Skip to main content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
J Clin Invest. 1994 Dec; 94(6): 2504–2510.
doi: 10.1172/JCI117620
PMCID: PMC330084
PMID: 7989609

Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction.

R C Harris, J A McKanna, Y Akai, H R Jacobson, R N Dubois, and M D Breyer
Author information Copyright and License information PMC Disclaimer

Abstract

The kidney is a rich source of prostaglandins. These eicosanoids, formed by cyclooxygenase-dependent metabolism of arachidonic acid, are important physiologic mediators of renal glomerular hemodynamics and tubular sodium and water reabsorption. Two separate isoforms of cyclooxygenase (COX) have now been identified: constitutive COX-1, encoded by a 2.8-kb mRNA, and mitogen-activated COX-2, encoded by a 4.0-4.5-kb mRNA. COX-2 expression increases during development and inflammation, but, except for brain, constitutive expression is low. It has been generally accepted that physiologic renal production of prostaglandins is mediated by COX-1. However, in the absence of inflammation, low levels of COX-2 mRNA are also detectable in the kidney. To examine the role of COX-2 in the kidney and determine its intrarenal localization, we used a 1.3-kb cDNA probe specific for the 3' untranslated region of rat COX-2 and COX-2-specific antiserum. The COX-2-specific cDNA probe hybridized with a 4.4-kb transcript in total RNA from adult rat kidney. Immunoblots of microsomes isolated from kidney cortex and papilla indicated immunoreactive COX-2 in both locations. In situ hybridization and immunohistochemistry indicated that renal cortical COX-2 expression was localized to the macula densa of the juxtaglomerular apparatus and to adjacent epithelial cells of the cortical thick ascending limb of Henle. In addition, COX-2 immunoreactivity was detected in interstitial cells in the papilla. No COX-2 message or immunoreactive protein was detected in arterioles, glomeruli, or cortical or medullary collecting ducts. When animals were chronically sodium restricted, the level of COX-2 in the region of the macula densa increased threefold (from 0.86 +/- 0.08 to 2.52 +/- 0.43/mm2) and the total area of the COX-2 immunoreactive cells in cortex increased from 34 microns2/mm2 of cortex to 226 microns2/mm2 of cortex. The intrarenal distribution of COX-2 and its increased expression in response to sodium restriction suggest that in addition to its proposed role in inflammatory and growth responses, this enzyme may play an important role in the regulation of salt, volume, and blood pressure homeostasis.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.7M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

 
icon of scanned page 2504
2504
icon of scanned page 2505
2505
icon of scanned page 2506
2506
icon of scanned page 2507
2507
icon of scanned page 2508
2508
icon of scanned page 2509
2509
icon of scanned page 2510
2510
 

