PloS one, 2012-03, Vol.7 (3), p.e34026
2012
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- Autor(en) / Beteiligte
- Titel
- Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition
- Ist Teil von
- PloS one, 2012-03, Vol.7 (3), p.e34026
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. 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. 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. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0034026Titel-ID: cdi_plos_journals_1324394013
- Format
- –
- Schlagworte
- Actin, Aldosterone, Angiotensin AT1 receptors, Angiotensinogen, Angiotensinogen - biosynthesis, Angiotensins, Animals, Binding sites, Biology, Bone morphogenetic proteins, Breast cancer, Chronic kidney failure, Cresol, Cresols - toxicity, Cytomegalovirus, Development and progression, E-cadherin, Epithelial-Mesenchymal Transition, Esophagus, Fibronectin, Fibronectins, Fibrosis, Fibrosis - chemically induced, Gene Expression Regulation, Glucocorticoids, Growth factors, Indican - toxicity, Kidney - pathology, Kidney diseases, Kidney Failure, Chronic - complications, Kidney Failure, Chronic - pathology, Kidney Tubules, Kinases, Losartan - pharmacology, Male, Medical research, Medicine, Mesenchyme, Mice, Models, Biological, Motility, Mouse devices, Muscle proteins, Muscles, Nephrology, Ovarian cancer, p-Cresol, Polymerase chain reaction, Proteins, Receptor, Angiotensin, Type 1 - biosynthesis, Renal tubules, Renin, Renin - biosynthesis, Renin-Angiotensin System - physiology, Rodents, Smad2 protein, Smad3 protein, Smad4 protein, Smooth muscle, Snail Family Transcription Factors, Snail protein, Stem cells, Steroids (Organic compounds), Sulfates, Sulfuric Acid Esters - toxicity, Thermal cycling, Toxins, Transcription factors, Transcription Factors - biosynthesis, Transforming growth factor, Transforming Growth Factor beta1 - biosynthesis, Transforming growth factor-b1, Transforming growth factors, Uremia - complications