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Angiotensin-II and rosuvastatin influence matrix remodeling in human mesangial cells via metalloproteinase modulation.
J Hypertens. 2011 Oct; 29(10):1930-9.JH

Abstract

OBJECTIVE

Persistent inflammation and oxidative stress influence the progression of diabetic nephropathy. Metalloproteinases (MMPs) participate in extracellular matrix remodeling. Statins show favorable anti-inflammatory effects in chronic kidney disease. We evaluated the effect of rosuvastatin on inflammatory and pro-fibrotic responses due to exposure to different glucose or free fatty acid (FFA) concentrations.

METHODS

Human mesangial cells (HMCs) grown at 5.5 (normal glucose) or 22 mmol/l (high glucose) glucose or exposed to FFA were treated with angiotensin-II in the presence or absence of rosuvastatin. We measured MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 expression and activity, and quantified the fibrotic factors transforming growth factor-β1 (TGF-β1), fibronectin, and collagen IV.

RESULTS

At normal glucose, angiotensin-II induced a dose-dependent downregulation of MMP-2; rosuvastatin reversed this effect. On the contrary, TIMP-2 and MMP-9 were upregulated by angiotensin-II and downregulated by rosuvastatin; the effects on TIMP-1 were negligible. Some of the angiotensin-II effects were potentiated in the presence of high glucose and FFA; under both conditions, rosuvastatin was able to reverse these effects. MMP-2 and MMP-9 activity followed the same trend of expression, with rosuvastatin able to upregulate MMP-2 activity. The modulation of the MMP/TIMP system was paralleled by an increase in TGF-β1, fibronectin, and collagen-IV; all were reduced by rosuvastatin treatment. Silencing the MMP-2 gene confirmed its role in modulating some of these angiotensin-II effects.

CONCLUSION

Angiotensin-II induces a pro-fibrotic response in HMCs mainly via a dysregulation of the MMP-2/TIMP-2 pattern. This effect, partially amplified in the presence of high glucose and FFA, is reversed by rosuvastatin, suggesting another potential therapeutic application for this 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor.

Authors+Show Affiliations

Department of Internal Medicine, University of Pisa, Pisa, Italy. anna.solini@med.unipi.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

21881526

Citation

Solini, Anna, et al. "Angiotensin-II and Rosuvastatin Influence Matrix Remodeling in Human Mesangial Cells Via Metalloproteinase Modulation." Journal of Hypertension, vol. 29, no. 10, 2011, pp. 1930-9.
Solini A, Rossi C, Santini E, et al. Angiotensin-II and rosuvastatin influence matrix remodeling in human mesangial cells via metalloproteinase modulation. J Hypertens. 2011;29(10):1930-9.
Solini, A., Rossi, C., Santini, E., Madec, S., Salvati, A., & Ferrannini, E. (2011). Angiotensin-II and rosuvastatin influence matrix remodeling in human mesangial cells via metalloproteinase modulation. Journal of Hypertension, 29(10), 1930-9. https://doi.org/10.1097/HJH.0b013e32834abceb
Solini A, et al. Angiotensin-II and Rosuvastatin Influence Matrix Remodeling in Human Mesangial Cells Via Metalloproteinase Modulation. J Hypertens. 2011;29(10):1930-9. PubMed PMID: 21881526.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Angiotensin-II and rosuvastatin influence matrix remodeling in human mesangial cells via metalloproteinase modulation. AU - Solini,Anna, AU - Rossi,Chiara, AU - Santini,Eleonora, AU - Madec,Stephanie, AU - Salvati,Antonio, AU - Ferrannini,Ele, PY - 2011/9/2/entrez PY - 2011/9/2/pubmed PY - 2012/1/17/medline SP - 1930 EP - 9 JF - Journal of hypertension JO - J Hypertens VL - 29 IS - 10 N2 - OBJECTIVE: Persistent inflammation and oxidative stress influence the progression of diabetic nephropathy. Metalloproteinases (MMPs) participate in extracellular matrix remodeling. Statins show favorable anti-inflammatory effects in chronic kidney disease. We evaluated the effect of rosuvastatin on inflammatory and pro-fibrotic responses due to exposure to different glucose or free fatty acid (FFA) concentrations. METHODS: Human mesangial cells (HMCs) grown at 5.5 (normal glucose) or 22 mmol/l (high glucose) glucose or exposed to FFA were treated with angiotensin-II in the presence or absence of rosuvastatin. We measured MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 expression and activity, and quantified the fibrotic factors transforming growth factor-β1 (TGF-β1), fibronectin, and collagen IV. RESULTS: At normal glucose, angiotensin-II induced a dose-dependent downregulation of MMP-2; rosuvastatin reversed this effect. On the contrary, TIMP-2 and MMP-9 were upregulated by angiotensin-II and downregulated by rosuvastatin; the effects on TIMP-1 were negligible. Some of the angiotensin-II effects were potentiated in the presence of high glucose and FFA; under both conditions, rosuvastatin was able to reverse these effects. MMP-2 and MMP-9 activity followed the same trend of expression, with rosuvastatin able to upregulate MMP-2 activity. The modulation of the MMP/TIMP system was paralleled by an increase in TGF-β1, fibronectin, and collagen-IV; all were reduced by rosuvastatin treatment. Silencing the MMP-2 gene confirmed its role in modulating some of these angiotensin-II effects. CONCLUSION: Angiotensin-II induces a pro-fibrotic response in HMCs mainly via a dysregulation of the MMP-2/TIMP-2 pattern. This effect, partially amplified in the presence of high glucose and FFA, is reversed by rosuvastatin, suggesting another potential therapeutic application for this 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor. SN - 1473-5598 UR - https://www.unboundmedicine.com/medline/citation/21881526/Angiotensin_II_and_rosuvastatin_influence_matrix_remodeling_in_human_mesangial_cells_via_metalloproteinase_modulation_ L2 - https://doi.org/10.1097/HJH.0b013e32834abceb DB - PRIME DP - Unbound Medicine ER -