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

• Published in: Nature communications 2022-03, Vol.13 (1), p.1600-1600, Article 1600
• Main Authors: Sun, Hui, Li, Hui, Yan, Jie, Wang, Xiangdong, Xu, Mengyuan, Wang, Mingxia, Fan, Baozhen, Liu, Jieying, Lin, Ninghua, Wang, Xin, Li, Li, Zhao, Shengtian, Gong, Yongfeng
• Format: Article
• Language: English
• Subjects: 14; 38; 42; 49; 49/91; 631/443/272; 631/80/79/1987; 64/60; 692/4022/1585/3182; 82/51; 96/34; 96/44; 96/95; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Claudin-5 - metabolism; Deletion; Deregulation; Diabetes; Diabetes mellitus; Diabetic Nephropathies - pathology; Diabetic nephropathy; Epithelial cells; Epithelium; Fibrosis; Humanities and Social Sciences; Kidney diseases; Kidneys; Membrane proteins; Membranes; Mice; multidisciplinary; Nephropathy; Nuclear transport; Paracrine signalling; Plasma membranes; Podocytes - metabolism; Proteins; Proteinuria; Science; Science (multidisciplinary); Signal transduction; Signaling; Tight junctions; Transcription; Translocation; Ureteral Obstruction - metabolism; Wnt protein; Wnt Signaling Pathway
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29277-6

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. Claudin-5 is a tight junction integral membrane protein, but it is also expressed in mature podocytes which lack tight junctions. Here the authors report that podocyte claudin-5 regulates WNT signaling activity by modulating WIF1 expression, and its downregulation contributes to kidney disease progression in mice.