Abstract
<title>Abstract</title> <p>Obstructive cholestasis is increasingly recognized to induce renal injury beyond the liver, yet the mechanisms underlying cholestasis-associated glomerular damage remain poorly defined. Autophagy is essential for podocyte homeostasis, but its role in obstructive cholestasis–related renal injury is unclear. A common bile duct ligation (CBDL) rat model was used to characterize the temporal progression of hepatic and renal injury. Liver function, oxidative stress, renal function, glomerular injury, fibrosis, and renal autophagy were assessed at multiple time points. Autophagy was modulated in vivo using 3-methyladenine or rapamycin. In parallel, mouse podocyte MPC-5 cells were exposed to serum from CBDL rats, with autophagy further manipulated using AMPK modulators. CBDL induced liver injury and oxidative stress, followed by delayed but sustained renal dysfunction. Podocyte injury and glomerular structural damage preceded overt renal functional decline. Ultrastructural analysis demonstrated early podocyte foot process effacement, while autophagosomes were observed following autophagy modulation. Renal autophagy exhibited dynamic regulation, characterized by early activation followed by progressive impairment, as reflected by increased Beclin-1 expression and LC3-II/LC3-I ratios together with subsequent p62 accumulation. Autophagy inhibition exacerbated podocyte loss, glomerular injury, fibrosis, and renal dysfunction, whereas autophagy activation preserved podocyte markers, improved glomerular architecture, and attenuated renal dysfunction. Altered AMPK–mTOR signaling was associated with autophagy-related changes in renal tissues and podocytes. These findings suggest that autophagy-related alterations may contribute to podocyte injury and glomerular damage during obstructive cholestasis and are associated with changes in AMPK–mTOR signaling.</p>