Suppression of endoplasmic reticulum stress restores renal microarchitecture in a mouse model of simulated microgravity

Abstract

Background: Hindlimb-unloaded (HU) mice are animal models of simulated microgravity that exhibit pathological changes in several organs; however, relevant findings regarding the kidneys remain elusive. We investigated the possible contribution of protein dysregulation through endoplasmic reticulum (ER) stress to renal pathology in HU mice. Methods: We categorized male C57BL/6j mice into ground-based control and HU groups and treated them daily with a placebo or 4-phenylbutyrate (4PBA, an ER stress inhibitor), respectively, for 3 weeks. HU mice showed reduced body weight, whereas kidney weight remained unchanged. Results: Treatment with 4PBA increased the kidney weight of HU mice. The histopathological changes in HU mouse kidneys, including the widening of the Bowman's capsule and increased glomerular area, were reversed through 4PBA treatment, accompanied by a 4PBA-induced reduction in the expression of several ER stress markers. Particularly, we found a reduction in the splicing of the X-box binding protein, indicating reduced ER stress in 4PBA-treated HU mice. Thus, 4PBA may use additional mechanisms to suppress ER stress and prevent renal pathology in HU mice. Conclusion: Our findings are the first to suggest that HU causes disruption of renal microarchitecture and that 4PBA may be a potent drug for kidney restoration under HU. Our preliminary findings have translational potential for conditions that mimic HU, such as prolonged bed rest.