Surendran Kameswaran, Schiavi Susan, Hruska Keith A
Department of Pediatrics, Washington University School of Medicine, 5th Floor MPRB, Campus Box 8208, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
J Am Soc Nephrol. 2005 Aug;16(8):2373-84. doi: 10.1681/ASN.2004110949. Epub 2005 Jun 8.
beta-Catenin functions as a transducer of Wnt signals to the nucleus, where it interacts with the T cell factor (TCF) family of DNA binding proteins to regulate gene expression. On the basis of the genes regulated by beta-catenin and TCF in various biologic settings, two predicted functions of beta-catenin/TCF-dependent transcription are to mediate the loss of epithelial polarity and to promote fibroblast activities, such as the increased synthesis of fibronectin during chronic renal disease. These predictions were tested by determination of the expression and function of an inhibitor of Wnt signaling, secreted frizzled-related protein 4 (sFRP4), during renal tubular epithelial injury initiated by unilateral ureteral obstruction (UUO). Despite increased sFRP4 gene expression in perivascular regions of injured kidneys, total sFRP4 protein levels decreased after injury. The decreased sFRP4 protein levels after UUO accompanied increased Wnt-dependent beta-catenin signaling in tubular epithelial and interstitial cells, along with increased expression of markers of fibrosis. Administration of recombinant sFRP4 protein caused a reduction in tubular epithelial beta-catenin signaling and suppressed the progression of renal fibrosis, as evidenced by a partial maintenance of E-cadherin mRNA expression and a reduction in the amount of fibronectin and alpha-smooth muscle actin proteins. Furthermore, recombinant sFRP4 reduced the number of myofibroblasts, a central mediator of fibrosis. It is concluded that beta-catenin signaling is activated in tubular epithelial and interstitial cells after renal injury, and recombinant sFRP4 can interfere with epithelial de-differentiation and with fibroblast differentiation and function during progression of renal fibrosis.
β-连环蛋白作为Wnt信号传导至细胞核的转导分子，在细胞核中它与DNA结合蛋白的T细胞因子（TCF）家族相互作用以调节基因表达。基于β-连环蛋白和TCF在各种生物学环境中调控的基因，β-连环蛋白/TCF依赖转录的两个预测功能是介导上皮极性的丧失以及促进成纤维细胞活性，例如在慢性肾病期间纤连蛋白合成增加。通过测定在单侧输尿管梗阻（UUO）引发的肾小管上皮损伤过程中Wnt信号抑制剂分泌型卷曲相关蛋白4（sFRP4）的表达和功能，对这些预测进行了验证。尽管损伤肾脏的血管周围区域中sFRP4基因表达增加，但损伤后sFRP4总蛋白水平下降。UUO后sFRP4蛋白水平下降伴随着肾小管上皮细胞和间质细胞中Wnt依赖的β-连环蛋白信号增加，以及纤维化标志物表达增加。给予重组sFRP4蛋白导致肾小管上皮β-连环蛋白信号减少，并抑制肾纤维化进展，这表现为E-钙黏蛋白mRNA表达部分维持以及纤连蛋白和α-平滑肌肌动蛋白蛋白量减少。此外，重组sFRP4减少了肌成纤维细胞的数量，肌成纤维细胞是纤维化的核心介质。结论是肾损伤后肾小管上皮细胞和间质细胞中β-连环蛋白信号被激活，并且重组sFRP4可以在肾纤维化进展过程中干扰上皮去分化以及成纤维细胞分化和功能。
