Tubule-Derived Wnts Are Required for Fibroblast Activation and Kidney Fibrosis.
Cell-cell communicationviaWnt ligands is necessary in regulating embryonic development and has been implicated in CKD. Because Wnt ligands are ubiquitously expressed, the exact cellular source of the Wnts involved in CKD remains undefined. To address this issue, we generated two conditional knockout mouse lines in which Wntless (Wls), a dedicated cargo receptor that is obligatory for Wnt secretion, was selectively ablated in tubular epithelial cells or interstitial fibroblasts. Blockade of Wnt secretion by genetic deletion of Wls in renal tubules markedly inhibited myofibroblast activation and reduced renal fibrosis after unilateral ureteral obstruction. This effect associated with decreased activation ofβ-catenin and downstream gene expression and preserved tubular epithelial integrity. In contrast, fibroblast-specific deletion of Wls exhibited little effect on the severity of renal fibrosis after obstructive or ischemia-reperfusion injury.In vitro, incubation of normal rat kidney fibroblasts with tubule-derived Wnts promoted fibroblast proliferation and activation. Furthermore, compared with kidney specimens from patients without CKD, biopsy specimens from patients with CKD also displayed increased expression of multiple Wnt proteins, predominantly in renal tubular epithelium. These results illustrate that tubule-derived Wnts have an essential role in promoting fibroblast activation and kidney fibrosisviaepithelial-mesenchymal communication.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Dong
D
Zhou
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Haiyan
H
Fu
Division of Nephrology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
Lu
L
Zhang
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Ke
K
Zhang
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Yali
Y
Min
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Liangxiang
L
Xiao
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Lin
L
Lin
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Sheldon I
SI
Bastacky
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; liuy@upmc.edu.|State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
Youhua
Y
Liu
D000818:Animals; D002450:Cell Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D005355:Fibrosis / Q000209:etiology; D006801:Humans; D007668:Kidney / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D051153:Wnt Proteins / Q000096:biosynthesis / Q000502:physiology*; D060449:Wnt Signaling Pathway
D051153:Wnt Proteins
Wnt signaling; Wntless; chronic kidney disease; fibroblast; renal fibrosis