Uremic Toxins Induce Kidney Fibrosis by Activating Intrarenal Renin-Angiotensin-Aldosterone System Associated Epithelial-to-Mesenchymal Transition

作者：Sun Chiao Yin^*; Chang Shih Chung; Wu Mai Szu

来源：PLos One, 2012, 7(3): e34026.

DOI：10.1371/journal.pone.0034026

Background: Uremic toxins are considered to have a determinant pathological role in the progression of chronic kidney disease. The aim of this study was to define the putative pathological roles of the renal renin-angiotensin-aldosterone system (RAAS) and renal tubular epithelial-to-mesenchymal transition (EMT) in kidney fibrosis induced by (indoxyl sulfate) IS and (p-cresol sulfate) PCS. %26lt;br%26gt;Methods: Mouse proximal renal tubular cells (PKSV-PRs) treated with IS or PCS were used. Half-nephrectomized B-6 mice were treated with IS or PCS for 4 weeks. In the losartan treatment study, the study animal was administrated with IS+losartan or PCS+losartan for 4 weeks. %26lt;br%26gt;Results: IS and PCS significantly activated the intrarenal RAAS by increasing renin, angiotensinogen, and angiotensin 1 (AT1) receptor expression, and decreasing AT2 receptor expression in vitro and in vivo. IS and PCS significantly increased transforming growth factor-beta 1 (TGF-beta 1) expression and activated the TGF-beta pathway by increasing Smad2/Smad2-P, Smad3/Smad3-P, and Smad4 expression. The expression of the EMT-associated transcription factor Snail was increased by IS and PCS treatment. IS and PCS induced the phenotype of EMT-like transition in renal tubules by increasing the expression of fibronectin and alpha-smooth muscle actin and decreasing the expression of E-cadherin. Losartan significantly attenuated the expression of TGF-beta 1 and Snail, and decreased kidney fibrosis induced by IS and PCS in vivo. %26lt;br%26gt;Conclusion: Activating the renal RAAS/TGF-beta pathway has an important pathological role in chronic kidney injury caused by IS and PCS. IS and PCS may increase Snail expression and induce EMT-like transition.

• 出版日期2012-3-30
• 单位长春大学