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Endothelin and the podocyte.

Barton M, Tharaux PL - Clin Kidney J (2012)

Bottom Line: Like blockade of the renin-angiotensin system, ERA treatment-under certain conditions-may even cause disease regression, effects that could be achieved on top of renin-angiotensin-aldosterone system blockade, suggesting independent therapeutic mechanisms by which ERAs convey nephroprotection.In this article, we will review pre-clinical studies demonstrating a causal role for endothelin in proteinuric chronic kidney disease (with a particular focus on functional and structural integrity of podocytes in vitro and in vivo).We will also review the evidence suggesting a therapeutic benefit of ERA treatment on the functional integrity of podocytes in humans.

View Article: PubMed Central - PubMed

Affiliation: Molecular Internal Medicine, University of Zürich, Zürich, Switzerland.

ABSTRACT
In the past decade, research has advanced our understanding how endothelin contributes to proteinuria and glomerulosclerosis. Data from pre-clinical and clinical studies now provide evidence that proteinuric diseases such as focal segmental glomerulosclerosis and diabetic nephropathy as well as hypertension nephropathy are sensitive to treatment with endothelin receptor antagonists (ERAs). Like blockade of the renin-angiotensin system, ERA treatment-under certain conditions-may even cause disease regression, effects that could be achieved on top of renin-angiotensin-aldosterone system blockade, suggesting independent therapeutic mechanisms by which ERAs convey nephroprotection. Beneficial effects of ERAs on podocyte function, which is essential to maintain the glomerular filtration barrier, have been identified as one of the key mechanisms by which inhibition of the endothelin ETA receptor ameliorates renal structure and function. In this article, we will review pre-clinical studies demonstrating a causal role for endothelin in proteinuric chronic kidney disease (with a particular focus on functional and structural integrity of podocytes in vitro and in vivo). We will also review the evidence suggesting a therapeutic benefit of ERA treatment on the functional integrity of podocytes in humans.

No MeSH data available.


Related in: MedlinePlus

Effect of ETA receptor inhibition in laser-dissected glomeruli of rats with FSGS in vivo (a) and in podocytes in vitro (b-f). (a) Darusentan reduced MMP-9 gene expression (a marker of podocyte injury [103]) compared with placebo-treated rats. (b) In vitro treatment with puromycin aminonucleoside (PAN) caused podocyte apoptosis and up-regulation of MMP-9; (c) peptide (BQ) or non-peptide (LU, darusentan) ETA receptor antagonists prevented this effect, as did ETA receptor gene silencing (siRNA) (d). (e) Gene silencing of ETA receptors increased podocyte growth as determined by de novo DNA synthesis. (f) Actin cytoskeleton disruption was largely prevented by ETA antagonists; representative examples of these experiments are shown in Figure 3. ncRNA, non-coding RNA control; O, old; AU, arbitrary units; OLU, old, darusentan. *P < 0.05 versus control (CTL); †P < 0.05 versus PAN alone/old. Figure reproduced from reference [39] with permission of the publisher.
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fig2: Effect of ETA receptor inhibition in laser-dissected glomeruli of rats with FSGS in vivo (a) and in podocytes in vitro (b-f). (a) Darusentan reduced MMP-9 gene expression (a marker of podocyte injury [103]) compared with placebo-treated rats. (b) In vitro treatment with puromycin aminonucleoside (PAN) caused podocyte apoptosis and up-regulation of MMP-9; (c) peptide (BQ) or non-peptide (LU, darusentan) ETA receptor antagonists prevented this effect, as did ETA receptor gene silencing (siRNA) (d). (e) Gene silencing of ETA receptors increased podocyte growth as determined by de novo DNA synthesis. (f) Actin cytoskeleton disruption was largely prevented by ETA antagonists; representative examples of these experiments are shown in Figure 3. ncRNA, non-coding RNA control; O, old; AU, arbitrary units; OLU, old, darusentan. *P < 0.05 versus control (CTL); †P < 0.05 versus PAN alone/old. Figure reproduced from reference [39] with permission of the publisher.

Mentions: Similarly, ETA receptor antagonists prevent disruption of the podocyte actin cytoskeleton following exposure to puromycin aminonucleoside [39] (Figures 2 and 3), an effect that can also be obtained with angiotensin AT1 receptor antagonists [46, 99, 100]. Puromycin aminonucleoside (which causes FSGS in vivo) [101, 102] results in podocyte apoptosis and up-regulation of matrix metalloproteinase-9 (MMP-9) as a marker of podocyte injury [103]; up-regulation of MMP-9 and disruption of the actin cytoskeleton can be completely prevented by ETA receptor (but not ETB) antagonists or ETA receptor gene silencing (Figure 2 and 3) [39]. These observations were confirmed by Benigni's group [39, 97] showing similar cytoskeleton-protective effects of ETA receptor blockade [98]. Little is known about the mechanisms that would explain how endothelin might regulate podocyte proliferation or motility [44]. We found that ETA receptor gene silencing stimulates podocyte growth (Figure 2E), a finding compatible with the notion that endogenous endothelin produced by the podocyte itself [81, 82] acts as a negative regulator of podocyte cell proliferation.


