Cyclooxygenase (COX) exists in 2 related but unique isoforms: one is constitutive (COX-1) and functions in normal cell physiology, and the other is inducible (COX-2) and is expressed in response to inflammatory stimuli. Nonsteroidal antiinflammatory drugs (NSAIDs) cause renal toxicity following inhibition of renal cyclooxygenases. Humans and animals exhibit differences in susceptibility to NSAID-related renal toxicity, which may be associated with differences in expression of 1 or both isoforms of COX in the kidney. In this study, we evaluated COX-1 and COX-2 expression in the kidneys of mixed-breed dogs, Sprague-Dawley rats, cynomolgus monkeys, and humans. In addition, the effect of volume depletion on renal COX expression was investigated in rats, dogs, and monkeys. COX expression was evaluated using 1 or more of the following procedures: reverse transcriptase polymerase chain reaction, in situ hybridization, and immunohistochemistry. We demonstrated that both COX isoforms are expressed in the kidneys of all species examined, with differences in the localization and level of basal expression. COX-1 is expressed at high levels in the collecting ducts and renal vasculature of all species and in a small number of papillary interstitial cells in rats, monkeys, and humans. Basal levels of COX-2 are present in the maculae densa, thick ascending limbs, and papillary interstitial cells in rats and dogs and in glomerular podocytes and small blood vessels in monkeys and humans. COX-2 expression is markedly increased in volume-depleted rats and dogs but not monkeys. These results indicate that significant interspecies differences exist in the presence and distribution of COX isoforms, which may help explain the difference in species susceptibility to NSAID-related renal toxicity.
1. Alden CL and Frith CH (1991). Urinary system. In: Handbook of Toxicologic Pathology, WM Haschek and CG Rousseaux (eds). Academic Press, New York, pp. 347–348.
2.
2. Arnold L, Collins C, and Starmer GA (1974). Renal and gastric lesions after phenylbutazone and indomethacin in the rat. Pathology. 6: 303–313.
3.
3. Bach PH and Hardy TL (1985). Relevance of animal models to analgesic-associated renal papillary necrosis in humans. Kidney Int.. 28: 605–613.
4.
4. Bennett WM, Henrich WL, and Stoff JS (1996). The renal effects of non-steroidal anti-inflammatory drugs: Summary and recommendations. Am. J. Kidney Dis.28(suppl. 1): 356–362.
5.
5. Black HE (1986). Renal toxicity of non-steroidal anti-inflammatory drugs. Toxicol. Pathol.. 14: 83–90.
6.
6. Burrell JH, Yong JLC, and Macdonald GJ (1991). Irreversible damage to the medullary interstitium in experimental analgesic nephropathy in F344 rats. J. Pathol.. 164: 329–338.
7.
7. Clive DM and Stoff JS (1984). Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N. Engl. J. Med.. 310: 563–572.
8.
8. Cupples WA, Sakai T, and Marsh DJ (1985). Angiotensin II and prostaglandins in control of vasa recta blood flow. Am. J. Physiol.. 23: F779–F784.
9.
9. Delmas PD (1995). Non-steroidal anti-inflammatory drugs and renal function. Br. J. Rheumatol.. 34: 25–28.
10.
10. DeWitt DL, Meade EA, and Smith WL (1993). PGH synthase isoenzyme selectivity: The potential for safer nonsteroidal anti-inflammatory drugs. Am. J. Med.. 95: 2A–40S.
11.
11. DeWitt DL and Smith WL (1988). Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc. Natl. Acad. Sci. USA. 85: 1412–1416.
12.
12. DeWitt DL and Smith WL (1990). Cloning of sheep and mouse prostaglandin endoperoxide synthases. Methods Enzymol.. 187: 469–479.
13.
13. DeWitt DL and Smith WL (1995). Yes, but do they still get headaches? Minireview. Cell. 83: 345–348.
14.
14. Dinchuk JE, Car BD, Focht RJ, Johnston JJ, Jaffee BD, Covington MB, Contel NR, Eng VM, Collins RJ, Czerniak PM, Gorry SA, and Trzaskos JM (1995). Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature. 378: 406–409.
15.
15. Dunn MJ, Staley RS, and Harrison M (1976). Characterization of prostaglandin production in tissue culture of rat renal medullar cells. Prostaglandins. 12: 37–49.
16.
16. Fletcher BS, Kujubu DA, Perrin DM, and Herschman HR (1992). Structure of the mitogen-inducible TISIO gene and demonstration that the TISIO-encoded protein is a functional prostaglandin G/H synthase. J. Biol. Chem.. 293: 4338–4344.
17.
17. Francisco LC, Osbon JL, and Dubini GF (1982). Prostaglandins in renin release during sodium deprivation. Am. J. Physiol.. 243: F537–F542.
18.
18. Funk CD, Funk LB, Kennedy ME, Pong AS, and Fitzgerald GA (1988). Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J.. 5: 2304–2312.
19.
