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

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.