Tubular β-catenin and FoxO3 interactions protect in chronic kidney disease

Abstract

The Wnt/beta-catenin signaling pathway plays an important role in renal development and is re-expressed in the injured kidney and other organs. Beta-catenin signaling is protective in acute kidney injury (AKI) through actions on the proximal tubule, but the current dogma is that Wnt/beta-catenin signaling promotes fibrosis and development of chronic kidney disease (CKD). As the role of proximal tubular beta-catenin signaling in CKD remains unclear, we genetically stabilized (i.e. activated) beta-catenin specifically in murine proximal tubules. Mice with increased tubular beta-catenin signaling were protected in two different murine models of AKI to CKD progression. Oxidative stress, a common feature of CKD, reduced the conventional TCF/LEF-dependent beta-catenin signaling and augmented FoxO3-dependent activity in proximal tubule cells in vitro and in vivo. The protective effect of proximal tubular beta-catenin in renal injury required the presence of FoxO3 in vivo. Furthermore, we identified cystathionine gamma-lyase (CSE) as a novel transcriptional target of beta-catenin/FoxO3 interactions in the proximal tubule. Thus, our studies overturn the conventional dogma about beta-catenin signaling and CKD by showing a protective effect of proximal tubule beta-catenin in CKD and identified a new transcriptional target of beta-catenin/FoxO3 signaling that has therapeutic potential for CKD.