Loss of Erbin in tubular epithelial cells sensitizes mice to acute kidney injury and aggravates renal fibrosis

Abstract

Aging is a major contributor to the increasing incidence of acute kidney injury (AKI) and chronic kidney disease (CKD), however the molecular events explaining aging-related nephropathies remains elusive. Here, we found that the RAS signaling adapter protein Erbin (ErbB2-interacting protein) is abundantly expressed in renal tubular cells, but its levels are decreased in murine AKI models and human CKD patient samples. Tubule-specific deletion of Erbin rendered mice highly susceptible to acute kidney injury, and exacerbated renal fibrosis. In contrast, restoring Erbin protected against AKI and CKD. Moreover, tubular Erbin loss in the naturally-aged kidney aggravates aging-associated nephropathies. Transcriptome sequencing revealed a causal association between Erbin loss and cell-cycle alterations in tubular epithelial cells. Depleting Erbin increased the proportion of tubular cells in G2/M phase and accelerated cellular senescence in vitro and in vivo. Mechanistically, Erbin protects tubular cells from senescence by stabilizing YB-1, which maintains CDK1 and cyclin B1 expression, and facilitates cell-cycle progression. Thus, restoring Erbin represents a potential strategy for chronic kidney disease and aging nephropathies. The molecular events initiating aging-related nephropathies such as acute kidney injury (AKI) and chronic kidney disease (CKD) remain elusive. This study shows that loss of ErbB2-interacting protein (Erbin) triggers senescence in renal tubule cells by destabilizing YB-1 and impairing cell-cycle progression. Erbin is predominately expressed in the tubular epithelial cells and is decreased during the progression of AKI, CKD, and kidney aging. Tubule-specific deletion of Erbin sensitizes mice to AKI, exacerbates renal fibrosis, and accelerates kidney aging. Loss of Erbin increases the proportion of G2/M-phase cells and leads to cellular senescence in tubular epithelial cells. Erbin protects tubular cells from senescence by stabilising cell-cycle regulator YB-1. Erbin is predominately expressed in the tubular epithelial cells and is decreased during the progression of AKI, CKD, and kidney aging. Tubule-specific deletion of Erbin sensitizes mice to AKI, exacerbates renal fibrosis, and accelerates kidney aging. Loss of Erbin increases the proportion of G2/M-phase cells and leads to cellular senescence in tubular epithelial cells. Erbin protects tubular cells from senescence by stabilising cell-cycle regulator YB-1. ErbB2-interacting protein Erbin protects from senescence and fibrosis during renal aging by stabilizing YB-1 and ensuring cell cycle progression.