Wnt4/β−Catenin Signaling in Medullary Kidney Myofibroblasts

Abstract

Injury to the adult kidney induces a number of developmental genes thought to regulate repair, including Wnt4. During kidney development, early nephron precursors and medullary stroma both express Wnt4, where it regulates epithelialization and controls smooth muscle fate, respectively. Expression patterns and roles for Wnt4 in the adult kidney, however, remain unclear. In this study, we used reporters, lineage analysis, and conditional knockout or activation of the Wnt/β-catenin pathway to investigate Wnt4 in the adult kidney. Proliferating, medullary, interstitial myofibroblasts strongly expressed Wnt4 during renal fibrosis, whereas tubule epithelia, except for the collecting duct, did not. Exogenous Wnt4 drove myofibroblast differentiation of a pericyte-like cell line, suggesting that Wnt4 might regulate pericyte-to-myofibroblast transition through autocrine signaling. However, conditional deletion of Wnt4 in interstitial cells did not reduce myofibroblast proliferation, cell number, or myofibroblast gene expression during fibrosis. Because the injured kidney expresses multiple Wnt ligands that might compensate for the absence of Wnt4, we generated a mouse model with constitutive activation of canonical Wnt/β-catenin signaling in interstitial pericytes and fibroblasts. Kidneys from these mice exhibited spontaneous myofibroblast differentiation in the absence of injury. Taken together, Wnt4 expression in renal fibrosis defines a population of proliferating medullary myofibroblasts. Although Wnt4 may be dispensable for myofibroblast transformation, canonical Wnt signaling through β-catenin stabilization is sufficient to drive spontaneous myofibroblast differentiation in interstitial pericytes and fibroblasts, emphasizing the importance of this pathway in renal fibrosis.