CNP gene expression is activated by Wnt signaling and correlates with Wnt4 expression during renal injury.
C-type natriuretic peptide (CNP) regulates salt excretion, vascular tone, and fibroblast proliferation and activation. CNP inhibits fibroblast activation in vitro and fibrosis in vivo, but endogenous CNP gene (Nppc) expression during tissue fibrosis has not been reported. We determined that Nppc is induced in renal tubular epithelia and then in interstitial myofibroblasts after unilateral ureteral obstruction (UUO). Induction of Nppc occurred in identical cell populations to those in which Wnt4 is induced after renal injury. In addition, Nppc was activated in Wnt4-expressing cells during nephrogenesis. Wnt signaling components beta-catenin and T cell factor/lymphoid enhancer binding factor (TCF/LEF) specifically bound to cognate elements in the Nppc proximal promoter. Wnt-4, beta-catenin, and LEF-1 activated an Nppc transgene in cultured cells, and transgene activation by Wnt-4 and LEF-1 was dependent on the presence of intact cognate elements. These findings suggest that Wnt-4 stimulates Nppc in a TCF/LEF-dependent manner after renal injury and thus may contribute to limiting renal fibrosis.
Surendran
Kameswaran
K
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Simon
Theodore C
TC
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D007668:Kidney / Q000196:embryology / Q000503:physiopathology*; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D020098:Natriuretic Peptide, C-Type / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014517:Ureteral Obstruction / Q000503:physiopathology*; D051153:Wnt Proteins; D060528:Wnt4 Protein; D029961:Zebrafish Proteins
D004268:DNA-Binding Proteins; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D029961:Zebrafish Proteins; D020098:Natriuretic Peptide, C-Type