Vascular endothelial cell-specific overexpression of CNP did not improve liver fibrosis in HFFCD-induced NASH, but did improve renal lesions

Abstract

Mice with endothelial-cell-specific overexpression of C-type natriuretic peptide (E-CNP Tg mice) were shown to be protected against hepatic fibrosis and inflammation induced by high fat diet (HFD) feeding, with improved insulin sensitivity and attenuated weight gain. A recently developed high-fat, high-fructose, high-cholesterol diet (HFFCD) is considered to be a superior model to HFD, owing to the resemblance to human non-alcoholic steatohepatitis (NASH). In this study, we therefore aimed to reveal whether these previous findings with E-CNP Tg mice on HFD can be observed in a newly developed NASH model. Patients with NASH have been suggested to be at higher risk of developing chronic kidney disease, so we also assessed the kidney histology of these mice. After 8 months of HFFCD feeding, the livers of E-CNP Tg mice and controls showed progressive fibrosis, which resembled the features of human NASH. However, no significant differences were observed in NAFLD activity scores between E-CNP Tg mice and controls, although there was a tendency for improvement in E-CNP Tg mice. The reduced levels of GCB, a receptor for CNP, may have weakened the action of CNP in the current model. In the kidneys, HFFCD showed glomerular hypertrophy and tubular atrophy in the cortical region, which were suppressed in E-CNP Tg mice. The present study did not prove the therapeutic effect of CNP on NASH in the HFFCD model, but provided evidence of its potential beneficial effects on NASH-associated renal damage.