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Weidenbusch, Marc; Song, Shangqing; Iwakura, Takamasa; Shi, Chongxu; Rodler, Severin; Kobold, Sebastian; Mulay, Shrikant R.; Honarpisheh, Mohsen M.; Anders, Hans-Joachim
(2018):
IL-22 sustains epithelial integrity in progressive kidney remodeling and fibrosis.
In: Physiological Reports, Vol. 6, No. 16, e13817
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Abstract
IL-22, a member of the IL-10 cytokine family, accelerates tubule regeneration upon acute kidney injury, hence we speculated on a protective role also in chronic kidney disease. We quantified intrarenal IL-22 expression after unilateral ureteral (UUO) in wild-type mice and performed UUO in IL-22 knock-out animals. Obstruction phenotypic differences between IL22(+/+) and IL22(-/-) mice were assessed by histology, immunohistochemistry, immunofluorescence as well as western blotting and reverse-transcriptase quantitative PCR ex vivo. Additionally, we performed in vitro experiments using both murine and human tubular cells to characterize IL-22 effects in epithelial healing. We found increasing IL22 positivity in infiltrating immune cells over time upon UUO in wild-type mice. UUO in IL22(-/-) mice caused more tubular cell injury as defined by TUNEL positive cells and loss of tetragonolobus lectin staining. Instead, tubular dilation, loss of CD31+ perivascular capillaries, and interstitial fibrosis were independent of the Il22 genotype as assessed by standard histology, immunostaining, and mRNA expression profiling. In vitro experiments showed that recombinant human IL-22 significantly enhanced human tubular epithelial cell proliferation and wound closure upon mechanical injury, and electric cell-substrate impedance sensing studies revealed that recombinant IL-22 sustained tubular epithelial barrier function upon injury. In contrast, IL-22 had no such direct effects on human fibroblasts. Together, in progressive kidney remodeling upon UUO, infiltrating immune cells secrete IL-22, which augments tubular epithelial integrity and epithelial barrier function, but does not affect vascular rarefaction or fibrogenesis. We conclude that IL-22 could represent a molecular target to specifically modulate tubular atrophy.
