The Renal TGF-β System in the db/db Mouse Model of Diabetic Nephropathy

Cohen, Morrel H.; Sharma, Kumar; Guo, Jia; Eltayeb, B; Ziyadeh, Fuad N.

doi:10.1159/000020527

Cited by 44 publications

(36 citation statements)

References 37 publications

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“…31,32 Activated TGF-␤1 participates in the development of renal failure in controlling extracellular matrix deposition and remodeling by stimulating collagen and fibronectin synthesis. 33,34 Despite the positive-feedback loop between TGF-␤1 and NO under physiological conditions, the inhibitory effect of NO on TGF-␤1 production was found to be reduced after salt intake in DSS rats. 35,36 In this study, we showed that kallistatin administration restored NO levels and significantly prevented salt-induced TGF-␤1 expression.…”

Section: Discussionmentioning

confidence: 99%

Salutary Effect of Kallistatin in Salt-Induced Renal Injury, Inflammation, and Fibrosis via Antioxidative Stress

et al. 2008

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Abstract-An inverse relationship exists between kallistatin levels and salt-induced oxidative stress in Dahl-salt sensitive rats. We further investigated the role of kallistatin in inhibiting inflammation and fibrosis through antioxidative stress in Dahl-salt sensitive rats and cultured renal cells. High-salt intake in Dahl-salt sensitive rats induced elevation of thiobarbituric acid reactive substances (an indicator of lipid peroxidation), malondialdehyde levels, reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, and superoxide formation, whereas kallistatin gene delivery significantly reduced these oxidative stress parameters. Kallistatin treatment improved renal function and reduced kidney damage as evidenced by diminished proteinuria and serum urea nitrogen levels, glomerular sclerosis, tubular damage, and protein cast formation. Kallistatin significantly decreased interstitial monocyte-macrophage infiltration and the expression of tumor necrosis factor-␣, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Kallistain also reduced collagen fraction volume and the deposition and expression of collagen types I and III. Renal protection by kallistatin was associated with increased NO levels and endothelial NO synthase expression and decreased p38 mitogen-activated protein kinase, extracellular signal-regulated kinase phosphorylation, and transforming growth factor-␤1 expression. Moreover, kallistatin attenuated tumor necrosis factor-␣-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression via inhibition of reactive oxygen species formation and p38 mitogen-activated protein kinase and nuclear factor-B activation in cultured proximal tubular cells. Kallistatin inhibited fibronectin and collagen expression by suppressing angiotensin II-induced reactive oxygen species generation and transforming growth factor-␤1 expression in cultured mesangial cells. These combined findings reveal that kallistatin is a novel antioxidant, which prevents salt-induced kidney injury, inflammation, and fibrosis by inhibiting reactive oxygen species-induced proinflammatory cytokine and transforming growth factor-␤1 expression. (Hypertension. 2008;51:1358-1365.)

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Section: Discussionmentioning

confidence: 99%

Salutary Effect of Kallistatin in Salt-Induced Renal Injury, Inflammation, and Fibrosis via Antioxidative Stress

et al. 2008

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“…Because excessive extracellular glucose concentrations increase expression of both TGF-␤ and TGF-␤ receptor (1,(7)(8)(9)(10)(11)(12), the enhanced hSGK transcription could have been due to autocrine stimulation by TGF-␤. As a matter of fact, TGF-␤-1 indeed exerts a similarly strong effect on hSGK transcription in fibroblasts (this study) as in U 937 macrophages (21) and HepG2 liver cells (21).…”

Section: Discussionmentioning

confidence: 99%

“…protein kinase C ͉ endothelial cells ͉ kidney ͉ epithelial Na ϩ channel ͉ Na ϩ ,K ϩ ,2Cl Ϫ cotransporter T ransforming growth factor ␤ (TGF-␤) is considered to be a crucial pathophysiological component in the generation of diabetic nephropathy (1)(2)(3)(4)(5)(6). A sequence of events has been postulated, which causes the enhanced production of both TGF-␤ and TGF-␤ receptors in hyperglycemia (1,(7)(8)(9)(10)(11)(12).…”

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Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy

