Bile acids-induced renal injury is a cholestasis-associated clinical complication known as cholemic nephropathy (CN).
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Severe renal tissue necrosis and fibrosis along with serum electrolytes imbalance are evident in CN.
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There is no precise cellular/molecular mechanism(s) for CN.
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Oxidative stress and mitochondrial impairment are fundamental mechanisms in the pathogenesis of CN.
Abstract
Cholemic nephropathy (CN) is a clinical complication associated with cholestasis and chronic liver diseases. CN could lead to renal failure and the need for kidney transplantation if not appropriately managed. On the other hand, although the clinical features of CN are well described, there is no clear idea on the precise cellular and molecular mechanisms of CN. The current study was designed to evaluate kidney mitochondrial function in cholestasis-associated CN. Rats underwent bile duct ligation (BDL) surgery, and kidney mitochondria were isolated at scheduled time intervals (14, 28, and 42 days after BDL operation). Several mitochondrial indices including mitochondrial permeabilization and swelling, glutathione and ATP content, mitochondrial depolarization, and lipid peroxidation were evaluated. Renal tissue markers of oxidative stress along with tissue histopathological changes and serum biochemistry were also analyzed. Severe kidney tissue histopathological alterations including interstitial inflammation, necrosis, and Bowman capsule dilation were detected in the BDL animals. Moreover, drastic elevation in renal fibrosis and collagen deposition was detected in BDL rats. Oxidative stress markers were also significantly enhanced in the kidney tissue of BDL animals. On the other hand, it was found that mitochondrial indices of functionality were significantly deteriorated in BDL rats. These data introduce mitochondrial dysfunction and energy metabolism disturbances as a fundamental mechanism involved in the pathogenesis of bile acids-associated renal injury during cholestasis.
Graphical abstract
A schematic representation of the role of bile acid-induced mitochondrial dysfunction and energy crisis in the renal injury and tubular defect during cholestasis/cirrhosis. The image of bile duct ligation surgery steps (A-E´), was adapted from C.G. Tag, S. Sauer-Lehnen, S. Weiskirchen, E. Borkham-Kamphorst, R.H. Tolba, F. Tacke, R. Weiskirchen, Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis, J Vis Exp, 2015 (96). DOI: 10.3791/52438.
