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Increased dietary sodium induces COX2 expression by activating NFκB in renal medullary interstitial cells

  • Signaling and cell physiology
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Abstract

High salt diet induces renal medullary cyclooxygenase 2 (COX2) expression. Selective blockade of renal medullary COX2 activity in rats causes salt-sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8 % NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6 J mice. Co-immunofluorescence using a COX2 antibody and antibodies against aquaporin-2, ClC-K, aquaporin-1, and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a sevenfold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of enhanced green fluorescent protein (EGFP) expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet-fed C57Bl/6 J mice with selective IκB kinase inhibitor IMD-0354 (8 mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary prostaglandin E2 (PGE2). These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium.

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References

  1. Bergstrom G, Evans RG (2004) Mechanisms underlying the antihypertensive functions of the renal medulla. Acta Physiol Scand 181(4):475–486

    Article  CAS  PubMed  Google Scholar 

  2. Breyer MD, Hao C, Qi Z (2001) Cyclooxygenase-2 selective inhibitors and the kidney. Curr Opin Crit Care 7(6):393–400

    Article  CAS  PubMed  Google Scholar 

  3. Breyer RM, Kennedy CR, Zhang Y, Breyer MD (2000) Structure–function analyses of eicosanoid receptors. Physiologic and therapeutic implications. Ann N Y Acad Sci 905:221–231

    Article  CAS  PubMed  Google Scholar 

  4. Chen G, Wood EG, Wang SH, Warner TD (1999) Expression of cyclooxygenase-2 in rat vascular smooth muscle cells is unrelated to nuclear factor-kappaB activation. Life Sci 64(14):1231–1242

    Article  CAS  PubMed  Google Scholar 

  5. Chen J, Zhao M, He W, Milne GL, Howard JR, Morrow J, Hebert RL, Breyer RM, Chen J, Hao CM (2008) Increased dietary NaCl induces renal medullary PGE2 production and natriuresis via the EP2 receptor. Am J Physiol Renal Physiol 295(3):F818–F825

    Article  CAS  PubMed  Google Scholar 

  6. Chen J, Zhao M, Rao R, Inoue H, Hao CM (2005) C/EBP{beta} and its binding element are required for NF{kappa}B-induced COX2 expression following hypertonic stress. J Biol Chem 280(16):16354–16359

    Article  CAS  PubMed  Google Scholar 

  7. Connelly L, Robinson-Benion C, Chont M, Saint-Jean L, Li H, Polosukhin VV, Blackwell TS, Yull FE (2007) A transgenic model reveals important roles for the NF-kappa B alternative pathway (p100/p52) in mammary development and links to tumorigenesis. J Biol Chem 282(13):10028–10035

    Article  CAS  PubMed  Google Scholar 

  8. Curtis JJ, Luke RG, Dustan HP, Kashgarian M, Whelchel JD, Jones P, Diethelm AG (1983) Remission of essential hypertension after renal transplantation. N Engl J Med 309(17):1009–1015

    Article  CAS  PubMed  Google Scholar 

  9. Dahl LK, Heine M (1975) Primary role of renal homografts in setting chronic blood pressure levels in rats. Circ Res 36(6):692–696

    Article  CAS  PubMed  Google Scholar 

  10. Fan M, Ahmed KM, Coleman MC, Spitz DR, Li JJ (2007) Nuclear factor-kappaB and manganese superoxide dismutase mediate adaptive radioresistance in low-dose irradiated mouse skin epithelial cells. Cancer Res 67(7):3220–3228

    Article  CAS  PubMed  Google Scholar 

  11. Fierro-Carrion GA, Ram CV (1997) Nonsteroidal anti-inflammatory drugs (NSAIDs) and blood pressure. Am J Cardiol 80(6):775–776

    Article  CAS  PubMed  Google Scholar 

  12. Guan Y, Chang M, Cho W, Zhang Y, Redha R, Davis L, Chang S, DuBois RN, Hao CM, Breyer M (1997) Cloning, expression, and regulation of rabbit cyclooxygenase-2 in renal medullary interstitial cells. Am J Physiol 273(1 Pt 2):F18–F26

    CAS  PubMed  Google Scholar 

  13. Guyton AC (1991) Blood pressure control—special role of the kidneys and body fluids. Science 252(5014):1813–1816

    Article  CAS  PubMed  Google Scholar 

  14. Hao CM, Breyer MD (2007) Physiologic and pathophysiologic roles of lipid mediators in the kidney. Kidney Int 71(11):1105–1115

    Article  CAS  PubMed  Google Scholar 

  15. Hao CM, Komhoff M, Guan Y, Redha R, Breyer MD (1999) Selective targeting of cyclooxygenase-2 reveals its role in renal medullary interstitial cell survival. Am J Physiol 277(3 Pt 2):F352–F359