Images in this article

Image

Image
on p.2505

Image

Image
on p.2506

Image

Image
on p.2508

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  • Needleman P, Turk J, Jakschik BA, Morrison AR, Lefkowith JB. Arachidonic acid metabolism. Annu Rev Biochem. 1986;55:69–102. [PubMed] [Google Scholar]
  • DeWitt DL, Smith WL. Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1412–1416. [PMC free article] [PubMed] [Google Scholar]
  • Smith WL, Bell TG. Immunohistochemical localization of the prostaglandin-forming cyclooxygenase in renal cortex. Am J Physiol. 1978 Nov;235(5):F451–F457. [PubMed] [Google Scholar]
  • Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem. 1991 Jul 15;266(20):12866–12872. [PubMed] [Google Scholar]
  • Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2692–2696. [PMC free article] [PubMed] [Google Scholar]
  • O'Banion MK, Winn VD, Young DA. cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4888–4892. [PMC free article] [PubMed] [Google Scholar]
  • O'Banion MK, Sadowski HB, Winn V, Young DA. A serum- and glucocorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein. J Biol Chem. 1991 Dec 5;266(34):23261–23267. [PubMed] [Google Scholar]
  • Fletcher BS, Kujubu DA, Perrin DM, Herschman HR. Structure of the mitogen-inducible TIS10 gene and demonstration that the TIS10-encoded protein is a functional prostaglandin G/H synthase. J Biol Chem. 1992 Mar 5;267(7):4338–4344. [PubMed] [Google Scholar]
  • Tippetts MT, Varnum BC, Lim RW, Herschman HR. Tumor promoter-inducible genes are differentially expressed in the developing mouse. Mol Cell Biol. 1988 Oct;8(10):4570–4572. [PMC free article] [PubMed] [Google Scholar]
  • Masferrer JL, Seibert K, Zweifel B, Needleman P. Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3917–3921. [PMC free article] [PubMed] [Google Scholar]
  • Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11693–11697. [PMC free article] [PubMed] [Google Scholar]
  • DuBois RN, Tsujii M, Bishop P, Awad JA, Makita K, Lanahan A. Cloning and characterization of a growth factor-inducible cyclooxygenase gene from rat intestinal epithelial cells. Am J Physiol. 1994 May;266(5 Pt 1):G822–G827. [PubMed] [Google Scholar]
  • O'Neill GP, Ford-Hutchinson AW. Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett. 1993 Sep 13;330(2):156–160. [PubMed] [Google Scholar]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed] [Google Scholar]
  • Breyer MD, Jacobson HR, Davis LS, Breyer RM. In situ hybridization and localization of mRNA for the rabbit prostaglandin EP3 receptor. Kidney Int. 1993 Dec;44(6):1372–1378. [PubMed] [Google Scholar]
  • Akai Y, Homma T, Burns KD, Yasuda T, Badr KF, Harris RC. Mechanical stretch/relaxation of cultured rat mesangial cells induces protooncogenes and cyclooxygenase. Am J Physiol. 1994 Aug;267(2 Pt 1):C482–C490. [PubMed] [Google Scholar]
  • McKanna JA, Chuncharunee A, Munger KA, Breyer JA, Cohen S, Harris RC. Localization of p35 (annexin I, lipocortin I) in normal adult rat kidney and during recovery from ischemia. J Cell Physiol. 1992 Dec;153(3):467–476. [PubMed] [Google Scholar]
  • Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron. 1993 Aug;11(2):371–386. [PubMed] [Google Scholar]
  • Sirois J, Richards JS. Purification and characterization of a novel, distinct isoform of prostaglandin endoperoxide synthase induced by human chorionic gonadotropin in granulosa cells of rat preovulatory follicles. J Biol Chem. 1992 Mar 25;267(9):6382–6388. [PubMed] [Google Scholar]
  • Habib A, Créminon C, Frobert Y, Grassi J, Pradelles P, Maclouf J. Demonstration of an inducible cyclooxygenase in human endothelial cells using antibodies raised against the carboxyl-terminal region of the cyclooxygenase-2. J Biol Chem. 1993 Nov 5;268(31):23448–23454. [PubMed] [Google Scholar]
  • Feng L, Sun W, Xia Y, Tang WW, Chanmugam P, Soyoola E, Wilson CB, Hwang D. Cloning two isoforms of rat cyclooxygenase: differential regulation of their expression. Arch Biochem Biophys. 1993 Dec;307(2):361–368. [PubMed] [Google Scholar]
  • Stokes JB. Integrated actions of renal medullary prostaglandins in the control of water excretion. Am J Physiol. 1981 Jun;240(6):F471–F480. [PubMed] [Google Scholar]
  • Dunn MJ, Staley RS, Harrison M. Characterization of prostaglandin production in tissue culture of rat renal medullary cells. Prostaglandins. 1976 Jul;12(1):37–49. [PubMed] [Google Scholar]
