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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 4 weeks of treatment with the ERA darusentan on renal structure in established FSGS [39]. (a) Untreated animal, transmission electron microscopy demonstrates GBM hypertrophy and podocyte injury with diffuse foot process effacement and vacuolar degeneration involving autophagy [113]. (b) ERA-treated animal, showing regression of GBM hypertrophy and disappearance of podocyte vacuoles. (c) Untreated animal, light microscopy image (haematoxilin/eosin) demonstrating hypertrophy of podocytes with enlarged nuclei, prominent nucleoles and vacuolar degeneration due to autophagy. (d) Treated animal, showing normal sized podocyte nuclei and virtually complete disappearance of vacuolar degeneration (arrows). Scale bar, 10 μm (c, d). Panels adapted from reference [39] and reproduced with permission of the publisher.
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fig4: Effect of 4 weeks of treatment with the ERA darusentan on renal structure in established FSGS [39]. (a) Untreated animal, transmission electron microscopy demonstrates GBM hypertrophy and podocyte injury with diffuse foot process effacement and vacuolar degeneration involving autophagy [113]. (b) ERA-treated animal, showing regression of GBM hypertrophy and disappearance of podocyte vacuoles. (c) Untreated animal, light microscopy image (haematoxilin/eosin) demonstrating hypertrophy of podocytes with enlarged nuclei, prominent nucleoles and vacuolar degeneration due to autophagy. (d) Treated animal, showing normal sized podocyte nuclei and virtually complete disappearance of vacuolar degeneration (arrows). Scale bar, 10 μm (c, d). Panels adapted from reference [39] and reproduced with permission of the publisher.

Mentions: Ageing in rodents and humans is associated with spontaneous development of FSGS [22], which is characterized by podocyte injury and hypertrophy, glomerular enlargement and glomerulosclerosis [110, 111]. Pharmacologically induced FSGS results in podocyte injury leading to cytoplasmic accumulation of functional synaptic-like vesicles, which occurs even before detachment of the cells from the GBM [112]. These vesicles or vacuoles are also present in spontaneous age-dependent FSGS [39] (Figure 4, untreated animals, left panels). Interestingly, susceptibility to develop age-dependent FSGS has recently been linked to autophagy-related mechanisms controlling podocyte vacuolation [113].


Endothelin and the podocyte.

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

Effect of 4 weeks of treatment with the ERA darusentan on renal structure in established FSGS [39]. (a) Untreated animal, transmission electron microscopy demonstrates GBM hypertrophy and podocyte injury with diffuse foot process effacement and vacuolar degeneration involving autophagy [113]. (b) ERA-treated animal, showing regression of GBM hypertrophy and disappearance of podocyte vacuoles. (c) Untreated animal, light microscopy image (haematoxilin/eosin) demonstrating hypertrophy of podocytes with enlarged nuclei, prominent nucleoles and vacuolar degeneration due to autophagy. (d) Treated animal, showing normal sized podocyte nuclei and virtually complete disappearance of vacuolar degeneration (arrows). Scale bar, 10 μm (c, d). Panels adapted from reference [39] and reproduced with permission of the publisher.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

fig4: Effect of 4 weeks of treatment with the ERA darusentan on renal structure in established FSGS [39]. (a) Untreated animal, transmission electron microscopy demonstrates GBM hypertrophy and podocyte injury with diffuse foot process effacement and vacuolar degeneration involving autophagy [113]. (b) ERA-treated animal, showing regression of GBM hypertrophy and disappearance of podocyte vacuoles. (c) Untreated animal, light microscopy image (haematoxilin/eosin) demonstrating hypertrophy of podocytes with enlarged nuclei, prominent nucleoles and vacuolar degeneration due to autophagy. (d) Treated animal, showing normal sized podocyte nuclei and virtually complete disappearance of vacuolar degeneration (arrows). Scale bar, 10 μm (c, d). Panels adapted from reference [39] and reproduced with permission of the publisher.
Mentions: Ageing in rodents and humans is associated with spontaneous development of FSGS [22], which is characterized by podocyte injury and hypertrophy, glomerular enlargement and glomerulosclerosis [110, 111]. Pharmacologically induced FSGS results in podocyte injury leading to cytoplasmic accumulation of functional synaptic-like vesicles, which occurs even before detachment of the cells from the GBM [112]. These vesicles or vacuoles are also present in spontaneous age-dependent FSGS [39] (Figure 4, untreated animals, left panels). Interestingly, susceptibility to develop age-dependent FSGS has recently been linked to autophagy-related mechanisms controlling podocyte vacuolation [113].

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