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Wnt/&bgr;-catenin signaling and renin–angiotensin system in chronic kidney disease

Purpose of reviewIntrarenal activation of the renin–angiotensin system (RAS) plays an essential role in the pathogenesis of hypertension and chronic kidney diseases (CKD). However, how RAS genes are regulated in vivo was poorly understood until recently. This review focuses on recent findings of the transcriptional regulation of RAS components, as well as their implication in developing novel strategies to treat the patients with CKD. Recent findingsBioinformatics analyses have uncovered the presence of putative binding sites for T-cell factor/&bgr;-catenin in the promoter region of all RAS genes. Both in-vitro and in-vivo studies confirm that Wnt/&bgr;-catenin is the master upstream regulator that controls the expression of all RAS components tested, such as angiotensinogen, renin, angiotensin converting enzyme and the angiotensin II type I receptor in the kidney. Targeted inhibition of Wnt/&bgr;-catenin, by either small molecule ICG-001 or endogenous Wnt antagonist Klotho, represses RAS activation and ameliorates proteinuria and kidney injury. Blockade of Wnt/&bgr;-catenin signaling also normalizes blood pressure in a mouse model of CKD. SummaryThese recent studies identify Wnt/&bgr;-catenin as the master regulator that controls multiple RAS genes, and suggest that targeting this upstream signaling could be an effective strategy for the treatment of patients with hypertension and CKD.