Chronic kidney disease (CKD) has become a public health problem worldwide. At present, treatment options for CKD are limited and often ineffective, underscoring enormous unmet medical need. The mainstay of clinical therapy for CKD is inhibition of renin-angiotensin system (RAS), using angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II type 1 receptor (AT1) blocker (ARB). However, current therapy with RAS inhibition is insufficient, partially because of compensatory upregulation of

more »

... renin expression. Thus, it is paramount to develop new therapeutic strategy with better outcomes. Methods: Using two mouse models of CKD induced by adriamycin (ADR) or unilateral ischemic/reperfusion injury (UIRI), we directly compared the therapeutic efficacy of small-molecule Wnt/b-catenin inhibitor ICG-001 with trandolapril (ACEI) alone, or the combination of trandolapril and losartan (ARB). The effect of renin on fibroblast activation was also assessed in vitro. Results: Compared to ACEI, or ACEI plus ARB, ICG-001 displayed superior therapeutic efficacy in both models. ICG-001 almost completely abolished proteinuria, ameliorated glomerular injury and fibrotic lesions and reduced serum creatinine in ADR nephropathy, whereas trandolapril, or trandolapril plus losartan only displayed as 50% efficacy as ICG-001. Similar results were obtained in UIRI model. We found that ICG-001 completely abolished renal expression of all RAS components including angiotensinogen, renin, ACE and AT1 in both models. However, trandolapril or trandolapril plus losartan actually induced angiotensinogen and renin expression in the kidneys. In vitro, incubation of kidney interstitial fibroblasts (NRK-49F) with renin protein induced fibronectin expression, and this effect was dependent on ERK-1/2 activation. Losartan did not block renin-induced fibronectin expression, suggesting that renin elicited its effect by an angiotensin II-independent mechanism. Conclusion: Our studies demonstrate that blockade of Wnt/b-catenin, the master upstream regulator of all RAS genes, has superior therapeutic efficacy for the treatment of CKD than RAS inhibitors.