Retinoic acid and sodium butyrate attenuate renal fibrosis and inflammation in guanylyl cyclase‐A/natriuretic peptide receptor‐A gene‐targeted mice (796.13)

Abstract

Mice lacking functional guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA) gene (Npr1) exhibit hypertension, kidney disease, and heart failure. The objective of the present study was to elucidate the effect of all‐trans retinoic acid (ATRA) and histone deacetylase inhibitor, sodium butyrate (NaBu) on attenuation of renal fibrosis and remodeling in Npr1 gene‐targeted mutant mice. Mice (24‐week old) were injected intraperitonealy with ATRA (0.5 mg/Kg/day), NaBu (0.5 mg/Kg/day), and ATRA‐NaBu (1.0 mg/Kg/day) for 2‐week. The results showed that Npr1 gene‐disrupted heterozygous (1‐copy; +/‐) mice exhibited renal fibrosis and augmented levels of proinflammatory cytokines compared with wild‐type (2‐copy; +/+) and gene‐duplicated heterozygous (3‐copy; ++/+) mice. Retinoic acid and NaBu treatment significantly lowered systolic blood pressure in 1‐copy mice and increased plasma cGMP levels in Npr1 gene dose‐dependent manner with pronounced effects in 1‐copy mice. Treatment with ATRA‐NaBu combination synergistically attenuated renal fibrosis by 70%, immunoexpression of renal α‐SMA by 75%, and plasma and renal levels of proinflammatory cytokines TNF‐α and IL‐6 in 1‐copy mice compared with vehicle‐treated control mice. The present results provide direct evidence that ATRA and NaBu act as potent immunosuppressive and antifibrotic agents and repair the abnormal renal pathology in mice with reduced Npr1 gene copy number, which will have important implications in prevention of hypertension‐related renal pathophysiological conditions.