Inotodiol ameliorates oxidative stress and apoptosis by regulating PI3K/Akt/GSK-3β signaling pathways in diabetic nephropathy.

Abstract

Diabetic nephropathy (DN) is a major microvascular complication of diabetes and a leading cause of end-stage renal disease, but effective therapies remain scarce. This study investigated the renoprotective effects and mechanisms of inotodiol (INO), a lanostane triterpenoid from Inonotus obliquus, using db/db mice (in vivo) and high glucose-treated MPC5 podocytes (in vitro). Renal histopathology, function, and oxidative stress markers were assessed in vivo; reactive oxygen species, cytotoxicity, and apoptosis were measured in vitro. Protein expression levels of apoptosis-related factors, podocyte injury markers, oxidative stress indicators, and PI3K/Akt/GSK-3β pathway components were analyzed. INO treatment significantly reduced fasting blood glucose, blood urea nitrogen, serum creatinine, and urinary albumin-to-creatinine ratio in db/db mice while restoring podocyte markers (synaptopodin, WT-1). It ameliorated renal histopathology and oxidative stress, as evidenced by decreased KEAP1, NOX4, and malondialdehyde, along with increased superoxide dismutase, catalase, glutathione peroxidase, Nrf2, NQO1, and heme oxygenase-1. INO also suppressed apoptosis, reducing cytochrome c, Bax, and cleaved caspase-3 while elevating Bcl-2. Mechanistically, INO activated the PI3K/Akt pathway, which in turn inhibited GSK-3β activity, thereby attenuating oxidative stress, apoptosis, and podocyte injury both in vivo and in vitro. Taken together, INO protects against DN by mitigating oxidative stress and apoptosis via the PI3K/Akt/GSK-3β signaling pathway, highlighting its potential as a promising therapeutic candidate for DN.

Key Findings

• Inotodiol treatment reduced fasting blood glucose, blood urea nitrogen, serum creatinine, and urinary albumin-to-creatinine ratio in diabetic nephropathy mouse models.
• Inotodiol ameliorated renal histopathology and oxidative stress by decreasing KEAP1, NOX4, and malondialdehyde levels while increasing antioxidant enzymes including superoxide dismutase, catalase, glutathione peroxidase, Nrf2, NQO1, and heme oxygenase-1.
• Inotodiol suppressed apoptosis by modulating apoptosis-related proteins (reducing cytochrome c, Bax, cleaved caspase-3 and increasing Bcl-2) and activated the PI3K/Akt pathway, which inhibited GSK-3β activity, thereby protecting podocytes from injury.

Clinical Significance

Citation

Tian Lingling, Zhang SiJie, Ye Ziyanget al.. Inotodiol ameliorates oxidative stress and apoptosis by regulating PI3K/Akt/GSK-3β signaling pathways in diabetic nephropathy. Renal failure. 2026-Dec.