  • Persson AE, Salomonsson M, Westerlund P, Greger R, Schlatter E, Gonzalez E. Macula densa cell function. Kidney Int Suppl. 1991 Jun;32:S39–S44. [PubMed] [Google Scholar]
  • Franco M, Bell PD, Navar LG. Evaluation of prostaglandins as mediators of tubuloglomerular feedback. Am J Physiol. 1988 May;254(5 Pt 2):F642–F649. [PubMed] [Google Scholar]
  • Takabatake T, Hara H, Ishida Y, Ohta H, Kobayashi K. Renal effects of endogenous prostaglandin synthesis promoter ONO-3122. Am J Physiol. 1992 Jun;262(6 Pt 2):F1047–F1054. [PubMed] [Google Scholar]
  • Welch WJ, Wilcox CS. Potentiation of tubuloglomerular feedback in the rat by thromboxane mimetic. Role of macula densa. J Clin Invest. 1992 Jun;89(6):1857–1865. [PMC free article] [PubMed] [Google Scholar]
  • Burns KD, Homma T, Harris RC. The intrarenal renin-angiotensin system. Semin Nephrol. 1993 Jan;13(1):13–30. [PubMed] [Google Scholar]
  • Schlatter E, Salomonsson M, Persson AE, Greger R. Macula densa cells sense luminal NaCl concentration via furosemide sensitive Na+2Cl-K+ cotransport. Pflugers Arch. 1989 Jul;414(3):286–290. [PubMed] [Google Scholar]
  • Martínez-Maldonado M, Gely R, Tapia E, Benabe JE. Role of macula densa in diuretics-induced renin release. Hypertension. 1990 Sep;16(3):261–268. [PubMed] [Google Scholar]
  • Lorenz JN, Greenberg SG, Briggs JP. The macula densa mechanism for control of renin secretion. Semin Nephrol. 1993 Nov;13(6):531–542. [PubMed] [Google Scholar]
  • Whorton AR, Misono K, Hollifield J, Frolich JC, Inagami T, Oates JA. Prostaglandins and renin release: I. Stimulation of renin release from rabbit renal cortical slices by PGI2. Prostaglandins. 1977;14(6):1095–1104. [PubMed] [Google Scholar]
  • Francisco LL, Osborn JL, DiBona GF. Prostaglandin in renin release during sodium deprivation. Am J Physiol. 1982 Dec;243(6):F537–F542. [PubMed] [Google Scholar]
  • Linas SL. Role of prostaglandins in renin secretion in the isolated kidney. Am J Physiol. 1984 Jun;246(6 Pt 2):F811–F818. [PubMed] [Google Scholar]
  • Ito S, Carretero OA, Abe K, Beierwaltes WH, Yoshinaga K. Effect of prostanoids on renin release from rabbit afferent arterioles with and without macula densa. Kidney Int. 1989 May;35(5):1138–1144. [PubMed] [Google Scholar]
  • Greenberg SG, Lorenz JN, He XR, Schnermann JB, Briggs JP. Effect of prostaglandin synthesis inhibition on macula densa-stimulated renin secretion. Am J Physiol. 1993 Oct;265(4 Pt 2):F578–F583. [PubMed] [Google Scholar]
  • Stokes JB. Effect of prostaglandin E2 on chloride transport across the rabbit thick ascending limb of Henle. Selective inhibitions of the medullary portion. J Clin Invest. 1979 Aug;64(2):495–502. [PMC free article] [PubMed] [Google Scholar]
  • Okuda T, Kojima I, Ogata E, Kurokawa K. Ambient C1- ions modify rat mesangial cell contraction by modulating cell inositol trisphosphate and Ca2+ via enhanced prostaglandin E2. J Clin Invest. 1989 Dec;84(6):1866–1872. [PMC free article] [PubMed] [Google Scholar]
  • Bonvalet JP, Pradelles P, Farman N. Segmental synthesis and actions of prostaglandins along the nephron. Am J Physiol. 1987 Sep;253(3 Pt 2):F377–F387. [PubMed] [Google Scholar]
  • Wilcox CS, Welch WJ, Murad F, Gross SS, Taylor G, Levi R, Schmidt HH. Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11993–11997. [PMC free article] [PubMed] [Google Scholar]
  • Mundel P, Bachmann S, Bader M, Fischer A, Kummer W, Mayer B, Kriz W. Expression of nitric oxide synthase in kidney macula densa cells. Kidney Int. 1992 Oct;42(4):1017–1019. [PubMed] [Google Scholar]
  • Ito S, Ren Y. Evidence for the role of nitric oxide in macula densa control of glomerular hemodynamics. J Clin Invest. 1993 Aug;92(2):1093–1098. [PMC free article] [PubMed] [Google Scholar]
  • Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P. Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7240–7244. [PMC free article] [PubMed] [Google Scholar]
  • Salvemini D, Seibert K, Masferrer JL, Misko TP, Currie MG, Needleman P. Endogenous nitric oxide enhances prostaglandin production in a model of renal inflammation. J Clin Invest. 1994 May;93(5):1940–1947. [PMC free article] [PubMed] [Google Scholar]
Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation
-