ERMP1 as a newly identified endoplasmic reticulum stress gatekeeper in chronic kidney disease.

Abstract

Endoplasmic reticulum metallopeptidase 1 (ERMP1) is involved in the unfolded protein response (UPR) pathway in response to the endoplasmic reticulum (ER) stress. Given the pivotal role of ER stress in the pathogenesis of acute and chronic kidney diseases, we hypothesized that ERMP1 could be instrumental in the development of renal injury. In silico analysis of RNA sequencing datasets from renal biopsies were exploited to assess the expression of ERMP1 in the kidney under normal or pathological conditions. CRISPR-Cas9-mediated heterozygous genetic ablation of the exon 1 of Ermp1 was performed in vivo, followed by histological analysis and assessment of renal injury and ER stress markers in the newly generated Ermp1 knockout mouse model. In addition, knockdown and overexpression of ERMP1 were conducted in human tubular cells to investigate cell viability, metabolism, the UPR pathway, and ER Ca²⁺ release under these conditions. Our findings from patient datasets showed that ERMP1 is expressed in all renal cell types and is upregulated in chronic kidney disease. Further in silico investigations suggest a role for ERMP1 in renal development. ERMP1 knockout in mice revealed that homozygous loss of ERMP1 expression is lethal, whereas heterozygous loss exacerbated age-related chronic kidney alteration. In human tubular cells, ERMP1 knockdown decreased viability and metabolic rate, whereas overexpression conferred protection against ER stress. These results highlight the importance of ERMP1 in renal physiology and pathology and suggest that its upregulation could be a protective mechanism against excessive ER stress in renal tubule epithelial cells.NEW & NOTEWORTHY Our study reveals an increase in ERMP1 expression in acute and chronic kidney diseases, potentially serving as a protective mechanism against excessive ER stress. Conversely, a decline in ERMP1 expression in the kidney exacerbates age-related chronic kidney disease. Overall, the study enhances our understanding of the role of ERMP1 in kidney pathophysiology, paving the way for future research and therapeutic developments aimed at improving outcomes for patients with kidney diseases.