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

Sun CY, Chang SC, Wu MS - PLoS ONE (2012)

Bottom Line: 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 may increase Snail expression and induce EMT-like transition.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine, Chang Gung University, Taoyuan, Taiwan.

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.

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Related in: MedlinePlus

Indoxyl sulfate and p-cresol sulfate induced epithelial-to-mesenchymal-like transition in vivo.A: Real-time polymearse chain reaction results show that mice treated with indoxyl sulfate (IS) and p-cresol sulfate (PCS) had significantly increased fibronectin and α- smooth muscle actin (SMA) expression in kidney. E-cadherin expression was significantly decreased in mice treated with IS and PCS. B: Results of immunohistological staining show that the staining for fibronectin and α-SMA was significantly increased in mice treated with IS and PCS. The staining for E-cadherin was significantly decreased in mice treated with IS and PCS. (400×) (*: P<0.05; **: P<0.01; ***: P<0.001, vs. control).
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pone-0034026-g006: Indoxyl sulfate and p-cresol sulfate induced epithelial-to-mesenchymal-like transition in vivo.A: Real-time polymearse chain reaction results show that mice treated with indoxyl sulfate (IS) and p-cresol sulfate (PCS) had significantly increased fibronectin and α- smooth muscle actin (SMA) expression in kidney. E-cadherin expression was significantly decreased in mice treated with IS and PCS. B: Results of immunohistological staining show that the staining for fibronectin and α-SMA was significantly increased in mice treated with IS and PCS. The staining for E-cadherin was significantly decreased in mice treated with IS and PCS. (400×) (*: P<0.05; **: P<0.01; ***: P<0.001, vs. control).

Mentions: The animal study results show that chronic treatment with IS or PCS could significantly increase renal fibronectin and α-SMA mRNA expression. IS and PCS significantly decreased renal E-cadherin mRNA expression in vivo (Figure 6A). The results of immunostaining in study animals also revealed that chronic IS or PCS treatment significantly increased the interstitial expression of fibronectin and α-SMA and decreased E-cadherin expression (Figure 6B).


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

Sun CY, Chang SC, Wu MS - PLoS ONE (2012)

Indoxyl sulfate and p-cresol sulfate induced epithelial-to-mesenchymal-like transition in vivo.A: Real-time polymearse chain reaction results show that mice treated with indoxyl sulfate (IS) and p-cresol sulfate (PCS) had significantly increased fibronectin and α- smooth muscle actin (SMA) expression in kidney. E-cadherin expression was significantly decreased in mice treated with IS and PCS. B: Results of immunohistological staining show that the staining for fibronectin and α-SMA was significantly increased in mice treated with IS and PCS. The staining for E-cadherin was significantly decreased in mice treated with IS and PCS. (400×) (*: P<0.05; **: P<0.01; ***: P<0.001, vs. control).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3316590&req=5

pone-0034026-g006: Indoxyl sulfate and p-cresol sulfate induced epithelial-to-mesenchymal-like transition in vivo.A: Real-time polymearse chain reaction results show that mice treated with indoxyl sulfate (IS) and p-cresol sulfate (PCS) had significantly increased fibronectin and α- smooth muscle actin (SMA) expression in kidney. E-cadherin expression was significantly decreased in mice treated with IS and PCS. B: Results of immunohistological staining show that the staining for fibronectin and α-SMA was significantly increased in mice treated with IS and PCS. The staining for E-cadherin was significantly decreased in mice treated with IS and PCS. (400×) (*: P<0.05; **: P<0.01; ***: P<0.001, vs. control).
Mentions: The animal study results show that chronic treatment with IS or PCS could significantly increase renal fibronectin and α-SMA mRNA expression. IS and PCS significantly decreased renal E-cadherin mRNA expression in vivo (Figure 6A). The results of immunostaining in study animals also revealed that chronic IS or PCS treatment significantly increased the interstitial expression of fibronectin and α-SMA and decreased E-cadherin expression (Figure 6B).

Bottom Line: 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 may increase Snail expression and induce EMT-like transition.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine, Chang Gung University, Taoyuan, Taiwan.

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.

Show MeSH
Related in: MedlinePlus