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

Chronic kidney disease (CKD) patients have an increased risk of cardiovascular diseases (CVDs). The present study aimed to investigate the gut microbiota and blood trimethylamine-N-oxide concentration (TMAO) in Chinese CKD patients and explore the underlying explanations through the animal experiment. The median plasma TMAO level was 30.33 μmol/L in the CKD patients, which was significantly higher than the 2.08 μmol/L concentration measured in the healthy controls. Next-generation sequence revealed obvious dysbiosis of the gut microbiome in CKD patients, with reduced bacterial diversity and biased community constitutions. CKD patients had higher percentages of opportunistic pathogens from gamma-Proteobacteria and reduced percentages of beneficial microbes, such as Roseburia, Coprococcus, and Ruminococcaceae. The PICRUSt analysis demonstrated that eight genes involved in choline, betaine, L-carnitine and trimethylamine (TMA) metabolism were changed in the CKD patients. Moreover, we transferred faecal samples from CKD patients and healthy controls into antibiotic-treated C57BL/6 mice and found that the mice that received gut microbes from the CKD patients had significantly higher plasma TMAO levels and different composition of gut microbiota than did the comparative mouse group. Our present study demonstrated that CKD patients had increased plasma TMAO levels due to contributions from both impaired renal functions and dysbiosis of the gut microbiota.