Sun, Chiao-YinChiao-YinSunChang, Shih-ChungShih-ChungChangWu, Mai-SzuMai-SzuWu2012-10-192018-07-062012-10-192018-07-06201219326203http://ntur.lib.ntu.edu.tw//handle/246246/243060http://ntur.lib.ntu.edu.tw/bitstream/246246/243060/-1/24.pdfhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84859144273&doi=10.1371%2fjournal.pone.0034026&partnerID=40&md5=6ad0dccbcd9bbb41140149ac18fc07c6Background: 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. 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. 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-β1 (TGF-β1) expression and activated the TGF-β 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 α-smooth muscle actin and decreasing the expression of E-cadherin. Losartan significantly attenuated the expression of TGF-β1 and Snail, and decreased kidney fibrosis induced by IS and PCS in vivo. Conclusion: Activating the renal RAAS/TGF-β 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. © 2012 Sun et al.en-US[SDGs]SDG3alpha smooth muscle actin; angiotensin 1 receptor; angiotensin 2 receptor; angiotensinogen; fibronectin; indican; losartan; para cresol sulfate; renin; Smad2 protein; Smad3 protein; Smad4 protein; transcription factor Snail; transforming growth factor beta1; unclassified drug; uremic toxin; uvomorulin; 4 cresol sulfate; 4-cresol sulfate; angiotensin 1 receptor; angiotensinogen; cresol; losartan; renin; snail family transcription factors; sulfate; transcription factor; transforming growth factor beta1; animal cell; animal experiment; animal model; animal tissue; article; C57BL 6 mouse; controlled study; enzyme activation; epithelial mesenchymal transition; histopathology; in vitro study; in vivo study; kidney fibrosis; kidney proximal tubule; kidney tubule cell; male; mouse; nephrectomy; nonhuman; phenotype; protein expression; protein synthesis inhibition; renin angiotensin aldosterone system; signal transduction; animal; biological model; biosynthesis; chemically induced disorder; chronic kidney failure; epithelial mesenchymal transition; fibrosis; gene expression regulation; kidney; kidney tubule; pathology; physiology; uremia; Animalia; Gastropoda; Mus; Angiotensinogen; Animals; Cresols; Epithelial-Mesenchymal Transition; Fibrosis; Gene Expression Regulation; Indican; Kidney; Kidney Failure, Chronic; Kidney Tubules; Losartan; Male; Mice; Models, Biological; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Sulfuric Acid Esters; Transcription Factors; Transforming Growth Factor beta1; Uremiajournal article10.1371/journal.pone.0034026224795082-s2.0-84859144273http://ntur.lib.ntu.edu.tw/bitstream/246246/243060/-1/24.pdf