Sitagliptin protects against bile duct ligation-induced cholemic nephropathy in male rats through modulation of inflammation, sestrin2, and the Nrf2/SOD pathway

Abstract

Background and purpose:Cholestasis or bile duct ligation (BDL) could develop cirrhosis and may lead to other organ dysfunction, including the kidneys, which is called cholemic nephropathy (CN). Hyperbilirubinemia, bile acid accumulation, renal hypoperfusion, oxidative stress, and inflammation are implicated in the pathogenesis of CN. Sitagliptin is an oral antihyperglycemic drug with anti-inflammatory and anti-oxidative effects. Its effects on CN were unknown. Experimental approach:The BDL-induced CN model was performed in 35 male Wistar rats (200-250 g), which were divided into five groups (n = 7) as follows: sham group receiving distilled water as vehicle (sham + Veh), BDL group receiving vehicle (BDL + Veh), and BDL groups receiving sitagliptin at the doses of 10, 50, or 100 mg/kg/day by gavage for 14 days named BDL + Sit 10, BDL + Sit 50, and BDL + Sit 100, respectively. Aspartate transferase, alkaline phosphatase, total bilirubin (T-Bil), renal function biomarkers, creatinine (Cr) clearance, redox system status, TNF-alpha, and renal histopathology were evaluated. Findings/Results:BDL increased serum liver enzymes, T-Bil, Cr, urea, urine Cr, albumin to Cr ratio, and decreased Cr clearance. Also, BDL elevated renal sestrin2, malondialdehyde, TNF-alpha, renal index, and kidney tissue injury score, while reducing superoxide dismutase (SOD) activity, total antioxidant capacity, and nuclear factor erythroid 2-related factor 2 (Nrf2). Sitagliptin, especially at the low dose, reversed these effects. Conclusion and implications:Sitagliptin improved renal injury and function via ameliorating inflammation and oxidative stress by activating the Nrf2/SOD pathway in BDL rats. Sitagliptin might help treat renal complications in cirrhosis and liver diseases.