ABSTRACT: 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.