Läng

Klingel²,

Wagner³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

204

237

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Transforming growth factor ␤ (TGF-␤) has been shown to participate in the pathophysiology of diabetic complications. As shown most recently, TGF-␤ stimulates the expression of a distinct serine͞threonine kinase (hSGK) which had previously been cloned as an early gene transcriptionally regulated by cell volume alterations. The present study was performed to elucidate transcription and function of hSGK in diabetic nephropathy. As shown by Northern blotting, an increase of extracellular glucose concentration increased hSGK mRNA levels in cultured cells, an effect qualitatively mimicked by osmotic cell shrinkage or treatment with TGF-␤ (2 g͞liter), phorbol 12,13-didecanoate (1 M), or the Ca 2؉ ionophore ionomycin (1 M) and blunted by high concentrations of nifedipine (10 and 100 M). In situ hybridization revealed that hSGK transcription was markedly enhanced in diabetic nephropathy, with particularly high expression in mesangial cells, interstitial cells, and cells in thick ascending limbs of Henle's loop and distal tubules. According to voltage clamp and tracer flux studies in Xenopus oocytes expressing the renal epithelial Na ؉ channel ENaC or the mouse thick ascending limb Na ؉ ,K ؉ ,2Cl ؊ cotransporter BSC-1, coexpression with hSGK stimulated ENaC and BSC-1 11-fold and 6-fold, respectively, effects reversed by kinase inhibitors staurosporine (1 M) and chelerythrine (1 M) and not elicited by inactive hSGK. In conclusion, excessive extracellular glucose concentrations enhance hSGK transcription, which in turn stimulates renal tubular Na ؉ transport. These observations disclose an additional element in the pathophysiology of diabetic nephropathy.protein kinase C ͉ endothelial cells ͉ kidney ͉ epithelial Na ϩ channel ͉ Na ϩ ,K ϩ ,2Cl Ϫ cotransporter

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“…7,8) Transforming growth factor (TGF)-β regulates extracellular matrix (ECM) metabolism and genesis of tissue fibrosis through overproduction of type I collagen. [9][10][11][12] Several signaling pathways, including the Smad and ERK pathways, mediate TGF-β-induced extracellular matrix production and fibrosis. [13][14][15] Members of the TGF-β family regulate numerous cellular activities, including cell differentiation and ECM production, 16,17) and are the primary stimulators for ECM production.…”

mentioning

confidence: 99%

β-Lapachone Regulates the Transforming Growth Factor-β–Smad Signaling Pathway Associated with Collagen Biosynthesis in Human Dermal Fibroblasts

Park

Jeong

Kim

2016

Biological & Pharmaceutical Bulletin

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The transforming growth factor (TGF)-β-Smad signaling pathway regulates collagen biosynthesis in human dermal fibroblasts. We found that β-lapachone stimulated type I collagen expression in human dermal fibroblasts. In this study, we evaluated whether the β-lapachone-induced upregulation of collagen biosynthesis in human dermal fibroblasts is associated with the TGF-β-Smad signaling pathway. In cultured human dermal fibroblasts, both Smad 2 and Smad 3 (Smad 2/3) were phosphorylated by β-lapachone treatment in a concentration-dependent manner. SB431542, a specific inhibitor of TGF-β receptor I kinase, inhibited the β-lapachone-mediated Smad 2/3 phosphorylation and type I collagen expression, suggesting that β-lapachone stimulates collagen production via the TGF-β receptor I kinase-dependent pathway. β-Lapachone did not increase TGF-β1 synthesis in human dermal fibroblasts, suggesting that the molecular mechanism of β-lapachone for the upregulation of collagen synthesis is due to the extracellular regulation of availability and activities of TGF-β. This study provides new insights into the role of β-lapachone in collagen synthesis in human dermal fibroblasts and suggests that β-lapachone can be used as a pharmacological tool to study collagen homeostasis associated with TGF-β-Smad signaling. Key words β-lapachone; collagen; human dermal fibroblast; Smad; transforming growth factor-βSkin regeneration treatments are of considerable interest to cosmeceutical researchers and dermatologists for treating skin damage that is primarily induced by aging and exposure to sunlight. Various noninvasive treatments and topical cosmeceuticals are used to treat symptoms of photo-aged skin, including wrinkles.1-3) Aging can be induced by intrinsic and extrinsic factors that reduce collagen synthesis and increase the levels of matrix metalloproteinases, which results in degradation of the connective tissue network. 4-6)Type I collagen is the most abundant structural protein in skin connective tissue and it confers strength and resilience to skin. Type I collagen is primarily synthesized by fibroblasts residing within the skin connective tissue. Type I procollagen, a soluble precursor of collagen, is secreted by fibroblasts and then proteolytically processed to form insoluble collagen fibers. Disorganization, fragmentation, and dispersion of collagen bundles are prominent features of photodamaged human skin. 7,8)Transforming growth factor (TGF)-β regulates extracellular matrix (ECM) metabolism and genesis of tissue fibrosis through overproduction of type I collagen.9-12) Several signaling pathways, including the Smad and ERK pathways, mediate TGF-β-induced extracellular matrix production and fibrosis.13-15) Members of the TGF-β family regulate numerous cellular activities, including cell differentiation and ECM production, 16,17) and are the primary stimulators for ECM production. In addition, other cytokines, such as connective tissue growth factor and interleukin-4, may also contribute to elevated collagen deposition.18) In fibrobl...

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The Renal TGF-β System in the db/db Mouse Model of Diabetic Nephropathy

Cited by 44 publications

References 37 publications

Salutary Effect of Kallistatin in Salt-Induced Renal Injury, Inflammation, and Fibrosis via Antioxidative Stress

Salutary Effect of Kallistatin in Salt-Induced Renal Injury, Inflammation, and Fibrosis via Antioxidative Stress

Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy

β-Lapachone Regulates the Transforming Growth Factor-β–Smad Signaling Pathway Associated with Collagen Biosynthesis in Human Dermal Fibroblasts

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