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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

Proposed interactions of endothelin (ET-1) with the glomerular basement membrane (GBM) of the glomerular capillary, its endothelial cells (GEC) and podocytes/slit diaphragm. ET-1 is produced by cells on both sides of the GBM, namely GEC and podocytes. ET-1 is released from GEC and may interact either directly with GBM (1) the slit diaphragm (2) or the podocyte, also in the reverse direction (3). Podocyte-derived ET-1 (4) may also affect the GBM and vice versa. ET-1 activates podocyte endothelin ETA receptors (ETA R) activating mitogen-activated protein kinases (MAPKs) p38 and p44/p42 (5), growth promoters (p21waf/cip1), or inflammation (NF-kappaB) (6). ET-1 also causes disruption of the podocyte F-actin cytoskeleton (7) and slit diaphragm dysfunction via activation of rho kinase and PI3-kinase. Figure reproduced from reference [11] with permission of the publisher.
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fig1: Proposed interactions of endothelin (ET-1) with the glomerular basement membrane (GBM) of the glomerular capillary, its endothelial cells (GEC) and podocytes/slit diaphragm. ET-1 is produced by cells on both sides of the GBM, namely GEC and podocytes. ET-1 is released from GEC and may interact either directly with GBM (1) the slit diaphragm (2) or the podocyte, also in the reverse direction (3). Podocyte-derived ET-1 (4) may also affect the GBM and vice versa. ET-1 activates podocyte endothelin ETA receptors (ETA R) activating mitogen-activated protein kinases (MAPKs) p38 and p44/p42 (5), growth promoters (p21waf/cip1), or inflammation (NF-kappaB) (6). ET-1 also causes disruption of the podocyte F-actin cytoskeleton (7) and slit diaphragm dysfunction via activation of rho kinase and PI3-kinase. Figure reproduced from reference [11] with permission of the publisher.

Mentions: Podocyte loss and podocyturia have been proposed as potential diagnostic markers of glomerular disease severity [15, 16]. Indeed, as disease progresses, viable—in addition to senescent—podocytes are shed in the urine [17] and thus provide a sensitive indicator of the degree of glomerular injury [16]. CKD is characterized by mesangial cell injury as well as by defects of the glomerular filtration barrier [15]. This includes injury of the glomerular endothelial cells, the glomerular basement membrane (GBM), glomerular epithelial cells, and the slit diaphragm (Figure 1) [11, 15].


Endothelin and the podocyte.

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

Proposed interactions of endothelin (ET-1) with the glomerular basement membrane (GBM) of the glomerular capillary, its endothelial cells (GEC) and podocytes/slit diaphragm. ET-1 is produced by cells on both sides of the GBM, namely GEC and podocytes. ET-1 is released from GEC and may interact either directly with GBM (1) the slit diaphragm (2) or the podocyte, also in the reverse direction (3). Podocyte-derived ET-1 (4) may also affect the GBM and vice versa. ET-1 activates podocyte endothelin ETA receptors (ETA R) activating mitogen-activated protein kinases (MAPKs) p38 and p44/p42 (5), growth promoters (p21waf/cip1), or inflammation (NF-kappaB) (6). ET-1 also causes disruption of the podocyte F-actin cytoskeleton (7) and slit diaphragm dysfunction via activation of rho kinase and PI3-kinase. Figure reproduced from reference [11] with permission of the publisher.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

fig1: Proposed interactions of endothelin (ET-1) with the glomerular basement membrane (GBM) of the glomerular capillary, its endothelial cells (GEC) and podocytes/slit diaphragm. ET-1 is produced by cells on both sides of the GBM, namely GEC and podocytes. ET-1 is released from GEC and may interact either directly with GBM (1) the slit diaphragm (2) or the podocyte, also in the reverse direction (3). Podocyte-derived ET-1 (4) may also affect the GBM and vice versa. ET-1 activates podocyte endothelin ETA receptors (ETA R) activating mitogen-activated protein kinases (MAPKs) p38 and p44/p42 (5), growth promoters (p21waf/cip1), or inflammation (NF-kappaB) (6). ET-1 also causes disruption of the podocyte F-actin cytoskeleton (7) and slit diaphragm dysfunction via activation of rho kinase and PI3-kinase. Figure reproduced from reference [11] with permission of the publisher.
Mentions: Podocyte loss and podocyturia have been proposed as potential diagnostic markers of glomerular disease severity [15, 16]. Indeed, as disease progresses, viable—in addition to senescent—podocytes are shed in the urine [17] and thus provide a sensitive indicator of the degree of glomerular injury [16]. CKD is characterized by mesangial cell injury as well as by defects of the glomerular filtration barrier [15]. This includes injury of the glomerular endothelial cells, the glomerular basement membrane (GBM), glomerular epithelial cells, and the slit diaphragm (Figure 1) [11, 15].

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