PUBLICATION
CIN85 deficiency prevents nephrin endocytosis and proteinuria in diabetes
- Authors
- Teng, B., Schroder, P., Müller-Deile, J., Schenk, H., Staggs, L., Tossidou, I., Dikic, I., Haller, H., Schiffer, M.
- ID
- ZDB-PUB-160818-4
- Date
- 2016
- Source
- Diabetes 65(12): 3667-3679 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Creatinine/metabolism
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism*
- Diabetic Nephropathies/genetics
- Diabetic Nephropathies/metabolism
- Endocytosis/genetics
- Endocytosis/physiology*
- Genotype
- Humans
- Membrane Proteins/metabolism*
- Mice
- Microscopy, Electron, Transmission
- Neoplasm Proteins/deficiency
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism*
- Nerve Tissue Proteins/deficiency
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism*
- Podocytes/metabolism
- Podocytes/ultrastructure
- Proteinuria/genetics
- Proteinuria/metabolism*
- PubMed
- 27531950 Full text @ Diabetes
Citation
Teng, B., Schroder, P., Müller-Deile, J., Schenk, H., Staggs, L., Tossidou, I., Dikic, I., Haller, H., Schiffer, M. (2016) CIN85 deficiency prevents nephrin endocytosis and proteinuria in diabetes. Diabetes. 65(12):3667-3679.
Abstract
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 correlates 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. Therefore CIN85/RukL expression shows potential to be a novel target for anti-proteinuric therapy in diabetes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping