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CIN85 Deficiency Prevents Nephrin Endocytosis and Proteinuria in Diabetes

Diabetic nephropathy (DN) is the major cause of end-stage renal disease worldwide. Podocytes are important for glomerular filtration barrier function and maintenance of size selectivity in protein filtration in the kidney. Podocyte damage is the basis of many glomerular diseases characterized by los...

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Autores principales: Teng, Beina, Schroder, Patricia, Müller-Deile, Janina, Schenk, Heiko, Staggs, Lynne, Tossidou, Irini, Dikic, Ivan, Haller, Hermann, Schiffer, Mario
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314701/
https://www.ncbi.nlm.nih.gov/pubmed/27531950
http://dx.doi.org/10.2337/db16-0081
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author Teng, Beina
Schroder, Patricia
Müller-Deile, Janina
Schenk, Heiko
Staggs, Lynne
Tossidou, Irini
Dikic, Ivan
Haller, Hermann
Schiffer, Mario
author_facet Teng, Beina
Schroder, Patricia
Müller-Deile, Janina
Schenk, Heiko
Staggs, Lynne
Tossidou, Irini
Dikic, Ivan
Haller, Hermann
Schiffer, Mario
author_sort Teng, Beina
collection PubMed
description Diabetic nephropathy (DN) is the major cause of end-stage renal disease worldwide. Podocytes are important for glomerular filtration barrier function and maintenance of size selectivity in protein filtration in the kidney. Podocyte damage is the basis of many glomerular diseases characterized by loss of interdigitating foot processes and decreased expression of components of the slit diaphragm. Nephrin, a podocyte-specific protein, is the main component of the slit diaphragm. Loss of nephrin is observed in human and rodent models of diabetic kidney disease. The long isoform of CIN85 (RukL) is a binding partner of nephrin that mediates nephrin endocytosis via ubiquitination in podocytes. Here we demonstrate that the loss of nephrin expression and the onset of proteinuria in diabetic mice correlate with an increased accumulation of ubiquitinated proteins and expression of CIN85/RukL in podocytes. CIN85/RukL deficiency preserved nephrin surface expression on the slit diaphragm and reduced proteinuria in diabetic mice, whereas overexpression of CIN85 in zebrafish induced severe edema and disruption of the filtration barrier. Thus, CIN85/RukL is involved in endocytosis of nephrin in podocytes under diabetic conditions, causing podocyte depletion and promoting proteinuria. CIN85/RukL expression therefore shows potential to be a novel target for antiproteinuric therapy in diabetes.
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spelling pubmed-53147012017-12-01 CIN85 Deficiency Prevents Nephrin Endocytosis and Proteinuria in Diabetes Teng, Beina Schroder, Patricia Müller-Deile, Janina Schenk, Heiko Staggs, Lynne Tossidou, Irini Dikic, Ivan Haller, Hermann Schiffer, Mario Diabetes Complications Diabetic nephropathy (DN) is the major cause of end-stage renal disease worldwide. Podocytes are important for glomerular filtration barrier function and maintenance of size selectivity in protein filtration in the kidney. Podocyte damage is the basis of many glomerular diseases characterized by loss of interdigitating foot processes and decreased expression of components of the slit diaphragm. Nephrin, a podocyte-specific protein, is the main component of the slit diaphragm. Loss of nephrin is observed in human and rodent models of diabetic kidney disease. The long isoform of CIN85 (RukL) is a binding partner of nephrin that mediates nephrin endocytosis via ubiquitination in podocytes. Here we demonstrate that the loss of nephrin expression and the onset of proteinuria in diabetic mice correlate with an increased accumulation of ubiquitinated proteins and expression of CIN85/RukL in podocytes. CIN85/RukL deficiency preserved nephrin surface expression on the slit diaphragm and reduced proteinuria in diabetic mice, whereas overexpression of CIN85 in zebrafish induced severe edema and disruption of the filtration barrier. Thus, CIN85/RukL is involved in endocytosis of nephrin in podocytes under diabetic conditions, causing podocyte depletion and promoting proteinuria. CIN85/RukL expression therefore shows potential to be a novel target for antiproteinuric therapy in diabetes. American Diabetes Association 2016-12 2016-08-16 /pmc/articles/PMC5314701/ /pubmed/27531950 http://dx.doi.org/10.2337/db16-0081 Text en © 2016 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
spellingShingle Complications
Teng, Beina
Schroder, Patricia
Müller-Deile, Janina
Schenk, Heiko
Staggs, Lynne
Tossidou, Irini
Dikic, Ivan
Haller, Hermann
Schiffer, Mario
CIN85 Deficiency Prevents Nephrin Endocytosis and Proteinuria in Diabetes
title CIN85 Deficiency Prevents Nephrin Endocytosis and Proteinuria in Diabetes
title_full CIN85 Deficiency Prevents Nephrin Endocytosis and Proteinuria in Diabetes
title_fullStr CIN85 Deficiency Prevents Nephrin Endocytosis and Proteinuria in Diabetes
title_full_unstemmed CIN85 Deficiency Prevents Nephrin Endocytosis and Proteinuria in Diabetes
title_short CIN85 Deficiency Prevents Nephrin Endocytosis and Proteinuria in Diabetes
title_sort cin85 deficiency prevents nephrin endocytosis and proteinuria in diabetes
topic Complications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314701/
https://www.ncbi.nlm.nih.gov/pubmed/27531950
http://dx.doi.org/10.2337/db16-0081
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