Crosstalk of injured podocytes with parietal epithelial cells through Wnt4/β-Catenin signaling.

Focal segmental glomerular sclerosis (FSGS) is considered an irreversible lesion in kidney disease. Here, we investigated the role of the wnt4/β-Catenin signaling pathway in FSGS lesion formation and the crosstalk between PECs and podocytes in a transgenic FSGS rat model and human primary FSGS to explore potential sex-specific differences and therapeutic options. After model induction in rats, we observed strong podocytes loss on day 7, which was significantly higher in male than in female rats. Starting at d14, both glomerular mRNA and protein expression of Wnt4 were increased, but more pronounced in males. Wnt4 was localized to podocytes and β-Catenin to Pax8-positive lesions. The Wnt4 target gene CD44 was strongly upregulated on d7 and increased until the end of the experiment (d42). In cell culture, we confirmed that injured podocytes expressed and secreted Wnt4, which stimulated the expression of the Wnt target gene Axin2 in PECs but not in podocytes. Wnt4/β-Catenin pathway activation was confirmed in human biopsies with podocytopathic FSGS. In conclusion, the canonical Wnt/β-Catenin axis plays a critical role in the crosstalk between PECs and injured podocytes. Furthermore, sex-specific differences in podocyte injury and regeneration appear to be, at least in part, Wnt4-mediated.