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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 activated renin–angiotensin–aldosterone system in vivo.A: Real-time polymerase chain reaction analysis show that mice treated with indoxyl sulfate (IS) and p-cresol sulfate (PCS) had significantly increased intra-renal renin, angiotensinogen, and angiotensin 1 (AT1) receptor mRNA expression, and decreased AT2 receptor mRNA expression. B: Western blotting shows that mice treated with IS and PCS had significantly increased intrarenal AT1 receptor and decreased AT2 receptor protein expression. (*: P<0.05; **: P<0.01; ***: P<0.001, vs. control).
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pone-0034026-g002: Indoxyl sulfate and p-cresol sulfate activated renin–angiotensin–aldosterone system in vivo.A: Real-time polymerase chain reaction analysis show that mice treated with indoxyl sulfate (IS) and p-cresol sulfate (PCS) had significantly increased intra-renal renin, angiotensinogen, and angiotensin 1 (AT1) receptor mRNA expression, and decreased AT2 receptor mRNA expression. B: Western blotting shows that mice treated with IS and PCS had significantly increased intrarenal AT1 receptor and decreased AT2 receptor protein expression. (*: P<0.05; **: P<0.01; ***: P<0.001, vs. control).

Mentions: PKSV cells treated with IS or PCS had significantly increased renin, angiotensinogen, and angiotensin 1 (AT1) receptor mRNA expression, as revealed by real-time PCR assay. The mRNA expression of the AT2 receptor was significantly decreased in PKSV cells treated with IS or PCS (Figure 1A). Western blotting showed that PKSV cells treated with IS and PCS at concentrations of 5 and 50 mg/L had significantly increased AT1 receptor protein expression. IS and PCS at concentrations of 5 and 50 mg/L significantly decreased AT2 receptor protein expression in vitro (Figure 1B). The concentrations of angiotensin II in the culture medium were shown in the Figure 1C. The mice undergoing chronic IS or PCS treatment had significantly increased intrarenal renin, angiotensinogen, and AT1 receptor mRNA expression, as determined by real-time PCR assay. The mRNA expression of the AT2 receptor was significantly decreased in mice treated with IS or PCS than in the negative controls (Figure 2A). The results of western blotting showed that, compared with the negative control mice, the mice treated with IS or PCS had significantly increased AT1 receptor and decreased AT2 receptor expression (Figure 2B).


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 activated renin–angiotensin–aldosterone system in vivo.A: Real-time polymerase chain reaction analysis show that mice treated with indoxyl sulfate (IS) and p-cresol sulfate (PCS) had significantly increased intra-renal renin, angiotensinogen, and angiotensin 1 (AT1) receptor mRNA expression, and decreased AT2 receptor mRNA expression. B: Western blotting shows that mice treated with IS and PCS had significantly increased intrarenal AT1 receptor and decreased AT2 receptor protein expression. (*: P<0.05; **: P<0.01; ***: P<0.001, vs. control).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3316590&req=5

pone-0034026-g002: Indoxyl sulfate and p-cresol sulfate activated renin–angiotensin–aldosterone system in vivo.A: Real-time polymerase chain reaction analysis show that mice treated with indoxyl sulfate (IS) and p-cresol sulfate (PCS) had significantly increased intra-renal renin, angiotensinogen, and angiotensin 1 (AT1) receptor mRNA expression, and decreased AT2 receptor mRNA expression. B: Western blotting shows that mice treated with IS and PCS had significantly increased intrarenal AT1 receptor and decreased AT2 receptor protein expression. (*: P<0.05; **: P<0.01; ***: P<0.001, vs. control).
Mentions: PKSV cells treated with IS or PCS had significantly increased renin, angiotensinogen, and angiotensin 1 (AT1) receptor mRNA expression, as revealed by real-time PCR assay. The mRNA expression of the AT2 receptor was significantly decreased in PKSV cells treated with IS or PCS (Figure 1A). Western blotting showed that PKSV cells treated with IS and PCS at concentrations of 5 and 50 mg/L had significantly increased AT1 receptor protein expression. IS and PCS at concentrations of 5 and 50 mg/L significantly decreased AT2 receptor protein expression in vitro (Figure 1B). The concentrations of angiotensin II in the culture medium were shown in the Figure 1C. The mice undergoing chronic IS or PCS treatment had significantly increased intrarenal renin, angiotensinogen, and AT1 receptor mRNA expression, as determined by real-time PCR assay. The mRNA expression of the AT2 receptor was significantly decreased in mice treated with IS or PCS than in the negative controls (Figure 2A). The results of western blotting showed that, compared with the negative control mice, the mice treated with IS or PCS had significantly increased AT1 receptor and decreased AT2 receptor expression (Figure 2B).

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