Paracrine wnt1 drives interstitial fibrosis without inflammation by tubulointerstitial cross-talk

Omar H. Maarouf, Anusha Aravamudhan, Deepika Rangarajan, Tetsuro Kusaba, Victor Zhang, Jeremy Welborn, Daniel Gauvin, Xiuyun Hou, Rafael Kramann, Benjamin D. Humphreys

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

AKIwith incomplete epithelial repair is a major contributor to CKD characterized by tubulointerstitial fibrosis. Injury-inducedepithelial secretion of profibrotic factors is hypothesizedtounderlie this link,but the identity of these factors andwhether epithelial injury is required remain undefined.Wepreviously showed that activation of the canonical Wnt signaling pathway in interstitial pericytes cell autonomously drives myofibroblast activation in vivo. Here, we show that inhibition of canonical Wnt signaling also substantially prevented TGFb-dependentmyofibroblast activation in vitro. To investigate whetherWnt ligand derived fromproximal tubule is sufficient for renal fibrogenesis, we generated a novel mouse strain with inducible proximal tubule Wnt1 secretion. Adultmice were treated with vehicle or tamoxifen and euthanized at 12 or 24 weeks postinjection. Compared with vehicle-treated controls, kidneys with tamoxifen-induced Wnt1 expression from proximal tubules displayed interstitial myofibroblast activation and proliferation and increased matrix protein production. PDGF receptorb-positivemyofibroblasts isolatedfromthese kidneys exhibited increased canonicalWnt target gene expression compared with controls. Notably, fibrotic kidneys had no evidence of inflammatory cytokine expression, leukocyte infiltration, or epithelial injury, despite the close histologic correlation of each with CKD. These results provide the first example of noninflammatory renal fibrosis. The fact that epithelial-derivedWnt ligand is sufficient to drive interstitial fibrosis provides strong support for themaladaptive repair hypothesis in the AKI to CKD transition.

Original languageEnglish
Pages (from-to)781-790
Number of pages10
JournalJournal of the American Society of Nephrology
Volume27
Issue number3
DOIs
StatePublished - Mar 2016

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