IL-22 ameliorates renal ischemia-reperfusion injury by targeting proximal tubule epithelium.
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.
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China; and mingjiangxu@bjmu.edu.cn bgao@mail.nih.gov.
Ming-Jiang
MJ
Xu
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland;
Dechun
D
Feng
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland;
Hua
H
Wang
Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China; and.
Youfei
Y
Guan
Generon Corporation, Shanghai, China.
Xiaoqiang
X
Yan
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; mingjiangxu@bjmu.edu.cn bgao@mail.nih.gov.
Bin
B
Gao
D058186:Acute Kidney Injury / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D018390:Gene Targeting; D007378:Interleukins / Q000172:deficiency* / Q000494:pharmacology / Q000627:therapeutic use*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000502:physiology; D011994:Recombinant Proteins / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000235:genetics / Q000517:prevention & control*; D050796:STAT3 Transcription Factor / Q000097:blood / Q000235:genetics; D019459:Urothelium / Q000502:physiology*; D000097043:Interleukin-22
D007378:Interleukins; D051057:Proto-Oncogene Proteins c-akt; D018123:Receptors, Interleukin; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C494087:Stat3 protein, mouse; C415369:interleukin-22 receptor