Abstract
Background
Cholestasis or bile duct ligation (BDL) could develop cirrhosis and may lead to other organ dysfunction, including 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. The effects of sitagliptin on CN is unknown.
Methods
BDL was performed to induce CN model in 42 male Wistar rats (200–250 gr), which were divided equally into six groups: sham-operated received distilled water as the vehicle (sham + veh), sham received 50mg/kg sitagliptin (sham + sit 50), BDL group, BDL + sit 10, BDL + sit 50, BDL + sit 100 groups, received sitagliptin 10, 50, and 100mg/Kg respectively for 14 days by gavage. Aspartate transferase, alkaline phosphatase, total bilirubin (T-Bil), serum and urine biomarkers of renal function, redox system status, TNF-α, and renal histopathology were assessed.
Results
Induction of BDL increased serum liver enzymes, T-Bil, creatinine (Cr), urea, urine Cr, albumin to Cr ratio, and decreased Cr clearance. Renal sestrin2, malondialdehyde, TNF-α, renal index, and kidney tissue injury score were elevated, while superoxide dismutase activity, total antioxidant capacity, and nuclear factor erythroid 2–related factor 2 (Nrf2) were reduced. Treatment with sitagliptin especially in low dose reverse these effects.
Conclusions
Sitagliptin improves renal injury and function via ameliorating inflammation and oxidative stress by activating Nrf2/SOD pathway in BDL rats. Sitagliptin might be helpful in treating renal complications in cirrhosis and severe liver disease.