Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice

H Yokoi; M Mukoyama; K Mori; M Kasahara; T Suganami; K Sawai; T Yoshioka; Y Saito; Y Ogawa; T Kuwabara; A Sugawara; K Nakao

doi:10.1038/sj.ki.5002722

Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice

Kidney Int. 2008 Feb;73(4):446-55. doi: 10.1038/sj.ki.5002722. Epub 2007 Dec 12.

Authors

H Yokoi¹, M Mukoyama, K Mori, M Kasahara, T Suganami, K Sawai, T Yoshioka, Y Saito, Y Ogawa, T Kuwabara, A Sugawara, K Nakao

Affiliation

¹ Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.

PMID: 18075496
DOI: 10.1038/sj.ki.5002722

Abstract

Connective tissue growth factor (CTGF) is a potent inducer of extracellular matrix accumulation. In diabetic nephropathy, CTGF expression is markedly upregulated both in podocytes and mesangial cells, and this may play an important role in its pathogenesis. We established podocyte-specific CTGF-transgenic mice, which were indistinguishable at baseline from their wild-type littermates. Twelve weeks after streptozotocin-induced diabetes, these transgenic mice showed a more severe proteinuria, mesangial expansion, and a decrease in matrix metalloproteinase-2 activity compared to diabetic wild-type mice. Furthermore, diabetic transgenic mice exhibited less podocin expression and a decreased number of diffusely vacuolated podocytes compared to diabetic wild-type mice. Importantly, induction of diabetes in CTGF-transgenic mice resulted in a further elevation of endogenous CTGF mRNA expression and protein in the glomerular mesangium. Our findings suggest that overexpression of CTGF in podocytes is sufficient to exacerbate proteinuria and mesangial expansion through a functional impairment and loss of podocytes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Connective Tissue Growth Factor
Diabetes Mellitus, Experimental / chemically induced
Diabetes Mellitus, Experimental / complications
Diabetic Nephropathies / etiology*
Diabetic Nephropathies / genetics
Diabetic Nephropathies / pathology*
Extracellular Matrix / metabolism
Gene Expression
Glomerular Mesangium / chemistry
Glomerular Mesangium / metabolism*
Glomerular Mesangium / pathology*
Humans
Immediate-Early Proteins / analysis
Immediate-Early Proteins / genetics
Immediate-Early Proteins / metabolism*
Intercellular Signaling Peptides and Proteins / analysis
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
Matrix Metalloproteinase 2 / metabolism
Mice
Mice, Transgenic
Podocytes / chemistry
Podocytes / metabolism*
Podocytes / pathology*
Proteinuria / genetics
Proteinuria / metabolism
RNA, Messenger / analysis
RNA, Messenger / metabolism
Rabbits

Substances

CCN2 protein, human
CCN2 protein, mouse
Immediate-Early Proteins
Intercellular Signaling Peptides and Proteins
RNA, Messenger
Connective Tissue Growth Factor
Matrix Metalloproteinase 2