Constitutive Yap activation in distal nephron segments disrupts epithelial identity and nephron patterning.

Background: The distal convoluted tubule (DCT) and connecting tubule (CNT) are critical for fine-tuning electrolyte reabsorption and maintaining renal homeostasis. While the Hippo pathway effector Yap is known to regulate kidney development, its specific role within the distal nephron segments remains unknown. Methods: To investigate Yap function in the distal nephron segments, we generated a Cre-inducible Yap gain-of-function allele (Col1a1-Yap5SA) and a distal nephron-specific Slc12a3Cre to drive an active form of Yap in the distal nephron segments. We performed phenotypic assessments along with molecular and transcriptomic analyses to examine changes in epithelial organization and nephron segmentation. Results: Lineage tracing showed that Slc12a3Cre targets both DCT and CNT, suggesting that CNT cells arise from Slc12a3+ DCT cells. Constitutive Yap activation in these segments caused increased proliferation and ectopic cell migration into adjacent nephron segments. This was accompanied by disrupted expression of DCT/CNT marker genes, loss of apicobasal polarity, and compromised junctional architecture, indicating epithelial-to-mesenchymal transition. Notably, mutant kidneys also exhibited downregulation of proximal tubule markers, indicating a non-cell-autonomous effect. Conclusions: Our findings demonstrate that sustained Yap activation in the distal nephron segments disrupts epithelial identity and structure while also exerting non-cell-autonomous effects on nephron patterning, particularly in the proximal tubule. These results underscore the importance of tightly regulated Hippo-Yap signaling in maintaining epithelial integrity and proper nephron segmentation.