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Nitric oxide and superoxide in rat mesangial cells: modulation by C-reactive protein

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Abstract

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.

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Abbreviations

CRP:

C-reactive protein

DPI:

Diphenyleneiodium chloride

HSP:

Heat shock protein

INOS:

Inducible nitric oxide synthase

NO:

Nitric oxide

RMC:

Rat mesangial cell

References

  1. Volanakis JE (2001) Human C-reactive protein: expression, structure, and function. Mol Immunol 38:189–197

    CAS  PubMed  Google Scholar 

  2. Pepys MB, Hirschfeld GM (2003) C-reactive protein: A critical update. J Clin Invest 111:1805–1812

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Panichi V, Migliori M, De Pietro S, Taccola D, Bianchi AM, Norpoth M, Metelli MR, Giovannini L, Tetta C, Palla R (2001) C reactive protein in patients with chronic renal diseases. Renal Failure 23:551–562

    CAS  PubMed  Google Scholar 

  4. Goggins MG, Shah SA, Goh J, Cherukuri A, Weir DG, Kelleher D, Mahmudca N (2001) Increased urinary nitrite, a marker of nitric oxide, in active inflammatory bowel disease. Mediat Inflamm 10:69–73

    CAS  Google Scholar 

  5. Chew DP, Bhatt DL, Robbins MA, Penn MS, Schneider JP, Laue MS, Topol EJ, Ellis SG (2001) Incremental prognostic value of elevated C-reactive protein among baseline established markers of risk in percutaneous coronary interventions. Circulation 104:992–997

    CAS  PubMed  Google Scholar 

  6. Albert MA, Danielson E, Rifai N, Ridker PM, PRINCE Investigators (2001) Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PINCE): a randomized trial and cohort study. JAMA 286:64–70

    CAS  PubMed  Google Scholar 

  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 344:959–965

    Google Scholar 

  8. Sarnak MJ, Poindexter A, Wang SR, Beck GJ, Kusek JW, Marcovina SM, Greene T, Levey AS (2002) Serum C-reactive protein and leptin as predictors of kidney disease progression in the Modification of Diet in Renal disease Study. Kidney Int 62:2208–2215

    CAS  PubMed  Google Scholar 

  9. Nathan C, Xie QW (1994) Regulation of biosynthesis of nitric oxide. J Biol Chem 269:13725–13728

    CAS  PubMed  Google Scholar 

  10. Kanwar S, Kubes P (1995) Nitric oxide is an antiadhesive molecule for leukocytes. New Horiz 3:93–104

    CAS  PubMed  Google Scholar 

  11. Ito S, Ren YL (1993) Evidence for the role of nitric oxide in macula densa control of glomerular hemodynamics. J Clin Invest 92:1093–1098

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Shultz PJ, Tolins JP (1993) Adaptation to increased dietary salt intake in the rat: Role of endogenous nitric oxide. J Clin Invest 91:642–650

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Garg UC, Hassid A (1989) Inhibition of rat mesangial cell mitogenesis by nitric oxide-generating vasodilators. Am J Physiol 257:F60–F66

    CAS  PubMed  Google Scholar 

  14. Trachtman H, Futterweit S, Singhal P (1995) Nitric oxide modulates the synthesis of extracellular matrix proteins in cultured rat mesangial cells. Biochem Biophys Res Commun 207:120–125

    CAS  PubMed  Google Scholar 

  15. Trachtman H, Futterweit S, Garg P, Reddy K, Singhal PC (1996) Nitric oxide stimulates the activity of a 72-kDa neutral matrix metalloproteinase in cultured rat mesangial cells. Biochem Biophys Res Commun 208:704–708

    Google Scholar 

  16. Shultz PJ, Archer SL, Rosenberg ME (1994) Inducible nitric oxide synthase mRNA and activity in glomerular mesangial cells. Kidney Int 46:683–689

