IL-22 ameliorates renal ischemia-reperfusion injury by targeting proximal tubule epithelium.

Abstract

IL-22 is an epithelial cell survival cytokine that is currently under development for the treatment of acute liver damage. Here, we used a mouse model of renal ischemia/reperfusion (I/R) injury to investigate whether IL-22 has therapeutic potential for the treatment of AKI. The action of IL-22 is mediated by binding to IL-22R1 and leads to STAT3 activation. Under physiologic conditions, renal expression of IL-22R1 was detected only in the brush border of the renal proximal tubular epithelial cells (RPTECs). Renal I/R elevated serum IL-22 levels slightly but did not induce STAT3 phosphorylation in RPTECs. IL-22-deficient mice had slightly increased I/R-induced injury compared with wild-type mice. In contrast, treatment with IL-22 or overexpression of IL-22 by either gene targeting (IL-22 transgenic mice) or administration of adenovirus expressing IL-22 increased STAT3 phosphorylation in RPTECs, ameliorated I/R-induced renal inflammation and tubular cell injury, and preserved renal functions. Overexpression of IL-22 increased the phosphorylation of STAT3 and Akt, upregulated antiapoptotic genes (e.g., Bcl-2), and downregulated proapoptotic genes (e.g., Bad) in the kidneys of mice subjected to I/R. Notably, phosphorylation of Akt increased and expression of Bad decreased in proximal tubular cells under these conditions. Furthermore, compared with wild-type mice, IL-22 transgenic mice had increased survival rates, whereas IL-22-deficient mice had reduced survival rates after I/R injury. In summary, renal expression of IL-22R1 is restricted to RPTECs, and treatment with IL-22 protects against renal I/R injury by activating STAT3 and AKT, suggesting that IL-22 has therapeutic potential for the treatment of AKI.