Journal Article

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

Chang, Shih-Chung, Wu, Mai-Szu, Sun, Chiao-Yin

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Actin / Aldosterone / Angiotensin AT1 receptors / Angiotensinogen / Angiotensinogen - biosynthesis / Angiotensins / Animals / Binding sites / Biology / Bone morphogenetic proteins / Breast cancer / Chronic kidney failure / Cresol / Cresols / 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 / Kidneys / 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