Cellular senescence and its association with aldose reductase promote cyst growth in autosomal dominant polycystic kidney disease.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, life threatening inherited kidney diseases. In the kidney, senescence is accumulated in different renal cells, which are in a state of permanent cell cycle arrest and the development of a senescence-associated secretory phenotype (SASP) in response to stresses. However, the role of cellular senescence in ADPKD remains elusive. Here, using different senescence markers, senolytic drugs, and transgenic INK-ATTAC mice, we define the role of senescence in ADPKD. Additionally, we identify SASP senescence-associated secretory phenotype by using our single-cell RNA sequencing database to monitor differential gene expressions in mutant and control mouse kidneys. Senescence is increased in Pkd1 mutant mice and human ADPKD kidneys. Treatment with D-galactose, an inducer of senescence, promotes cyst progression, whereas treatment with senolytic drugs, including dasatinib (D), quercetin (Q), and D plus Q, delays disease progression in Pkd1 mutant kidneys. Clearance of p16^Ink4a-positive senescent cells delayed cyst growth in Pkd1^RC/RC:INK-ATTAC mice, supporting a direct role of those cells in promoting cystogenesis in ADPKD. The secretion of SASP from senescent Pkd1 mutant cells induces senescence in neighboring cells and increases kidney epithelial cell proliferation and the activation of fibroblasts. We identify AKR1B1 (aldose reductase) as one of the Pkd1 gene mutation-associated SASP factors. Targeting AKR1B1 with its non-competitive and reversible inhibitor epalrestat delayed cyst growth in Pkd1 mutant mouse kidneys. Our study supports the idea that senescence-targeting interventions including senolytics, removal of p16-positive senescent cells, and inhibition of AKR1B1 are promising therapeutic strategies to delay cyst growth in ADPKD.