19. Greenberg SG, Lorenz JN, He XR, Schnerman JB, and Briggs JB (1993). Effect of prostaglandin synthesis inhibition on macula den-sa-stimulated renin secretion. Am. J. Physiol. 265: F578–F583.
20.
20. Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, and Breyer MD (1994). CycIooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J. Clin. Invest.. 94: 2504–2510.
21.
21. Khan KNM, Allien CL, Gleissner SE, Gessford MK, and Maziasz TJ (1998). Effect of papillotoxic agents on expression of cyclooxygenase isoforms in the rat kidney. Toxicol. Pathol.. 26: 137–142.
22.
22. Khan KN, Paulson S, Seibert K, and Maziasz T (1997). Gastrointestinal and renal safety of a specific COX-2 inhibitor versus NSAIDs in dogs. Vet. Pathol.. 34: 509, A–150.
23.
23. Komhoff M, Grone HJ, Klein T, Seyberth HW. and Nusing RM (1997). Localization of cyclooxygenase-1 and cyclooxygenase-2 in adult and fetal human kidney: Implication for renal function. Am. J. Physiol.. 41: F460–F468.
24.
24. Kore AM (1990). Toxicology of nonsteroidal anti-inflammatory drugs. Vet. Clin. North Am. Small Anim. Pract.. 20: 419–430.
25.
25. Kramer SA, Meade EA, and DeWitt DL (1992). Prostaglandin endoperoxide synthase gene structure: Identification of the transcriptional start site and 5'-fianking regulatory sequences. Arch. Bio-chem. Biophys.. 293: 392–400.
26.
26. Lu LH and Gillett NA (1994). An optimized protocol for in situ hybridization using PCR-generated “P-labeled riboprobes. Cell Vision. 1: 169–174.
27.
27. Masfferer JL, Seibert K, Zwefel B, and Needleman P (1992). Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme. Proc. Natl. Acad. Sci. USA. 89: 3917–3921.
28.
28. Masfferer JL, Zweifel BS, Manning PT, Hauser SD, Leahy KM, Smith WG, Isakson PC, and Seibert K (1994). Selective inhibition of inducible cyclooxygenase-2 in vivo is anti-inflammatory and nonulcerogenic. Proc. Natl. Acad. Sci. USA. 91: 3228–3232.
29.
29. Meade EA, Smith WL, and DeWitt DL (1993). Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem.. 268: 6610–6614.
30.
30. Merlie PJ, Fagan D, Mudd J, and Needleman P (1988). Isolation and characterization of the complementary DNA for sheep seminal vesicle prostaglandin endoperoxide synthase (cyclooxygenase). J. Biol. Chem.. 263: 3550–3553.
32. Morham SG, Langenbach R, Loftin CD, Tiano HF, Vouloumanos N, Jennette JC, Mahler JF, Kluckman KD, Ledford A, Lee CA, and Smithies O (1995). Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell. 83: 473–482.
33.
33. Murray MD, and Brater DC (1993). Renal toxicity of the nonsteroidal anti-inflammatory drugs. Annu. Rev. Pharmacol. Toxicol.. 32: 435–465.
34.
34. Needleman P and Isakson PC (1997). The discovery and function of COX-2. J. Rheumatol.. 24: 6–7.
36. Segasothy M, Samad SA, Zulfigar A, and Bennett WM (1994). Chronic renal disease and papillary necrosis associated with the long-term use of nonsteroidal anti-inflammatory drugs as the sole of predominant analgesic. Am. J. Kidney Dis.. 24: 17–24.
37.
37. Seibert K, Zhang Y, Leahy K, Hauser S.Masfferer J, Perkins W, Lee L, and Isakson P (1994). Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc. Natl. Acad. Sci. USA. 91: 12013–12017.
38.
38. Simon LS (1994). Actions and toxic effects of the nonsteroidal antiinflammatory drugs. Curr. Opin. Rheumatol.. 6: 238–251.
39.
39. Sirois J and Richards JS (1992). 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.. 267: 6382–6388.
40.
40. Smith WL and DeWm DL (1995). Biochemistry of prostaglandin endoperoxide H synthase-1 and synthase-2 and their differential susceptibility to nonsteroidal anti-inflammatory drugs. Semin. Nephrol.. 15: 179–194.
41.
41. Stokes JB (1981). Integrated actions of renal medullary prostaglandins in the control of water excretion. Am. J. Physiol.. 240: F471-–F480.
42.
42. U.S. Department of Health and Human Services (1995). Guide for the Care and Use of Laboratory Animals.Animal Resources Program, Division of Reasearch Resources, National Institutes of Health, Bethesda, Maryland.
43.
43. Whelton A and Hamilton C (1991). Non-steroidal anti-inflammatory drugs: Effects on kidney function. J. Clin. Pharmacol.. 31: 588–598.
44.
44. Xie WQ and Rothblum LI (1991). Rapid, small-scale RNA isolation from tissue culture cells. BioTechniques11: 326–327
45.
45. Yokoyama C and Tanabe T (1989). Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme. Biochem. Biophys. Res. Cominun.. 165: 888–894.
