GSE184256
Chronic Kidney Disease in a Murine Model of non-Alcoholic Steatohepatitis (NASH)
Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease  (NAFLD) that underlies a growing prevalence of cirrhosis and liver cancer worldwide.  Clinical studies suggest that NASH is an independent risk factor for chronic kidney  disease (CKD), but models and mechanisms linking these two diseases are lacking. Here,  we have characterized the renal function, histological features, and transcriptomic profile  in a well-validated murine NASH model generated by feeding a western diet (WD), with  high contents of fat, fructose, and cholesterol, combined with a low dose of weekly IP  carbon tetrachloride (CCl4). NASH mice developed significant glomerulosclerosis, tubular  epithelial cell injury, and interstitial fibrosis at an intermediate stage (12 weeks). Animals  with advanced NASH (24 weeks) displayed renal dysfunction, proteinuria, and renal  fibrosis characterized by increased collagen deposition as tubulointerstitial fibrosis,  tubular atrophy, and inflammatory cell infiltration. Mice treated with a low dose of CCl4  alone did not develop renal injury, thereby excluding the possibility of CCl4-induced  nephrotoxicity. Transcriptomic analysis of kidney cortices revealed differentially  expressed genes (DEGs) that were highly enriched in mitochondrial dysfunction, ATP  synthesis, and oxidative stress at the intermediate stage (12 weeks) and dysregulation of  the immune response, lipid metabolic process, and insulin signaling pathways at the late  stage (24 weeks). NRF-mediated oxidative stress pathway, Sirtuin signaling, and AMPK  pathways were also highly enriched. Our results confirm a causative role of NASH in the  development of CKD and reveal potential mechanisms of NASH-induced kidney injury.  These findings establish valuable model to study the pathogenesis of NASH-associated CKD, an important feature of fatty liver disease that has been largely overlooked, yet has  clinical and prognostic importance. Overall design: Control mice for 12 weeks (mice were fed with normal diet and corn oil for 12 weeks) NASH mice for 12 weeks (mice were treated with WD and CCl4 for 12 weeks) Control mice at 24 weeks (mice were fed with normal diet and corn oil) NASH mice at 24 weeks (mice were treated with WD and CCl4) RNA-seq profilin of kidney cortices