title: Paracrine Wnt1 Drives Interstitial Fibrosis without Inflammation by Tubulointerstitial Cross-Talk.
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 TGFβ-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 β-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.
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts;
authors.forename: Omar H
authors.initials: OH
authors.lastname: Maarouf
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Anusha
authors.initials: A
authors.lastname: Aravamudhan
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Deepika
authors.initials: D
authors.lastname: Rangarajan
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kusaba
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Victor
authors.initials: V
authors.lastname: Zhang
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Welborn
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Daniel
authors.initials: D
authors.lastname: Gauvin
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Xiuyun
authors.initials: X
authors.lastname: Hou
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Division of Nephrology and Clinical Immunology and Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany; and.
authors.forename: Rafael
authors.initials: R
authors.lastname: Kramann
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts bhumphre@dom.wustl.edu.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Humphreys
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D007249:Inflammation / Q000150:complications; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology*; D008024:Ligands; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism* / Q000502:physiology; D019899:Paracrine Communication; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D018931:Antineoplastic Agents, Hormonal; D005353:Fibronectins; D008024:Ligands; D016212:Transforming Growth Factor beta; D051155:Wnt1 Protein; C544013:alpha-smooth muscle actin, mouse; D013629:Tamoxifen; D020797:Receptor, Platelet-Derived Growth Factor beta