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

Yokoi, Hideki; Mukoyama, Masashi; Mori, Kiyoshi; Kasahara, Masato; Suganami, Takayoshi; Sawai, Kenji; Yoshioka, Takakazu; Saito, Yoko; Ogawa, Yoshihiro; Kuwabara, Tomohiko; Sugawara, Akira; Nakao, Kazuwa

doi:10.1038/sj.ki.5002722

Cited by 112 publications

(147 citation statements)

References 49 publications

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“…The addition of HFD to STZ mice further enhanced albuminuria approximately twofold. To investigate podocyte injury, we investigated whether podocin protein production is decreased in the glomeruli of STZ-HFD mice [19]. Glomerular podocin level was significantly reduced in STZ-ND compared with nSTZ-ND and was lowest in STZ-HFD (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Here, to study the effects of an HFD on diabetes, we used a lean model of type 1 diabetes to avoid introducing complexity through alterations in insulin resistance and fat accumulation with the HFD or by Tlr4 gene disruption in the type 2 diabetes model [19,20]. The HFD-induced and hypertriacylglycerolaemia-associated renal injury observed in this study may have been caused through activation of TLR4 by NEFA [25,26], oxidised LDL [27], or triacylglycerol-rich lipoproteins [6].…”

Section: Discussionmentioning

confidence: 99%

“…Western blot analysis Proteins extracted from kidney samples were separated by SDS-PAGE, transferred onto PVDF membranes, incubated with primary antibodies and detected with peroxidase-conjugated secondary antibodies and chemiluminescence [19]. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal control.…”

Section: Measurement Of Metabolic Variablesmentioning

confidence: 99%

“…Real-time quantitative RT-PCR Total RNA was extracted with TRIzol reagent (Invitrogen, Carlsbad, CA, USA) and cDNA in each sample was synthesised using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA) from mouse kidneys and glomeruli isolated by graded sieving method [18,19]. TaqMan real-time PCR was performed using Premix Ex Taq (Takara Bio, Otsu, Japan) and StepOnePlus Real Time PCR System (Applied Biosystems, Foster City, CA, USA).…”

Section: Measurement Of Metabolic Variablesmentioning

confidence: 99%

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Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

et al. 2012

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Aims/hypothesis Hyperlipidaemia is an independent risk factor for the progression of diabetic nephropathy, but its molecular mechanism remains elusive. We investigated in mice how diabetes and hyperlipidaemia cause renal lesions separately and in combination, and the involvement of Toll-like receptor 4 (TLR4) in the process. Methods Diabetes was induced in wild-type (WT) and Tlr4 knockout (KO) mice by intraperitoneal injection of streptozotocin (STZ). At 2 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Functional and histological analyses were carried out 6 weeks later. Results Compared with treatment with STZ or HFD alone, treatment of WT mice with both STZ and HFD markedly aggravated nephropathy, as indicated by an increase in albuminuria, mesangial expansion, infiltration of macrophages and upregulation of pro-inflammatory and extracellularmatrix-associated gene expression in glomeruli. In Tlr4 KO mice, the addition of an HFD to STZ had almost no effects on the variables measured. Production of protein S100 calcium binding protein A8 (calgranulin A; S100A8), a potent ligand for TLR4, was observed in abundance in macrophages infiltrating STZ-HFD WT glomeruli and in glomeruli of diabetic nephropathy patients. High-glucose and fatty acid treatment synergistically upregulated S100a8 gene expression in macrophages from WT mice, but not from KO mice. As putative downstream targets of TLR4, phosphorylation of interferon regulatory factor 3 (IRF3) was enhanced in kidneys of WT mice co-treated with STZ and HFD. Conclusions/interpretation Activation of S100A8/TLR4 signalling was elucidated in an animal model of diabetic glomerular injury accompanied with hyperlipidaemia, which may provide novel therapeutic targets in progressive diabetic nephropathy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Measurement Of Metabolic Variablesmentioning

confidence: 99%

Section: Measurement Of Metabolic Variablesmentioning

confidence: 99%

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Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

et al. 2012

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“…The most definitive evidence for a role of CCN-2 in mediating DN is shown by studies that target CCN-2 specifically in the kidney: over-expression of CCN-2 in podocytes worsens diabetic nephropathy in mice (Yokoi et al 2008), and inhibition of CCN-2 expression in diabetes by antisense oligonucleotide administered to the kidney attenuates structural and functional changes of nephropathy in mouse models of diabetes (Guha et al 2007). …”

Section: Ccn-2 Regulation In Animal Diabetic Nephropathymentioning

confidence: 99%

Mastering a mediator: blockade of CCN-2 shows early promise in human diabetic kidney disease

Twigg

2010

J. Cell Commun. Signal.

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Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis

Sonnylal¹,

Xu²,

Leoni³

et al. 2010

Arthritis & Rheumatism

172

140

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Objective Connective tissue growth factor (CTGF) is a cysteine-rich secreted matricellular protein involved in wound healing and tissue repair. Enhanced and prolonged expression of CTGF has been associated with tissue fibrosis in humans. However, questions remain as to whether CTGF expression alone is sufficient to drive fibrosis. This study was undertaken to investigate whether CTGF alone is sufficient to cause fibrosis in intact animals and whether its effects are mediated through activation of transforming growth factor β (TGFβ) signaling or through distinct signal transduction pathways. Methods We generated mice overexpressing CTGF in fibroblasts under the control of the fibroblast-specific collagen α2(I) promoter enhancer. Tissues such as skin, lung, and kidney were harvested for histologic analysis. Mouse embryonic fibroblasts were prepared from embryos (14.5 days postcoitum) for biochemical analysis. Results Mice overexpressing CTGF in fibroblasts were susceptible to accelerated tissue fibrosis affecting the skin, lung, kidney, and vasculature, most notably the small arteries. We identified a marked expansion of the myofibroblast cell population in the dermis. RNA analysis of transgenic dermal fibroblasts revealed elevated expression of key matrix genes, consistent with a fibrogenic response. CTGF induced phosphorylation of p38, ERK-1/2, JNK, and Akt, but not Smad3, in transgenic mouse fibroblasts compared with wild-type mouse fibro-blasts. Transfection experiments showed significantly increased basal activity of the CTGF and serum response element promoters, and enhanced induction of the CTGF promoter in the presence of TGFβ. Conclusion These results demonstrate that selective expression of CTGF in fibroblasts alone causes tissue fibrosis in vivo through specific signaling pathways, integrating cues from the extracellular matrix into signal transduction pathways to orchestrate pivotal biologic responses relevant to tissue repair and fibrosis.

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

Cited by 112 publications

References 49 publications

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

Mastering a mediator: blockade of CCN-2 shows early promise in human diabetic kidney disease

Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis

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