title: (Pro)renin Receptor Is an Amplifier of Wnt/β-Catenin Signaling in Kidney Injury and Fibrosis.
abstract: The (pro)renin receptor (PRR) is a transmembrane protein with multiple functions. However, its regulation and role in the pathogenesis of CKD remain poorly defined. Here, we report that PRR is a downstream target and an essential component of Wnt/β-catenin signaling. In mouse models, induction of CKD by ischemia-reperfusion injury (IRI), adriamycin, or angiotensin II infusion upregulated PRR expression in kidney tubular epithelium. Immunohistochemical staining of kidney biopsy specimens also revealed induction of renal PRR in human CKD. Overexpression of either Wnt1 orβ-catenin induced PRR mRNA and protein expressionin vitroNotably, forced expression of PRR potentiated Wnt1-mediatedβ-catenin activation and augmented the expression of downstream targets such as fibronectin, plasminogen activator inhibitor 1, andα-smooth muscle actin (α-SMA). Conversely, knockdown of PRR by siRNA abolishedβ-catenin activation. PRR potentiation of Wnt/β-catenin signaling did not require renin, but required vacuolar H+ATPase activity. In the mouse model of IRI, transfection with PRR or Wnt1 expression vectors promotedβ-catenin activation, aggravated kidney dysfunction, and worsened renal inflammation and fibrotic lesions. Coexpression of PRR and Wnt1 had a synergistic effect. In contrast, knockdown of PRR expression ameliorated kidney injury and fibrosis after IRI. These results indicate that PRR is both a downstream target and a crucial element in Wnt signal transmission. We conclude that PRR can promote kidney injury and fibrosis by amplifying Wnt/β-catenin signaling.
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Miao
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
authors.forename: Xue
authors.initials: X
authors.lastname: Hong
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China; and liuy@upmc.edu.|Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis / Q000209:etiology; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011956:Receptors, Cell Surface / Q000502:physiology*; D051436:Renal Insufficiency, Chronic / Q000209:etiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000093342:Prorenin Receptor
chemical_list: D011956:Receptors, Cell Surface; D000093342:Prorenin Receptor
keywords: (pro)renin receptor; Wnt; betacatenin; chronic kidney disease; ischemia-reperfusion; renal fibrosis