Xu Ming-Jiang, Feng Dechun, Wang Hua, Guan Youfei, Yan Xiaoqiang, Gao Bin
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
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland;
J Am Soc Nephrol. 2014 May;25(5):967-77. doi: 10.1681/ASN.2013060611. Epub 2014 Jan 23.
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.
白细胞介素-22（IL-22）是一种上皮细胞存活细胞因子，目前正处于治疗急性肝损伤的研发阶段。在此，我们使用肾缺血/再灌注（I/R）损伤的小鼠模型来研究IL-22是否具有治疗急性肾损伤（AKI）的潜力。IL-22的作用是通过与IL-22R1结合介导的，并导致信号转导和转录激活因子3（STAT3）活化。在生理条件下，仅在肾近端小管上皮细胞（RPTECs）的刷状缘检测到IL-22R1的肾表达。肾I/R使血清IL-22水平略有升高，但未诱导RPTECs中的STAT3磷酸化。与野生型小鼠相比，IL-22缺陷型小鼠的I/R诱导损伤略有增加。相反，用IL-22治疗或通过基因靶向（IL-22转基因小鼠）或给予表达IL-22的腺病毒使IL-22过表达，可增加RPTECs中的STAT3磷酸化，改善I/R诱导的肾炎症和肾小管细胞损伤，并保留肾功能。IL-22过表达增加了I/R小鼠肾脏中STAT3和蛋白激酶B（Akt）的磷酸化，上调了抗凋亡基因（如Bcl-2），并下调了促凋亡基因（如Bad）。值得注意的是，在这些条件下，近端小管细胞中Akt的磷酸化增加，Bad的表达降低。此外，与野生型小鼠相比，IL-22转基因小鼠的存活率增加，而IL-22缺陷型小鼠在I/R损伤后的存活率降低。总之，IL-22R1的肾表达仅限于RPTECs，用IL-22治疗可通过激活STAT3和Akt来保护免受肾I/R损伤，表明IL-22具有治疗AKI的潜力。
