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

The hindlimb unloaded (HU) mouse, an animal model of prolonged bedrest and spaceflight, exhibits detriment of several body organs. However, relevant effects on renal tissues are unknown. We investigated the effects of protein dysregulation by endoplasmic reticulum (ER), termed ER stress to renal histology and molecular phenotype in HU mice. We categorized c57BL/6j mice into ground-based controls, (GC), and HU mice treated with vehicle (HU) or 4-phenyl butyrate (4PBA), an ER stress inhibitor for three weeks. We found an HU-induced glomerular widening and an obliteration of Bowman’s space, which were partly reversed by 4PBA (all p<0.05). The GO enrichment analysis validated the heightened ER stress in HU kidneys and its reversal with 4PBA treatment. The transcriptome analysis, including the differentially expressed genes analysis revealed a significant reversal of genetic perturbation by 4PBA and mitigation of microgravity-induced renal decline. These findings were supported by KEGG-based and Reactome-based pathway analysis. 4PBA treatment upregulated the PPAR signaling pathway, which provides protection against ER stress. Enrichment analysis based on Reactome database also reveals that 4PBA activated the detoxification of reactive oxygen species. Collectively, our novel findings show a role for elevated ER stress in HU-induced renal injury. We also propose 4PBA as a potential therapeutic to restore renal structure and function in microgravity conditions.