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Decorin deficiency in diabetic mice: aggravation of nephropathy due to overexpression of profibrotic factors, enhanced apoptosis and mononuclear cell infiltration.
- Source :
-
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society [J Physiol Pharmacol] 2009 Oct; Vol. 60 Suppl 4, pp. 5-13. - Publication Year :
- 2009
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Abstract
- Although deficiency of the small leucine-rich proteoglycan decorin aggravates diabetic nephropathy in mice, the precise mechanisms of action are not fully understood. In the present study we used decorin-deficient mice (Dcn(-/-)) to further elucidate the molecular mechanisms involved in the protective action of decorin in diabetes. We discovered that streptozotocin-induced diabetes in Dcn(-/-) mice led to increased proteinuria associated with enhanced cyclin-dependent kinase inhibitor p27Kip1 in podocytes and tubular epithelial cells. Furthermore, lack of decorin increased the rate of apoptosis and caused overexpression of the IGF-IR in tubular epithelial cells of diabetic kidneys. In vitro experiments using human proximal renal epithelial cells showed that recombinant decorin was bound to the IGF-IR and protected against high glucose-mediated apoptosis. Furthermore, overexpression of TGFbeta1 and CTGF triggered by decorin deficiency resulted in enhanced accumulation of extracellular matrix in diabetic kidneys. Notably, diabetic Dcn(-/-) kidneys revealed marked upregulation of the proinflammatory proteoglycan biglycan and enhanced infiltration of mononuclear cells. Collectively, our results indicate that decorin is a protective agent during the development of diabetic nephropathy. Future therapeutic approaches that would either enhance the endogenous production of decorin or deliver recombinant decorin to the diseased kidney might improve the outcome of patients with diabetic nephropathy.
- Subjects :
- Animals
Blotting, Northern
Blotting, Western
Cells, Cultured
Connective Tissue Growth Factor metabolism
Cyclin-Dependent Kinase Inhibitor p27 biosynthesis
Decorin
Diabetes Mellitus genetics
Epithelial Cells metabolism
Extracellular Matrix metabolism
Extracellular Matrix Proteins genetics
Fibrosis metabolism
Humans
Kidney metabolism
Mice
Mice, Knockout
Neutrophil Infiltration physiology
Podocytes metabolism
Polysaccharides metabolism
Proteinuria metabolism
Proteoglycans genetics
Receptor, IGF Type 1 metabolism
Transforming Growth Factor beta1 metabolism
Apoptosis physiology
Diabetes Mellitus metabolism
Diabetic Neuropathies metabolism
Diabetic Neuropathies pathology
Extracellular Matrix Proteins deficiency
Monocytes physiology
Proteoglycans deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1899-1505
- Volume :
- 60 Suppl 4
- Database :
- MEDLINE
- Journal :
- Journal of physiology and pharmacology : an official journal of the Polish Physiological Society
- Publication Type :
- Academic Journal
- Accession number :
- 20083846