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 IL‐22 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.
Highlights
Acute kidney injury (AKI) and its long-term consequence, chronic kidney disease (CKD), are increasing global health concerns (Levin et al 2017; Romagnani et al 2017)
Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society
Lipocalin (NGAL), insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase 2 (TIMP2) were increased in Il22À/À compared to Il22+/+ mice both on day 5 and day 10 after ureteral obstruction (UUO) (Fig. 3A), while we could not detect any significant differences in the expression of fibrotic markers such as COL1A1, transgelin or SSeCKs between Il22À/À and Il22+/+ mice (Fig. 3B)
Summary
Acute kidney injury (AKI) and its long-term consequence, chronic kidney disease (CKD), are increasing global health concerns (Levin et al 2017; Romagnani et al 2017). IL-22 in UUO of initial injurious triggers (ischemic, toxic, inflammatory, obstructive injury, etc.), most of these processes lead to inflammation and cell death, a phenomenon dubbed “necroinflammation”. This leads to progressive nephron loss and renal scaring/fibrosis, as tubular cells are replaced by mesenchymal tissue. We hypothesized that intrarenal leukocyte-derived IL22 would augment tubule integrity in progressive obstructive nephropathy To test this concept, we employed a series of in vitro and in vivo studies including UUO surgeries in Il22-deficient mice and experiments with recombinant IL-22 and human or murine renal parenchymal cells
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