Paracrine Wnt1 Drives Interstitial Fibrosis without Inflammation by
Tubulointerstitial Cross-Talk.
Authors Maarouf OH, Aravamudhan A, Rangarajan D, Kusaba T, Zhang V, Welborn J, Gauvin D,
Hou X, Kramann R, Humphreys BD
Submitted By Benjamin Humphreys on 7/2/2016
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2016
Date Published
Volume : Pages 27 : 781 - 90
PubMed Reference 26204899
Abstract AKI with incomplete epithelial repair is a major contributor to CKD
characterized by tubulointerstitial fibrosis. Injury-induced epithelial
secretion of profibrotic factors is hypothesized to underlie this link, but the
identity of these factors and whether epithelial injury is required remain
undefined. We previously 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 TGFß-dependent myofibroblast activation in vitro.
To investigate whether Wnt ligand derived from proximal tubule is sufficient for
renal fibrogenesis, we generated a novel mouse strain with inducible proximal
tubule Wnt1 secretion. Adult mice 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 receptor ß-positive myofibroblasts isolated from
these kidneys exhibited increased canonical Wnt 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-derived Wnt
ligand is sufficient to drive interstitial fibrosis provides strong support for
the maladaptive repair hypothesis in the AKI to CKD transition.


Investigators with authorship
NameInstitution
Benjamin HumphreysWashington University in St Louis

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