Exploring Bilirubin’s Impact on Autophagy and Apoptosis in Diabetic Kidney Disease

Background Diabetic kidney disease (DKD) affects nearly half of patients with type 1 or type 2 diabetes and is a leading cause of end‐stage renal disease (ESRD). Maladaptive autophagy and increased apoptosis have been observed in diabetic kidneys. Bilirubin, a natural antioxidant, may exert protective effects against DKD progression; however, the underlying mechanisms remain unclear. This study aimed to investigate the renoprotective effects of bilirubin and its potential mechanisms in DKD. Methods Forty adult male Sprague Dawley rats were randomly divided into five groups ( n = 8). Type 2 diabetes was induced via 14 weeks of high‐fat diet feeding followed by a low‐dose streptozotocin injection. Rats received bilirubin (10 mg/kg/day) via intraperitoneal injection. Renal expression levels of autophagy‐related genes ( Beclin1 , ATG5 , LC3 , and p62 ), apoptosis‐related genes ( Bax , Cas3 , and Bcl2 ), and regulatory genes ( SIRT1 , FOXO1 , and AMPK ) were evaluated using RT‐PCR. Histopathological and biochemical assessments, including fasting glucose, lipid profile, and kidney function markers, were also performed. Results Bilirubin administration significantly upregulated renal levels of Beclin1 , ATG5 , LC3 , SIRT1 , and AMPK , while attenuating the elevated expression of FOXO1 and p62 in diabetic rats. Moreover, bilirubin reduced pro‐apoptotic gene expression ( Bax , Cas3 ) and increased anti‐apoptotic Bcl2 . Improvements in fasting blood glucose, lipid profile, and kidney function parameters were also observed following bilirubin treatment. Conclusion The renoprotective effects of bilirubin in DKD may be mediated through enhanced autophagy and reduced apoptosis via activation of SIRT1 and AMPK, coupled with suppression of FOXO1.