Inhibition of endoplasmic reticulum stress prevents renal pathology in hindlimb unloaded mice

Abstract

Hindlimb unloaded (HU) mouse, an animal model of prolonged bed rest and spaceflight, exhibits extensive damage to several body organs. However, relevant effects on renal tissues are unknown. In this work effects of protein dysregulation by endoplasmic reticulum (ER), termed ER stress to renal histology and molecular phenotype in HU mice has been investigated. Role of 4-phenyl butyrate (4PBA) in reversal of these detrimental effects was also evaluated. c57BL/6j mice was categorized into three cohorts-ground-based controls, (GC),treated with vehicle (HU) , treated with 4PBA. It was observed that an HU-induced glomerular widening and an obliteration of Bowman’s space takes place in HU mice, which were partly reversed by 4PBA. The effect of protein dysregulation by endoplasmic reticulum in HU mice and its reversal was evaluated at transcriptome level using RNA-Seq analysis using an illumina next generation sequencing platform. Downstream analysis of mapped transcriptome provides support to the hypothesis that PBA has the potential to reverse renal stress in HU mice. The GO enrichment analysis validated heightened ER stress in HU kidneys and its reversal with 4PBA treatment. These findings were supported by KEGG-based and Reactome-based pathway analysis. 4PBA treatment upregulated PPAR signaling pathway, which protects against ER stress.