Nitric oxide and superoxide in rat mesangial cells: modulation by C-reactive protein
- 78 Downloads
Background: C-reactive protein (CRP) has been linked to cardiovascular and renal disease. We evaluated the effects of CRP on the production of nitric oxide (NO) and superoxide by rat mesangial cells (RMC) and the impact on cell function. Methods and Results: RMC were incubated with cytokines (IFN-γ, IL-1β, and LPS) and CRP (10–100 μg/ml) for 24–72 h. Exposure to CRP resulted in a time- and dose-dependent reduction in NO accumulation (p<0.05). Although inducible nitric oxide synthase (iNOS) protein expression was unaltered after 48 h, CRP stimulated expression of HSP90. Steady state abundance of iNOS mRNA increased nearly threefold after a 24-h exposure to CRP. Incubation with 100 μg/ml CRP for 60–120 min resulted in a 272% increase in superoxide production that was prevented by diphenyleneiodium chloride but not L-NAME (p<0.0001). Conclusion: CRP enhances superoxide release in RMC, which in turn inactivates NO and reduces net production. The functional relevance of these CRP-induced changes is supported by increased expression of HSP90 in RMC exposed to the mediator. These findings suggest that systemic inflammation, which contributes to the pathogenesis of atherosclerosis, may play a role in the progression of kidney disease.
KeywordsC-reactive protein Heat shock protein 90 Inducible nitric oxide synthase NADPH oxidase Nitric oxide Superoxide Rat mesangial cells
Heat shock protein
Inducible nitric oxide synthase
Rat mesangial cell
This work was supported in part by a grant from the National Institute of Health, NIDDK, RO1-52147 (HT). Portions of this work have been presented at the annual meetings of the Society for Pediatric Research, May 5, 2002 and the American Society of Nephrology, November 3, 2002, and have been published in abstract form (Pediatr Res 2002;51:428A and J Am Soc Nephrol 2002;13:556A).
- 7.Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr, Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators (2001) Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 344:959–965CrossRefGoogle Scholar
- 20.Xia Y, Zweier JL (1997) Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proc Natl Acad Sci USA 94:954–6958Google Scholar
- 28.Miyata K, Rahman M, Shokoji T, Nagai Y, Zhang GX, Sun GP, Kimura S, Yukimura T, Kiyomoto H, Kohno M, Abe Y, Nishiyama A (2005) Aldosterone stimulates reactive oxygen species production through activation of NADPH oxidase in rat mesangial cells. J Am Soc Nephrol 16:2906–2912PubMedCrossRefGoogle Scholar
- 29.Ford FS, Loucks EB, Berkman LF (2006) Social integration and concentrations off C-reactive protein among US adults. Ann Epidemiol 16:78–84Google Scholar
- 42.Beck FX, Neuhofer W, Muller E (2000) Molecular chaperones in the kidney distribution, putative roles, and regulation. Am J Physiol 279:F203–F215Google Scholar