IL-22 promotes acute kidney injury through activation of the DNA damage response and cell death in proximal tubule cells

Abstract

Acute kidney injury (AKI) affects over 13 million people world-wide annually and is associated with a fourfold increase in mortality. Our lab and others have shown that DNA damage response (DDR) governs the outcome of AKI in a bimodal manner. Activation of DDR sensor kinases protects against AKI, while hyperactivation of DDR effector proteins, such as p53, induces to cell death and worsens AKI. The factors that trigger the switch from pro-reparative to pro-cell death DDR remain to be resolved. Here we investigate the role of interleukin 22 (IL-22), an IL-10 family member whose receptor (IL-22RA1) is expressed on proximal tubule cells (PTCs), in DDR activation and AKI. Using cisplatin and aristolochic acid (AA) induced nephropathy as models of DNA damage, we identify PTCs as a novel source of urinary IL-22, making PTCs the only epithelial cells known to secret IL-22, to our knowledge. Functionally, IL-22 binding its receptor (IL-22RA1) on PTCs amplifies the DDR. Treating primary PTCs with IL-22 alone induces rapid activation of the DDR in vitro. The combination of IL-22 + cisplatin or AA treatment on primary PTCs induces cell death, while the same dose of cisplatin or AA alone does not. Global deletion of IL-22 protects against cisplatin or AA induced AKI. IL-22 deletion reduces expression of components of the DDR and inhibits PTC cell death. To confirm PTC IL-22 signaling contributes to AKI, we knocked out IL-22RA1 in renal epithelial cells by crossing IL-22RA1floxed mice with Six2-Cre mice. IL-22RA1 KO reduced DDR activation, cell death, and kidney injury. These data demonstrate that IL-22 promotes DDR activation in PTCs, switching pro-recovery DDR responses to a pro-cell death response and worsening AKI. Targeting IL-22 represents a novel therapeutic approach to prevent the negative consequences of the DDR activation while not interfering with the processes necessary for repair of damaged DNA. Translational statementAcute kidney injury, which affects 10-20% of hospitalized patients, is associated with a fourfold increase in mortality and predisposes patients to chronic kidney disease. In the present study, we identify interleukin 22 as a cofactor which worsens acute kidney injury. Interleukin 22 activates the DNA damage response, which in combination with nephrotoxic drugs amplifies the injury response in kidney epithelial cells and increases cell death. Deletion of interleukin 22 from mice or its receptor from mouse kidneys ameliorates cisplatin induced nephropathy. These findings may help clarify the molecular mechanisms of DNA damage induced kidney injury and identify interventions that can help treat acute kidney injury.