RAAS activation could further activate transforming growth factor-b, which is known as an important fibrogenic cytokine in the development of kidney fibrosis. IS stimulates renal synthesis of TGF-b1 and the progression of renal failure in vivo. Epithelial-to-mesenchymal transition is considered an important mechanism in the development and progression of malignancies. EMT induced by TGF-b1 has been reported as a possible mechanism for kidney fibrosis. In addition, RAAS activation is able to induce EMT by both TGFdependent and TGF-independent actions, both in vitro and in vivo In this study, we tested the hypothesis that IS and PCS could induce kidney fibrosis by activating the intrarenal RAAS and inducing renal tubular EMT. In addition, the putative pathological role of EMT in kidney fibrosis induced by IS and PCS was studied. The main findings of this study suggest that IS and PCS might activate the intrarenal RAAS and TGF/Smad pathway. EMT-like transition of tubular cells activated by the EMT-associated transcription factor Snail might be a possible mechanism for kidney fibrosis induced by IS and PCS. The main pathophysiological mechanisms associated with chronic kidney Lomefloxacin hydrochloride disease result from the activation of the RAAS. Oxidative stress leads to activation of the RAAS, with a subsequent increase in the SB242084 levels of angiotensin II and TGF-b1, which are 2 important molecular mediators of kidney injury. Our results show that both IS and PCS could activate renal RAAS, increasing renin, angiotensinogen, and AT1 receptor expression and decreasing AT2 receptor expression in vitro and in vivo. In addition, our data demonstrate that blocking RAAS with losartan could significantly decrease the severity of nephrosclerosis induced by IS and PCS. Accumulated evidence has demonstrated that TGF-b plays an important role in the progression of renal disease. Smad2/3 activation is critical for the pro-fibrotic effect of TGF-b. Smad4 binds to Smad2/3 and facilitates the translocation of the heteromeric complex into the nucleus. Previous studies have revealed that IS stimulates TGF-b1 synthesis in proximal tubular cells and the progression of renal failure. IS also increases renal TIMP-1 and pro-alpha 1 collagen expression in uremic rats. Activation of the RAAS is a key mediator in the progression of renal disease. Many profibrotic effects of RAAS activation are mediated by stimulation of TGF-b. Components of RAAS activation including renin, angiotensin II/III and aldosterone all upregulate TGF-b expression. There is accumulating evidence that angiotensin II is able to induce EMT by both TGF-b-dependent and TGF-b-independent actions, both in vitro and in vivo. Previous study has showed that blocking TGF-b-dependent pathway could significantly decrease chronic kidney fibrosis by inhibiting EMT. Our study has revealed that both IS and PCS could increase renal TGF-b1 expression in vitro and in vivo. In addition, our in vitro study has shown that IS and PCS activate the TGF-b pathway by activating the Smad2/3 pathway and increasing Smad4 expression. Blocking the RAAS with losartan could significantly decrease renal TGF-b1 expression in mice injected with IS or PCS. The results of this study suggested that activations of TGF-b-dependent signaling pathway by RAAS might have important roles in the kidney injury by IS and PCS. EMT is a process by which differentiated epithelial cells undergo a phenotypic conversion that gives rise to matrixproducing fibroblasts and myofibroblasts.