Endothelin and the podocyte.

Barton M, Tharaux PL - Clin Kidney J (2012)

Effect of ETA receptor inhibition in laser-dissected glomeruli of rats with FSGS in vivo (a) and in podocytes in vitro (b-f). (a) Darusentan reduced MMP-9 gene expression (a marker of podocyte injury [103]) compared with placebo-treated rats. (b) In vitro treatment with puromycin aminonucleoside (PAN) caused podocyte apoptosis and up-regulation of MMP-9; (c) peptide (BQ) or non-peptide (LU, darusentan) ETA receptor antagonists prevented this effect, as did ETA receptor gene silencing (siRNA) (d). (e) Gene silencing of ETA receptors increased podocyte growth as determined by de novo DNA synthesis. (f) Actin cytoskeleton disruption was largely prevented by ETA antagonists; representative examples of these experiments are shown in Figure 3. ncRNA, non-coding RNA control; O, old; AU, arbitrary units; OLU, old, darusentan. *P < 0.05 versus control (CTL); †P < 0.05 versus PAN alone/old. Figure reproduced from reference [39] with permission of the publisher.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400467&req=5

fig2: Effect of ETA receptor inhibition in laser-dissected glomeruli of rats with FSGS in vivo (a) and in podocytes in vitro (b-f). (a) Darusentan reduced MMP-9 gene expression (a marker of podocyte injury [103]) compared with placebo-treated rats. (b) In vitro treatment with puromycin aminonucleoside (PAN) caused podocyte apoptosis and up-regulation of MMP-9; (c) peptide (BQ) or non-peptide (LU, darusentan) ETA receptor antagonists prevented this effect, as did ETA receptor gene silencing (siRNA) (d). (e) Gene silencing of ETA receptors increased podocyte growth as determined by de novo DNA synthesis. (f) Actin cytoskeleton disruption was largely prevented by ETA antagonists; representative examples of these experiments are shown in Figure 3. ncRNA, non-coding RNA control; O, old; AU, arbitrary units; OLU, old, darusentan. *P < 0.05 versus control (CTL); †P < 0.05 versus PAN alone/old. Figure reproduced from reference [39] with permission of the publisher.
Mentions: Similarly, ETA receptor antagonists prevent disruption of the podocyte actin cytoskeleton following exposure to puromycin aminonucleoside [39] (Figures 2 and 3), an effect that can also be obtained with angiotensin AT1 receptor antagonists [46, 99, 100]. Puromycin aminonucleoside (which causes FSGS in vivo) [101, 102] results in podocyte apoptosis and up-regulation of matrix metalloproteinase-9 (MMP-9) as a marker of podocyte injury [103]; up-regulation of MMP-9 and disruption of the actin cytoskeleton can be completely prevented by ETA receptor (but not ETB) antagonists or ETA receptor gene silencing (Figure 2 and 3) [39]. These observations were confirmed by Benigni's group [39, 97] showing similar cytoskeleton-protective effects of ETA receptor blockade [98]. Little is known about the mechanisms that would explain how endothelin might regulate podocyte proliferation or motility [44]. We found that ETA receptor gene silencing stimulates podocyte growth (Figure 2E), a finding compatible with the notion that endogenous endothelin produced by the podocyte itself [81, 82] acts as a negative regulator of podocyte cell proliferation.

Bottom Line: Like blockade of the renin-angiotensin system, ERA treatment-under certain conditions-may even cause disease regression, effects that could be achieved on top of renin-angiotensin-aldosterone system blockade, suggesting independent therapeutic mechanisms by which ERAs convey nephroprotection.In this article, we will review pre-clinical studies demonstrating a causal role for endothelin in proteinuric chronic kidney disease (with a particular focus on functional and structural integrity of podocytes in vitro and in vivo).We will also review the evidence suggesting a therapeutic benefit of ERA treatment on the functional integrity of podocytes in humans.

View Article: PubMed Central - PubMed

Affiliation: Molecular Internal Medicine, University of Zürich, Zürich, Switzerland.

ABSTRACT
In the past decade, research has advanced our understanding how endothelin contributes to proteinuria and glomerulosclerosis. Data from pre-clinical and clinical studies now provide evidence that proteinuric diseases such as focal segmental glomerulosclerosis and diabetic nephropathy as well as hypertension nephropathy are sensitive to treatment with endothelin receptor antagonists (ERAs). Like blockade of the renin-angiotensin system, ERA treatment-under certain conditions-may even cause disease regression, effects that could be achieved on top of renin-angiotensin-aldosterone system blockade, suggesting independent therapeutic mechanisms by which ERAs convey nephroprotection. Beneficial effects of ERAs on podocyte function, which is essential to maintain the glomerular filtration barrier, have been identified as one of the key mechanisms by which inhibition of the endothelin ETA receptor ameliorates renal structure and function. In this article, we will review pre-clinical studies demonstrating a causal role for endothelin in proteinuric chronic kidney disease (with a particular focus on functional and structural integrity of podocytes in vitro and in vivo). We will also review the evidence suggesting a therapeutic benefit of ERA treatment on the functional integrity of podocytes in humans.

No MeSH data available.


Related in: MedlinePlus