Urinary CCN2 (CTGF) as a possible predictor of diabetic nephropathy: Preliminary report

Riser, Bruce L.; Cortés, Pedro; DeNichilo, Mark O.; Deshmukh, Poornima V.; Chahal, Parminder S.; Mohammed, Ali K.; Yee, Jerry; Kahkonen, Dorothy M.

doi:10.1046/j.1523-1755.2003.00130.x

Cited by 92 publications

(74 citation statements)

References 42 publications

(46 reference statements)

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“…Another attractive report showed that urinary CTGF was upregulated in STZ rat prior to the development of albuminuria. 33 However, it remained to be elucidated whether CTGF could reflect glomerular structural changes especially in the early phase of diabetic nephropathy. In our study, we have confirmed that urinary Smad1 was closely correlated with the severity of mesangial matrix expansion in diabetic rats.…”

Section: Smad1 In Diabetic Nephropathymentioning

confidence: 99%

Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy

Matsubara

Abe

Arai

et al. 2006

Laboratory Investigation

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Diabetic nephropathy is the leading cause of end-stage renal disease, and glomerular mesangial matrix expansion is the hallmark in diabetic nephropathy. However, the precise mechanism for the development of mesangial matrix expansion has remained unknown. The key component involved in mesangial matrix expansion is type IV collagen (Col4). Recently, we have reported that Smad1 transcriptionally regulates expression of Col4 under diabetic conditions in vitro. Here we show that this direct regulator of Col4 also plays a crucial role for mesangial matrix expansion in vivo. Streptozotocin-induced diabetic rats are the model of incipient diabetic nephropathy, and showed various levels of mesangial matrix expansion at 24 weeks. The glomerular expression of Smad1 was significantly increased in diabetic rats with more mesangial matrix expansion by Western blot and immunohistochemical analysis. Furthermore, the glomerular expression of Smad1 was closely correlated with the glomerular expression of Col4 and smooth muscle alpha actin (a-SMA), while albuminuria or glomerular filtration rate was not correlated with mesangial matrix expansion. We also found that urinary excretion of Smad1 was closely associated with the severity of mesangial matrix expansion. In cultured mesangial cells expression of Smad1 upregulated the transcriptional activity of key molecules in mesangial matrix expansion, such as Col4 and a-SMA. These data indicate the critical involvement of Smad1 in mesangial matrix expansion in the early phase of diabetic nephropathy. Our data imply that urinary Smad1 might be a representative diagnostic marker for mesangial matrix expansion in diabetic nephropathy.

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Section: Smad1 In Diabetic Nephropathymentioning

confidence: 99%

Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy

Matsubara

Abe

Arai

et al. 2006

Laboratory Investigation

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“…Expression of CTGF has been positively correlated with the degree of fibrosis, and indeed CTGF protein excretion in urine samples from patients with kidney disease has been identified as an effective indicator of renal function, with higher levels of CTGF protein reflecting increased renal damage (19,49).…”

mentioning

confidence: 99%

Hypoxic induction ofCtgfis directly mediated by Hif-1

Higgins

Biju²,

Akai³

et al. 2004

American Journal of Physiology-Renal Physiology

255

196

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CTGF plays a significant role in the development of renal fibrosis by mediating the fibrotic effects of transforming growth factor (TGF)-β1and has been shown to be hypoxia inducible in human breast cancer cells. It has been suggested that hypoxia is an important underlying cause for the development of renal fibrosis through the modulation of profibrotic genes. One of the key mediators of the cell's response to lowered oxygen environments is hypoxia-inducible-factor-1 (HIF-1), a basic helix-loop-helix transcription factor, which enables cells to adapt to hypoxia by regulating the expression of genes involved in increasing oxygen availability ( VEGF, erythropoietin) and enhancing glucose uptake and metabolism ( Glut-1, PGK). In this paper, we have used primary tubular epithelial cell cultures from a tetracycline-inducible- Hif- 1α knockout murine model to further elucidate the role of Hif-1 in the hypoxic-induction of Ctgf expression. We show that hypoxia response elements present upstream of Ctgf enable direct interaction of Hif-1 transcription factor with the Ctgf promoter, resulting in increased transcription of Ctgf mRNA. Cells deficient in Hif- 1α were incapable of inducing Ctgf mRNA in response to hypoxia, suggesting an absolute requirement of Hif-1. Furthermore, the observed Hif-1-mediated hypoxic stimulation of Ctgf expression was found to occur independently of TGF-β1signaling. Our findings have important implications for a number of fibrotic disorders in which hypoxia, CTGF, and TGF-β1are involved, including renal, dermal, hepatic, and pulmonary fibrosis.

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“…Several independent studies have evaluated CCN2 levels in the urine and/or serum in several chronic kidney diseases. Some groups have found elevated levels of the full-length CCN2, 5,6 or the N-terminal, 6,7 or the C-terminal [8][9][10] CCN2 fragments determined by ELISA, using antibodies that recognized each part of the molecule. Based on these data, CCN2 has been proposed as a risk biomarker of human diabetic nephropathy and other forms of chronic kidney disease, 2,5-10 and for cardiac dysfunction in patients exhibiting myocardial fibrosis and chronic heart failure.…”

mentioning

confidence: 99%

The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response

Rodrigues‐Díez

Rodrigues-Díez

Rayego‐Mateos

et al. 2013

Laboratory Investigation

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Urinary CCN2 (CTGF) as a possible predictor of diabetic nephropathy: Preliminary report

Cited by 92 publications

References 42 publications

Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy

Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy

Hypoxic induction ofCtgfis directly mediated by Hif-1

The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response

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