    CAS  PubMed  Google Scholar 

  17. Jaimes EA, Galceran JM, Raij L (1998) Angiotensin II induces superoxide anion production by mesangial cells. Kidney Int 54:775–784

    CAS  PubMed  Google Scholar 

  18. Hasdan G, Benchetrit S, Rashid G, Green J, Bernheim J, Rathaus M (2002) Endothelial dysfunction and hypertension in 5/6 nephrectomized rats are mediated by vascular superoxide. Kidney Int 61:586–59019

    CAS  PubMed  Google Scholar 

  19. Van Den Branden C, Ceyssens B, De Craemer D, Pauwels M, Vanden Houte K, De Bleser P, Hellemans K, Geerts A, Verbeelen D (2000) Renal antioxidant enzymes and fibrosis-related markers in the rat adriamycin model. Nephron 86:167–175

    PubMed  Google Scholar 

  20. Xia Y, Zweier JL (1997) Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proc Natl Acad Sci USA 94:954–6958

    Google Scholar 

  21. Pasceri V, Chang J, Willerson JT, Yeh ET (2001) Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation 103:2531–2534

    CAS  PubMed  Google Scholar 

  22. Abboud H, Poptic E, DiCorleto P (1987) Production of platelet-derived growth factorlike protein by rat mesangial cells in culture. J Clin Invest 80:675–683

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Trachtman H, Gauthier B, Frank R, Futterweit S, Goldstein A, Tomczak J (1996) Increased urinary nitrite excretion in children with minimal change nephrotic syndrome. J Pediatr 128:173–176

    CAS  PubMed  Google Scholar 

  24. Singhal PC, Pamarthi M, Shah R, Chandra D, Gibbons N (1994) Morphine stimulates Superoxide formation by glomerular mesangial cells. Inflammation 18:293–299

    CAS  PubMed  Google Scholar 

  25. Sood A, Mathew R, Trachtman H (2001) Cytoprotective effect of curcumin in human proximal tubule epithelial cells exposed to Shiga toxin. Biochem Biophys Res Commun 283:36–41

    CAS  PubMed  Google Scholar 

  26. Trachtman H, Futterweit S, Franki N, Singhal PC (1998) Effect of vascular endothelial growth factor on nitric oxide production by cultured rat mesangial cells. Biochem Biophys Res Commun 245:443–446

    CAS  PubMed  Google Scholar 

  27. Trachtman H, Futterweit S, Crimmins DL (1997) High glucose inhibits nitric oxide production in cultured rat mesangial cell. J Am Soc Nephrol 8:1276–1282

    CAS  PubMed  Google 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 16:2906–2912

    CAS  PubMed  Google Scholar 

  29. Ford FS, Loucks EB, Berkman LF (2006) Social integration and concentrations off C-reactive protein among US adults. Ann Epidemiol 16:78–84

    PubMed  Google Scholar 

  30. Chang JW, Kim CS, Kim SB, Park SK, Park JS, Lee SK (2005) C-reactive protein induces NF-kappaB activation through intracellular calcium and ROS in human mesangial cells. Nephron Exp Nephrol 101:e165–e172

    CAS  PubMed  Google Scholar 

  31. Bussolati B, Peri G, Salvidio G, Verzola D, Mantovani A, Camussi G (2003) The long pentraxin PTX3 is synthesized in IgA glomerulonephritis and activates mesangial cells. J Immunol 170:1466–1472

    CAS  PubMed  Google Scholar 

  32. Nauta AJ, Haij S, Bottazzi B, Mantovani A, Borrias MC, Aten J, Rastaldi MP, Daha MR, van Kooten C, Roos A (2005) Human renal epithelial cells produce the long petraxin PTX3. Kidney Int 67:543–553

    CAS  PubMed  Google Scholar 

  33. Colasanti M, Persichini T, Menegazzi M, Mariotto S, Giordano E, Caldarera CM, Sogos V, Lauro GM, Suzuki H (1995) Induction of nitric oxide synthase mRNA expression: Suppression by endogenous nitric oxide. J Biol Chem 270:26731–26733

