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Loss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease

Hui Sun, Hui Li, Jie Yan, Xiangdong Wang, Mengyuan Xu, Mingxia Wang, Baozhen Fan, Jieying Liu, Ninghua Lin, Xin Wang, Li Li, Shengtian Zhao () and Yongfeng Gong ()
Additional contact information
Hui Sun: Binzhou Medical University
Hui Li: West China Hospital, Sichuan University
Jie Yan: Binzhou Medical University
Xiangdong Wang: Binzhou Medical University
Mengyuan Xu: Binzhou Medical University
Mingxia Wang: Binzhou Medical University
Baozhen Fan: Binzhou Medical University
Jieying Liu: Binzhou Medical University
Ninghua Lin: Binzhou Medical University
Xin Wang: Qingdao University
Li Li: Binzhou Medical University
Shengtian Zhao: Binzhou Medical University Hospital
Yongfeng Gong: Binzhou Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Although mature podocytes lack tight junctions, tight junction integral membrane protein claudin-5 (CLDN5) is predominantly expressed on plasma membranes of podocytes under normal conditions. Using podocyte-specific Cldn5 knockout mice, we identify CLDN5 as a crucial regulator of podocyte function and reveal that Cldn5 deletion exacerbates podocyte injury and proteinuria in a diabetic nephropathy mouse model. Mechanistically, CLDN5 deletion reduces ZO1 expression and induces nuclear translocation of ZONAB, followed by transcriptional downregulation of WNT inhibitory factor-1 (WIF1) expression, which leads to activation of WNT signaling pathway. Podocyte-derived WIF1 also plays paracrine roles in tubular epithelial cells, as evidenced by the finding that animals with podocyte-specific deletion of Cldn5 or Wif1 have worse kidney fibrosis after unilateral ureteral obstruction than littermate controls. Systemic delivery of WIF1 suppresses the progression of diabetic nephropathy and ureteral obstruction-induced renal fibrosis. These findings establish a function for podocyte CLDN5 in restricting WNT signaling in kidney.

Date: 2022
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DOI: 10.1038/s41467-022-29277-6

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