    CAS  PubMed  Google Scholar 

  16. Hao CM, Yull F, Blackwell T, Komhoff M, Davis LS, Breyer MD (2000) Dehydration activates an NF-kappaB-driven, COX2-dependent survival mechanism in renal medullary interstitial cells. J Clin Invest 106(8):973–982

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Haugan K, Shalmi M, Petersen JS, Marcussen N, Spannow J, Christensen S (1997) Effects of renal papillary-medullary lesion on the antihypertensive effect of furosemide and development of salt-sensitive hypertension in Dahl-S rats. J Pharmacol Exp Ther 280(3):1415–1422

    CAS  PubMed  Google Scholar 

  18. He W, Wang Y, Zhang MZ, You L, Davis LS, Fan H, Yang HC, Fogo AB, Zent R, Harris RC, Breyer MD, Hao CM (2010) Sirt1 activation protects the mouse renal medulla from oxidative injury. J Clin Invest 120(4):1056–1068

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Herrera M, Garvin JL (2005) A high-salt diet stimulates thick ascending limb eNOS expression by raising medullary osmolality and increasing release of endothelin-1. Am J Physiol Renal Physiol 288(1):F58–F64

    Article  CAS  PubMed  Google Scholar 

  20. Herschman HR (1996) Prostaglandin synthase 2. Biochim Biophys Acta 1299(1):125–140

    Article  PubMed  Google Scholar 

  21. Hla T, Bishop-Bailey D, Liu CH, Schaefers HJ, Trifan OC (1999) Cyclooxygenase-1 and −2 isoenzymes. Int J Biochem Cell Biol 31(5):551–557

    Article  CAS  PubMed  Google Scholar 

  22. Inayama M, Nishioka Y, Azuma M, Muto S, Aono Y, Makino H, Tani K, Uehara H, Izumi K, Itai A, Sone S (2006) A novel IkappaB kinase-beta inhibitor ameliorates bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 173(9):1016–1022

    Article  CAS  PubMed  Google Scholar 

  23. Jackson EK (1989) Relation between renin release and blood pressure response to nonsteroidal anti-inflammatory drugs in hypertension. Hypertension 14(5):469–471

    Article  CAS  PubMed  Google Scholar 

  24. Kang KB, Wang TT, Woon CT, Cheah ES, Moore XL, Zhu C, Wong MC (2007) Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib: inhibition of tumor angiogenesis with extensive tumor necrosis. Int J Radiat Oncol Biol Phys 67(3):888–896

    Article  CAS  PubMed  Google Scholar 

  25. Khan KN, Alden CL, Gleissner SE, Gessford MK, Maziasz TJ (1998) Effect of papillotoxic agents on expression of cyclooxygenase isoforms in the rat kidney. Toxicol Pathol 26(1):137–142

    CAS  PubMed  Google Scholar 

  26. Komhoff M, Grone HJ, Klein T, Seyberth HW, Nusing RM (1997) Localization of cyclooxygenase-1 and −2 in adult and fetal human kidney: implication for renal function. Am J Physiol 272(4 Pt 2):F460–F468

    CAS  PubMed  Google Scholar 

  27. Komhoff M, Jeck ND, Seyberth HW, Grone HJ, Nusing RM, Breyer MD (2000) Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome. Kidney Int 58(6):2420–2424

    Article  CAS  PubMed  Google Scholar 

  28. Komhoff M, Wang JL, Cheng HF, Langenbach R, McKanna JA, Harris RC, Breyer MD (2000) Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development. Kidney Int 57(2):414–422

    CAS  PubMed  Google Scholar 

  29. Nakanishi T, Uyama O, Nakahama H, Takamitsu Y, Sugita M (1993) Determinants of relative amounts of medullary organic osmolytes: effects of NaCl and urea differ. Am J Physiol 264(3 Pt 2):F472–F479

    CAS  PubMed  Google Scholar 

  30. Newton R, Kuitert LM, Bergmann M, Adcock IM, Barnes PJ (1997) Evidence for involvement of NF-kappaB in the transcriptional control of COX-2 gene expression by IL-1beta. Biochem Biophys Res Commun 237(1):28–32

    Article  CAS  PubMed  Google Scholar 

  31. Onai Y, Suzuki J, Maejima Y, Haraguchi G, Muto S, Itai A, Isobe M (2007) Inhibition of NF-{kappa}B improves left ventricular remodeling and cardiac dysfunction after myocardial infarction. Am J Physiol Heart Circ Physiol 292(1):H530–H538

    Article  CAS  PubMed  Google Scholar 

  32. Park JW, Qi WN, Cai Y, Urbaniak JR, Chen LE (2007) Proteasome inhibitor attenuates skeletal muscle reperfusion injury by blocking the pathway of nuclear factor-kappaB activation. Plast Reconstr Surg 120(7):1808–1818

