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Podocytic PKC-Alpha Is Regulated in Murine and Human Diabetes and Mediates Nephrin Endocytosis

BACKGROUND: Microalbuminuria is an early lesion during the development of diabetic nephropathy. The loss of high molecular weight proteins in the urine is usually associated with decreased expression of slit diaphragm proteins. Nephrin, is the major component of the glomerular slit diaphragm and los...

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Autores principales: Tossidou, Irini, Teng, Beina, Menne, Jan, Shushakova, Nelli, Park, Joon-Keun, Becker, Jan U., Modde, Friedrich, Leitges, Michael, Haller, Hermann, Schiffer, Mario
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855708/
https://www.ncbi.nlm.nih.gov/pubmed/20419132
http://dx.doi.org/10.1371/journal.pone.0010185
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author Tossidou, Irini
Teng, Beina
Menne, Jan
Shushakova, Nelli
Park, Joon-Keun
Becker, Jan U.
Modde, Friedrich
Leitges, Michael
Haller, Hermann
Schiffer, Mario
author_facet Tossidou, Irini
Teng, Beina
Menne, Jan
Shushakova, Nelli
Park, Joon-Keun
Becker, Jan U.
Modde, Friedrich
Leitges, Michael
Haller, Hermann
Schiffer, Mario
author_sort Tossidou, Irini
collection PubMed
description BACKGROUND: Microalbuminuria is an early lesion during the development of diabetic nephropathy. The loss of high molecular weight proteins in the urine is usually associated with decreased expression of slit diaphragm proteins. Nephrin, is the major component of the glomerular slit diaphragm and loss of nephrin has been well described in rodent models of experimental diabetes as well as in human diabetic nephropathy. METHODOLOGY/PRINCIPAL FINDINGS: In this manuscript we analyzed the role of PKC-alpha (PKCα) on endocytosis of nephrin in podocytes. We found that treatment of diabetic mice with a PKCα-inhibitor (GÖ6976) leads to preserved nephrin expression and reduced proteinuria. In vitro, we found that high glucose stimulation would induce PKCα protein expression in murine and human podocytes. We can demonstrate that PKCα mediates nephrin endocytosis in podocytes and that overexpression of PKCα leads to an augmented endocytosis response. After PKC-activation, we demonstrate an inducible association of PKCα, PICK1 and nephrin in podocytes. Moreover, we can demonstrate a strong induction of PKCα in podocytes of patients with diabetic nephropathy. CONCLUSIONS/SIGNIFICANCE: We therefore conclude that activation of PKCα is a pathomechanistic key event during the development of diabetic nephropathy. PKCα is involved in reduction of nephrin surface expression and therefore PKCα inhibition might be a novel target molecule for anti-proteinuric therapy.
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spelling pubmed-28557082010-04-23 Podocytic PKC-Alpha Is Regulated in Murine and Human Diabetes and Mediates Nephrin Endocytosis Tossidou, Irini Teng, Beina Menne, Jan Shushakova, Nelli Park, Joon-Keun Becker, Jan U. Modde, Friedrich Leitges, Michael Haller, Hermann Schiffer, Mario PLoS One Research Article BACKGROUND: Microalbuminuria is an early lesion during the development of diabetic nephropathy. The loss of high molecular weight proteins in the urine is usually associated with decreased expression of slit diaphragm proteins. Nephrin, is the major component of the glomerular slit diaphragm and loss of nephrin has been well described in rodent models of experimental diabetes as well as in human diabetic nephropathy. METHODOLOGY/PRINCIPAL FINDINGS: In this manuscript we analyzed the role of PKC-alpha (PKCα) on endocytosis of nephrin in podocytes. We found that treatment of diabetic mice with a PKCα-inhibitor (GÖ6976) leads to preserved nephrin expression and reduced proteinuria. In vitro, we found that high glucose stimulation would induce PKCα protein expression in murine and human podocytes. We can demonstrate that PKCα mediates nephrin endocytosis in podocytes and that overexpression of PKCα leads to an augmented endocytosis response. After PKC-activation, we demonstrate an inducible association of PKCα, PICK1 and nephrin in podocytes. Moreover, we can demonstrate a strong induction of PKCα in podocytes of patients with diabetic nephropathy. CONCLUSIONS/SIGNIFICANCE: We therefore conclude that activation of PKCα is a pathomechanistic key event during the development of diabetic nephropathy. PKCα is involved in reduction of nephrin surface expression and therefore PKCα inhibition might be a novel target molecule for anti-proteinuric therapy. Public Library of Science 2010-04-16 /pmc/articles/PMC2855708/ /pubmed/20419132 http://dx.doi.org/10.1371/journal.pone.0010185 Text en Tossidou et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tossidou, Irini
Teng, Beina
Menne, Jan
Shushakova, Nelli
Park, Joon-Keun
Becker, Jan U.
Modde, Friedrich
Leitges, Michael
Haller, Hermann
Schiffer, Mario
Podocytic PKC-Alpha Is Regulated in Murine and Human Diabetes and Mediates Nephrin Endocytosis
title Podocytic PKC-Alpha Is Regulated in Murine and Human Diabetes and Mediates Nephrin Endocytosis
title_full Podocytic PKC-Alpha Is Regulated in Murine and Human Diabetes and Mediates Nephrin Endocytosis
title_fullStr Podocytic PKC-Alpha Is Regulated in Murine and Human Diabetes and Mediates Nephrin Endocytosis
title_full_unstemmed Podocytic PKC-Alpha Is Regulated in Murine and Human Diabetes and Mediates Nephrin Endocytosis
title_short Podocytic PKC-Alpha Is Regulated in Murine and Human Diabetes and Mediates Nephrin Endocytosis
title_sort podocytic pkc-alpha is regulated in murine and human diabetes and mediates nephrin endocytosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855708/
https://www.ncbi.nlm.nih.gov/pubmed/20419132
http://dx.doi.org/10.1371/journal.pone.0010185
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