Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition.

Abstract

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.

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.

• Authors: Chiao-Yin Sun, Shih-Chung Chang, Mai-Szu Wu
• Journal: PloS one (PLoS One) Vol. 7 Issue 3 Pg. e34026 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22479508 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cresols
• Receptor, Angiotensin, Type 1
• Snail Family Transcription Factors
• Sulfuric Acid Esters
• Transcription Factors
• Transforming Growth Factor beta1
• Angiotensinogen
• 4-cresol sulfate
• Renin
• Losartan
• Indican

Topics

• Angiotensinogen (biosynthesis)
• Animals
• Cresols (toxicity)
• Epithelial-Mesenchymal Transition
• Fibrosis (chemically induced)
• Gene Expression Regulation
• Indican (toxicity)
• Kidney (pathology)
• Kidney Failure, Chronic (complications, pathology)
• Kidney Tubules
• Losartan (pharmacology)
• Male
• Mice
• Models, Biological
• Receptor, Angiotensin, Type 1 (biosynthesis)
• Renin (biosynthesis)
• Renin-Angiotensin System (physiology)
• Snail Family Transcription Factors
• Sulfuric Acid Esters (toxicity)
• Transcription Factors (biosynthesis)
• Transforming Growth Factor beta1 (biosynthesis)
• Uremia (complications)