Surendran Kameswaran, Simon Theodore C
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Am J Physiol Renal Physiol. 2003 Apr;284(4):F653-62. doi: 10.1152/ajprenal.00343.2002. Epub 2002 Dec 10.
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.
C型利钠肽（CNP）调节盐排泄、血管张力以及成纤维细胞的增殖和活化。CNP在体外抑制成纤维细胞活化，在体内抑制纤维化，但组织纤维化过程中内源性CNP基因（Nppc）的表达尚未见报道。我们确定，单侧输尿管梗阻（UUO）后，Nppc先在肾小管上皮细胞中被诱导，随后在间质肌成纤维细胞中被诱导。Nppc的诱导发生在与肾损伤后Wnt4诱导相同的细胞群体中。此外，在肾脏发育过程中，Nppc在表达Wnt4的细胞中被激活。Wnt信号成分β-连环蛋白和T细胞因子/淋巴细胞增强因子结合因子（TCF/LEF）特异性结合Nppc近端启动子中的同源元件。Wnt-4、β-连环蛋白和LEF-1在培养细胞中激活Nppc转基因，且Wnt-4和LEF-1对转基因的激活依赖于完整同源元件的存在。这些发现表明，肾损伤后Wnt-4以TCF/LEF依赖的方式刺激Nppc，因此可能有助于限制肾纤维化。
