is a promising therapeutic candidate for early IgAN, although further mechanistic and long‐term studies are warranted.