Tubular ?-catenin and FoxO3 interactions protect in chronic kidney disease.

ABSTRACT: The Wnt/?-catenin signaling pathway plays an important role in renal development and is reexpressed in the injured kidney and other organs. ?-Catenin signaling is protective in acute kidney injury (AKI) through actions on the proximal tubule, but the current dogma is that Wnt/?-catenin signaling promotes fibrosis and development of chronic kidney disease (CKD). As the role of proximal tubular ?-catenin signaling in CKD remains unclear, we genetically stabilized (i.e., activated) ?-catenin specifically in murine proximal tubules. Mice with increased tubular ?-catenin signaling were protected in 2 murine models of AKI to CKD progression. Oxidative stress, a common feature of CKD, reduced the conventional T cell factor/lymphoid enhancer factor-dependent ?-catenin signaling and augmented FoxO3-dependent activity in proximal tubule cells in vitro and in vivo. The protective effect of proximal tubular ?-catenin in renal injury required the presence of FoxO3 in vivo. Furthermore, we identified cystathionine ?-lyase as a potentially novel transcriptional target of ?-catenin/FoxO3 interactions in the proximal tubule. Thus, our studies overturned the conventional dogma about ?-catenin signaling and CKD by showing a protective effect of proximal tubule ?-catenin in CKD and identified a potentially new transcriptional target of ?-catenin/FoxO3 signaling that has therapeutic potential for CKD.

SUBMITTER: Nlandu-Khodo S 

PROVIDER: S-EPMC7259539 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature