Because fibrotic kidneys exhibit aberrant activation of ␤-catenin signaling, this pathway may be a potential target for antifibrotic therapy. In this study, we examined the effects of ␤-catenin activation on tubular epithelial-mesenchymal transition (EMT) in vitro and evaluated the therapeutic efficacy of the peptidomimetic small molecule ICG-001, which specifically disrupts ␤-catenin-mediated gene transcription, in obstructive nephropathy. In vitro, ectopic expression of stabilized ␤-catenin in tubular epithelial (HKC-8) cells suppressed E-cadherin and induced Snail1, fibronectin, and plasminogen activator inhibitor-1 (PAI-1) expression. ICG-001 suppressed ␤-catenin-driven gene transcription in a dose-dependent manner and abolished TGF-␤1-induced expression of Snail1, PAI-1, collagen I, fibronectin, and ␣-smooth muscle actin (␣-SMA). This antifibrotic effect of ICG-001 did not involve disruption of Smad signaling. In the unilateral ureteral obstruction model, ICG-001 ameliorated renal interstitial fibrosis and suppressed renal expression of fibronectin, collagen I, collagen III, ␣-SMA, PAI-1, fibroblast-specific protein-1, Snail1, and Snail2. Late administration of ICG-001 also effectively attenuated fibrotic lesions in obstructive nephropathy. In conclusion, inhibiting ␤-catenin signaling may be an effective approach to the treatment of fibrotic kidney diseases.

Activation of the renin-angiotensin system (RAS) plays an essential role in the pathogenesis of CKD and cardiovascular disease. However, current anti-RAS therapy only has limited efficacy, partly because of compensatory upregulation of renin expression. Therefore, a treatment strategy to simultaneously target multiple RAS genes is necessary to achieve greater efficacy. By bioinformatics analyses, we discovered that the promoter regions of all RAS genes contained putative T-cell factor (TCF)/lymphoid enhancer factor ( Extensive studies over the last several decades have established that activation of the renin-angiotensin system (RAS) plays an essential role in the pathogenesis of CKD and cardiovascular disease. 1-3 RAS consists of several key components, including angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AT1), and angiotensin II type 2 receptor (AT2). Many studies indicate that, after kidney injury, intrarenal RAS is markedly activated because of concurrent upregulation of multiple RAS genes. 4,5 RAS activation contributes to kidney and cardiovascular injury through a range of mechanisms. In addition to regulating BP and hemodynamics, 6,7 angiotensin II, the principal and active mediator of RAS, activates TGF-b1 and NF-kB signaling and directly promotes renal inflammation and fibrosis. 8-10 Studies using both genetic and pharmacologic approaches have confirmed the relevance and importance of RAS activation in the development and progression of CKD and cardiovascular disease. However, current anti-RAS therapy using ACE inhibitors (ACEIs) or angiotensin II receptor

Sonic hedgehog (Shh) signaling is a developmental signal cascade that plays an essential role in regulating embryogenesis and tissue homeostasis. Here, we investigated the potential role of Shh signaling in renal interstitial fibrogenesis. Ureteral obstruction induced Shh, predominantly in the renal tubular epithelium of the fibrotic kidneys. Using Gli1 lacZ knock-in mice, we identified renal interstitial fibroblasts as Shhresponding cells. In cultured renal fibroblasts, recombinant Shh protein activated Gli1 and induced a-smooth muscle actin (a-SMA), desmin, fibronectin, and collagen I expression, suggesting that Shh signaling promotes myofibroblast activation and matrix production. Blockade of Shh signaling with cyclopamine abolished the Shh-mediated induction of Gli1, Snail1, a-SMA, fibronectin, and collagen I. In vivo, the kidneys of Gli1-deficient mice were protected against the development of interstitial fibrosis after obstructive injury. In wild-type mice, cyclopamine did not affect renal Shh expression but did inhibit induction of Gli1, Snail1, and a-SMA. In addition, cyclopamine reduced matrix expression and mitigated fibrotic lesions. These results suggest that tubule-derived Shh mediates epithelial-mesenchymal communication by targeting interstitial fibroblasts after kidney injury. We conclude that Shh/Gli1 signaling plays a critical role in promoting fibroblast activation, production of extracellular matrix, and development of renal interstitial fibrosis.