    Article  CAS  PubMed  Google Scholar 

  33. Peterson DP, Murphy KM, Ursino R, Streeter K, Yancey PH (1992) Effects of dietary protein and salt on rat renal osmolytes: covariation in urea and GPC contents. Am J Physiol 263(4 Pt 2):F594–F600

    CAS  PubMed  Google Scholar 

  34. Qi Z, Hao CM, Langenbach RI, Breyer RM, Redha R, Morrow JD, Breyer MD (2002) Opposite effects of cyclooxygenase-1 and −2 activity on the pressor response to angiotensin II. J Clin Invest 110(1):61–69

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Tanaka A, Konno M, Muto S, Kambe N, Morii E, Nakahata T, Itai A, Matsuda H (2005) A novel NF-kappaB inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors. Blood 105(6):2324–2331

    Article  CAS  PubMed  Google Scholar 

  36. Tanaka A, Muto S, Konno M, Itai A, Matsuda H (2006) A new IkappaB kinase beta inhibitor prevents human breast cancer progression through negative regulation of cell cycle transition. Cancer Res 66(1):419–426

    Article  CAS  PubMed  Google Scholar 

  37. Therland KL, Stubbe J, Thiesson HC, Ottosen PD, Walter S, Sorensen GL, Skott O, Jensen BL (2004) Cycloxygenase-2 is expressed in vasculature of normal and ischemic adult human kidney and is colocalized with vascular prostaglandin E2 EP4 receptors. J Am Soc Nephrol 15(5):1189–1198

    Article  CAS  PubMed  Google Scholar 

  38. Wadleigh DJ, Reddy ST, Kopp E, Ghosh S, Herschman HR (2000) Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages. J Biol Chem 275(9):6259–6266

    Article  CAS  PubMed  Google Scholar 

  39. Warnock LJ, Hunninghake GW (1995) Multiple second messenger pathways regulate IL-1 beta-induced expression of PGHS-2 mRNA in normal human skin fibroblasts. J Cell Physiol 163(1):172–178

    Article  CAS  PubMed  Google Scholar 

  40. Whelton A, White WB, Bello AE, Puma JA, Fort JG (2002) Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or =65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 90(9):959–963

    Article  CAS  PubMed  Google Scholar 

  41. White WB, Kent J, Taylor A, Verburg KM, Lefkowith JB, Whelton A (2002) Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension 39(4):929–934

    Article  CAS  PubMed  Google Scholar 

  42. Yang T, Singh I, Pham H, Sun D, Smart A, Schnermann JB, Briggs JP (1998) Regulation of cyclooxygenase expression in the kidney by dietary salt intake. Am J Physiol 274(3 Pt 2):F481–F489

    CAS  PubMed  Google Scholar 

  43. Ye W, Zhang H, Hillas E, Kohan DE, Miller RL, Nelson RD, Honeggar M, Yang T (2006) Expression and function of COX isoforms in renal medulla: evidence for regulation of salt sensitivity and blood pressure. Am J Physiol Renal Physiol 290(2):F542–F549

    Article  CAS  PubMed  Google Scholar 

  44. Zewde T, Mattson DL (2004) Inhibition of cyclooxygenase-2 in the rat renal medulla leads to sodium-sensitive hypertension. Hypertension 44(4):424–428

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Immunofluorescence experiments were performed in part through the use of the VUMC Cell Imaging Shared Resource. These studies were supported by Natural Science Foundation of China 81130075, Major State Basic Research Development Program of China (973 program) 2012CB517700, 985 Project of China 985III-YFX0302, and National Institute of Diabetes and Digestive and Kidney Disease grant DK071876 to CM Hao.

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Authors and Affiliations

  1. Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China

    Min Zhang & Chuan-Ming Hao

  2. Division of Nephrology, Department of Medicine and Cancer Biology, Veteran Affair Medical Center, Vanderbilt University, Nashville, TN, USA

    Wenjuan He, Min Zhao, Linda S. Davis & Chuan-Ming Hao

  3. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Timothy S. Blackwell & Fiona Yull

  4. Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA

    Matthew D. Breyer

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  1. Wenjuan He
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Correspondence to Chuan-Ming Hao.

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Wenjuan He and Min Zhang equally contributed to this work.

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He, W., Zhang, M., Zhao, M. et al. Increased dietary sodium induces COX2 expression by activating NFκB in renal medullary interstitial cells. Pflugers Arch - Eur J Physiol 466, 357–367 (2014). https://doi.org/10.1007/s00424-013-1328-7

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  • DOI: https://doi.org/10.1007/s00424-013-1328-7

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