Cell autonomous and non-autonomous effects of constitutive Yap1 activation in distal nephron segments

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 Yap1 is known to regulate renal development, its specific function in distal nephron segments remains poorly defined. To investigate Yap1 function in the distal nephron, we generated a Cre-inducible Yap1 gain-of-function allele (Col1a1-YAP5SA) and a distal nephron-specific Slc12a3-IRES-Cre to express constitutively active Yap1 in the distal nephron segments. Lineage tracing analysis showed that the Slc12a3Cre targets both DCT and CNT, suggesting that CNT cells arise from Slc12a3+ DCT cells. Constitutive activation of Yap1 in DCT and CNT results in increased proliferation and abnormal migration into adjacent nephron segments. This was accompanied by disrupted expression of DCT/CNT marker genes, loss of apicobasal polarity, and compromised junctional architecture. Unexpectedly, the mutant kidneys showed the downregulation of proximal tubule marker genes and Ren1 and the upregulation of inflammation and injury markers. These findings demonstrate that sustained Yap1 activation in the distal nephron segments impairs epithelial identity and structure, and also induces non–cell-autonomous effects in other nephron segments, particularly the proximal tubule. This highlights the importance of tightly regulated Hippo-Yap signaling in maintaining epithelial integrity and proper nephron segmentation.