3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/ p21 signaling pathway: Implications for diabetic nephropathy

Danesh, Farhad R.; Sadeghi, Mehran M.; Amro, Nail; Philips, Carrie L.; Zeng, Lixia; Sun, Lin; Sahai, Atul; Kanwar, Yashpal S.

doi:10.1073/pnas.122228799

Cited by 222 publications

(195 citation statements)

References 39 publications

(50 reference statements)

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“…Both FPP and GGPP are important lipid attachments required for the subcellular localization and function of a variety of proteins, including small GTPase-binding proteins (9). In support of cholesterol-independent or pleiotropic properties of statins in diabetic nephropathy, we and others recently showed that some of the beneficial effects of statin therapy in diabetic milieu may be mediated via modulation of small GTPase proteins (10,11).…”

mentioning

confidence: 87%

“…Anti-p27 antibody was purchased from BD Bioscience Pharmingen (San Diego, CA), and fluorescence probe 2', 7'-dichlorofluororescin diacetate (DCF-DA) was obtained from Molecular Probes (Eugene, OR). SMV and MEV were chemically activated as described previously (10).…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

“…Transfections of different mutants were performed as described previously (10). Briefly, in transfection studies, cells were grown tõ 50% confluence and then transfected with 1 g of fusion plasmid DNA using LipofectAMINE Reagent according to the manufacturer's protocol (Invitrogen).…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

“…MC were plated in 24-well plates, serum starved for 48 h, and then exposed to Ang II (100 nM) in the presence or absence of SMV (1 M) for 24 h with addition of 1 Ci of [ 3 H]leucine for 6 h (Amersham, Piscataway, NJ) and then processed for determination of incorporated radioactivity after precipitation with 10% TCA as described previously (10).…”

Section: [ 3 H]leucine Incorporationmentioning

confidence: 99%

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Simvastatin Modulates Angiotensin II Signaling Pathway by Preventing Rac1-Mediated Upregulation of p27

Zeng¹,

Xu²,

Chew

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Recent experimental observations have suggested that statins may exert modulatory effects on a number of pathobiological processes beyond their cholesterol-lowering properties. Some of the pleiotropic effects of statins seem to be mediated by their ability to block the synthesis of isoprenoid intermediates, which serve as important lipid attachments required for the proper function and activation of the small GTP-binding proteins. The current study explored the modulatory effects of simvastatin (SMV) on the angiotensin II (Ang II)-induced Rac1-mediated, upregulation of cyclin-dependent kinase inhibitor p27. Ang II (100 nM) stimulation of rat mesangial cells induced a significant increase in p27 protein expression. Co-treatment of cells with SMV (1 M) inhibited Ang II-induced upregulation of p27 protein. Addition of mevalonate (200 M) or geranylgeranyl pyrophosphate (5 M) reversed the inhibitory effect of SMV on p27 protein expression, suggesting that the effect of SMV is geranylgeranyl dependent. This study also provides evidence for a sequential link between Ang II stimulation and downstream activation of Rac1, intracellular H 2 O 2 production, and Akt kinase leading to upregulation of p27 protein in mesangial cells. It was also shown that SMV, by inhibiting Rac1 activity, reversed Ang II-induced increase in intracellular H 2 O 2 production, Akt activation, and p27 protein expression. The data presented in this study not only elucidate Ang II-mediated signaling cascade in mesangial cells but also demonstrate for the first time the modulatory effects of SMV on Ang II-induced signaling pathway at the cell cycle level.

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mentioning

confidence: 87%

Section: Reagents and Antibodiesmentioning

confidence: 99%

Section: Cell Culture and Transfectionmentioning

confidence: 99%

Section: [ 3 H]leucine Incorporationmentioning

confidence: 99%

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Simvastatin Modulates Angiotensin II Signaling Pathway by Preventing Rac1-Mediated Upregulation of p27

Zeng¹,

Xu²,

Chew

et al. 2004

Journal of the American Society of Nephrology

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“…In their active state, these proteins regulate important cellular functions including cell survival, proliferation, and differentiation, as well as cytoskeletal organization, by relaying extracellular ligand-stimulated signals to cytoplasmic signaling cascades (40,41). It is the inhibition of prenylation of the Rho-and Ras-related proteins by statins that is postulated to be responsible for some of the pleiotropic effects of this class of agents (42,43).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of systemic sclerosis dermal fibroblast type I collagen production and gene expression by simvastatin

Louneva¹,

Huaman²,

Fertala³

et al. 2006

Arthritis & Rheumatism

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Objective. To examine whether statins are capable of modulating collagen gene expression in cultured systemic sclerosis dermal fibroblasts.Methods. Cultured dermal fibroblasts from 3 patients with diffuse systemic sclerosis of recent onset were treated with 5 M and 10 M of simvastatin for 3 or 4 days. Morphologic features, cytotoxicity, and type I collagen production and messenger RNA (mRNA) levels in the fibroblasts were examined. The effects of mevalonate, geranylgeranyl pyrophosphate (GGPP), and farnesyl pyrophosphate (FPP), which are lipids downstream from the hydroxymethylglutaryl-coenzyme A block, were also examined. Transient transfections with COL1A1 promoter-reporter constructs and electrophoretic gel mobility shift assays were utilized to examine COL1A1 transcription and Sp1 and CCAAT-box binding factor (CBF) binding.Results. Simvastatin did not cause morphologic changes or cytotoxicity in the fibroblasts, even after 4 days of treatment. Type I collagen production and mRNA levels showed a potent and dose-related inhibition following 3 and 4 days of treatment. The inhibition of collagen gene expression by simvastatin was completely reversed by mevalonate and GGPP, but not by FPP. The statin effects occurred at the transcriptional level and involved the proximal COL1A1 promoter region encompassing ؊174 bp. A significant reduction in Sp1 and CBF binding activity was also found in simvastatin-treated cells.

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Medical Therapies: Statins

Sokalska¹,

Dulęba²

2011

Endometriosis

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3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/ p21 signaling pathway: Implications for diabetic nephropathy

Cited by 222 publications

References 39 publications

Simvastatin Modulates Angiotensin II Signaling Pathway by Preventing Rac1-Mediated Upregulation of p27

Simvastatin Modulates Angiotensin II Signaling Pathway by Preventing Rac1-Mediated Upregulation of p27

Inhibition of systemic sclerosis dermal fibroblast type I collagen production and gene expression by simvastatin

Medical Therapies: Statins

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