title: Increased dietary sodium induces COX2 expression by activating NFκB in renal medullary interstitial cells.
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.
authors.affiliation: Division of Nephrology, Department of Medicine and Cancer Biology, Vanderbilt University, Veteran Affair Medical Center, Nashville, TN.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: He
authors.affiliation: Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Department of Medicine and Cancer Biology, Vanderbilt University, Veteran Affair Medical Center, Nashville, TN.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Division of Nephrology, Department of Medicine and Cancer Biology, Vanderbilt University, Veteran Affair Medical Center, Nashville, TN.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Davis
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, 37232.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, 37232.
authors.forename: Fiona
authors.initials: F
authors.lastname: Yull
authors.affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46225, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
authors.affiliation: Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China.|Division of Nephrology, Department of Medicine and Cancer Biology, Vanderbilt University, Veteran Affair Medical Center, Nashville, TN.
authors.forename: Chuan-Ming
authors.initials: CM
authors.lastname: Hao
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage*
chemical_list: D001549:Benzamides; D016328:NF-kappa B; D017673:Sodium Chloride, Dietary; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide; D012964:Sodium; D051546:Cyclooxygenase 2
references.citation: Kidney Int. 2007 Jun;71(11):1105-15
references.pmid: 17361113
references.citation: Am J Physiol Renal Physiol. 2005 Jan;288(1):F58-64
references.pmid: 15353403
references.citation: Am J Respir Crit Care Med. 2006 May 1;173(9):1016-22
references.pmid: 16456147
references.citation: Toxicol Pathol. 1998 Jan-Feb;26(1):137-42
references.pmid: 9502396
references.citation: Am J Physiol. 1997 Jul;273(1 Pt 2):F18-26
references.pmid: 9249588
references.citation: J Am Soc Nephrol. 2004 May;15(5):1189-98
references.pmid: 15100359
references.citation: Science. 1991 Jun 28;252(5014):1813-6
references.pmid: 2063193
references.citation: J Biol Chem. 2007 Mar 30;282(13):10028-10035
references.pmid: 17261585
references.citation: Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):888-96
references.pmid: 17293239
references.citation: Am J Physiol. 1999 Sep;277(3):F352-9
references.pmid: 10484518
references.citation: Blood. 2005 Mar 15;105(6):2324-31
references.pmid: 15561889
references.citation: Am J Physiol. 1998 Mar;274(3):F481-9
references.pmid: 9530264
references.citation: Acta Physiol Scand. 2004 Aug;181(4):475-86
references.pmid: 15283761
references.citation: Am J Physiol. 1997 Apr;272(4 Pt 2):F460-8
references.pmid: 9140046
references.citation: J Clin Invest. 2002 Jul;110(1):61-9
references.pmid: 12093889
references.citation: Curr Opin Crit Care. 2001 Dec;7(6):393-400
references.pmid: 11805541
references.citation: Life Sci. 1999;64(14):1231-42
references.pmid: 10210266
references.citation: Hypertension. 2002 Apr;39(4):929-34
references.pmid: 11967252
references.citation: Ann N Y Acad Sci. 2000 Apr;905:221-31
references.pmid: 10818456
references.citation: Int J Biochem Cell Biol. 1999 May;31(5):551-7
references.pmid: 10399316
references.citation: Am J Cardiol. 2002 Nov 1;90(9):959-63
references.pmid: 12398962
references.citation: Am J Physiol. 1993 Mar;264(3 Pt 2):F472-9
references.pmid: 8456960
references.citation: Circ Res. 1975 Jun;36(6):692-6
references.pmid: 1093748
references.citation: Cancer Res. 2006 Jan 1;66(1):419-26
references.pmid: 16397257
references.citation: Am J Physiol Renal Physiol. 2008 Sep;295(3):F818-25
references.pmid: 18632796
references.citation: Am J Physiol Renal Physiol. 2006 Feb;290(2):F542-9
references.pmid: 16189289
references.citation: Hypertension. 1989 Nov;14(5):469-71
references.pmid: 2680960
references.citation: J Biol Chem. 2005 Apr 22;280(16):16354-9
references.pmid: 15713664
references.citation: Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H530-8
references.pmid: 16920808
references.citation: Biochim Biophys Acta. 1996 Jan 5;1299(1):125-40
references.pmid: 8555245
references.citation: J Clin Invest. 2000 Oct;106(8):973-82
references.pmid: 11032857
references.citation: J Cell Physiol. 1995 Apr;163(1):172-8
references.pmid: 7896894
references.citation: Kidney Int. 2000 Feb;57(2):414-22
references.pmid: 10652018
references.citation: Hypertension. 2004 Oct;44(4):424-8
references.pmid: 15314032
references.citation: Kidney Int. 2000 Dec;58(6):2420-4
references.pmid: 11115075
references.citation: Am J Cardiol. 1997 Sep 15;80(6):775-6
references.pmid: 9315588
references.citation: J Clin Invest. 2010 Apr;120(4):1056-68
references.pmid: 20335659
references.citation: Cancer Res. 2007 Apr 1;67(7):3220-8
references.pmid: 17409430
references.citation: N Engl J Med. 1983 Oct 27;309(17):1009-15
references.pmid: 6353230
references.citation: J Biol Chem. 2000 Mar 3;275(9):6259-66
references.pmid: 10692422
references.citation: Biochem Biophys Res Commun. 1997 Aug 8;237(1):28-32
references.pmid: 9266823
references.citation: J Pharmacol Exp Ther. 1997 Mar;280(3):1415-22
references.pmid: 9067331
references.citation: Plast Reconstr Surg. 2007 Dec;120(7):1808-1818
references.pmid: 18090742
references.citation: Am J Physiol. 1992 Oct;263(4 Pt 2):F594-600
references.pmid: 1415731