    CAS  PubMed  Google Scholar 

  34. Ratnam S, Mookerjea S (1998) The regulation of superoxide generation and nitric oxide synthesis by C-reactive protein. Immunology 94:560–568

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Cleland SJ, Sattar N, Petrie JR, Forouhi NG, Elliot HL, Connell JM (2000) Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease. Clin Sci 98:531–535

    CAS  PubMed  Google Scholar 

  36. Onur O, Akinci AS, Akbiyik F, Unsal I (2001) Elevated levels of nitrate in rheumatoid arthritis. Rheumatol Int 20:154–158

    CAS  PubMed  Google Scholar 

  37. Borderie D, Hilliquin P, Hernvann A, Kahan A, Menkes CJ, Ekindjian OG (1999) Nitric oxide synthase is expressed in the lymphomononuclear cells of synovial fluid in patients with rheumatoid arthritis. J Rheumatol 26:2083–2088

    CAS  PubMed  Google Scholar 

  38. Giovonnoni G, Miller D, Losseff NA, Sailer M, Lewellyn-Smith N, Thompson AJ, Thompson EJ (2001) Serum inflammatory markers and clinical/MRI markers of disease progression in multiple sclerosis. J Neurol 248:487–495

    Google Scholar 

  39. Onozato ML, Tojo A, Goto A, Fujita T, Wilcox CS (2002) Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: Effects of ACEI and ARB. Kidney Int 61:186–194

    CAS  PubMed  Google Scholar 

  40. Mortensen RF, Zhong W (2000) Regulation of phagocytic leukocyte activities by C-reactive protein. J Leukocyte Biol 67:495–500

    CAS  PubMed  Google Scholar 

  41. Prabhakar SS (2002) Inhibition of mesangial iNOS by reduced extracellular pH is associated with uncoupling of NADPH oxidation. Kidney Int 61:2015–2024

    CAS  PubMed  Google Scholar 

  42. Beck FX, Neuhofer W, Muller E (2000) Molecular chaperones in the kidney distribution, putative roles, and regulation. Am J Physiol 279:F203–F215

    CAS  Google Scholar 

  43. Xu O, Hu Y, Kleindienst R, Wick G (1997) Nitric oxide induces heat-shock protein 70 expression in vascular smooth muscle cells via activation of heat shock factor 1. J Clin Invest 100:1089–1097

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Diamond JR, Karnovsky MJ (1988) Focal and segmental glomerulosclerosis: analogies to atherosclerosis. Kidney Int 33:917–924

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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).

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Authors and Affiliations

  1. Department of Pediatrics (Division of Nephrology), Schneider Children’s Hospital, New Hyde Park, NY, USA

    Howard Trachtman, Stephen Futterweit, Christopher Arzberger, Jessica Bod, Judah Goldschmiedt, Haddassah Gorman, Krishna Reddy, Nicholas Franki & Pravin C. Singhal

  2. Department of Medicine (Division of Nephrology), Long Island Jewish Hospital, North Shore-Long Island Jewish Health System, Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, NY, USA

    Howard Trachtman, Stephen Futterweit, Christopher Arzberger, Jessica Bod, Judah Goldschmiedt, Haddassah Gorman, Krishna Reddy, Nicholas Franki & Pravin C. Singhal

  3. Division of Nephrology, Schneider Children’s Hospital, Room SCH 365, 269-01 76th Avenue, New Hyde Park, NY, 11040-1432, USA

    Howard Trachtman

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  1. Howard Trachtman
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Correspondence to Howard Trachtman.

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Trachtman, H., Futterweit, S., Arzberger, C. et al. Nitric oxide and superoxide in rat mesangial cells: modulation by C-reactive protein. Pediatr Nephrol 21, 619–626 (2006). https://doi.org/10.1007/s00467-006-0066-x

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  • DOI: https://doi.org/10.1007/s00467-006-0066-x

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