Pharmacology of cyclooxygenase-2 inhibition in the kidney
2002; Elsevier BV; Volume: 61; Issue: 4 Linguagem: Inglês
10.1046/j.1523-1755.2002.00263.x
ISSN1523-1755
AutoresKanwar Nasir M. Khan, Susan K. Paulson, Kenneth M. Verburg, J B Lefkowith, Timothy J. Maziasz,
Tópico(s)Estrogen and related hormone effects
ResumoPharmacology of cyclooxygenase-2 inhibition in the kidney. Cyclooxygenase (COX) exists as two unique isoforms (that is, COX-1 and COX-2) which are poorly understood with regard to their roles in renal function. The renal effects of conventional non-steroidal anti-inflammatory drugs (NSAIDs) are believed to result from the inhibition of one or both isoforms. Drugs that selectively inhibit COX-2 provide useful pharmacological tools for discerning the effects associated with the inhibition of the individual isoforms, and may help clarify the renal roles of COX-1 and COX-2. This review summarizes the current data on the renal expression of COX isoforms and their potential roles in renal function, and reviews the studies that have attempted to correlate renal functional changes with selective isoform inhibition. Since there are significant differences in the expression of COX isoforms in the kidneys of laboratory animals and humans, this review also examines the correlation of the results of COX inhibition in experimental studies in laboratory animals with clinical data. Because of potential interspecies differences in the roles of COX isoforms in renal function, animal models may have limited predictive value for patients, particularly those with renal risk factors. Accordingly, any uncertainty concerning the safety or therapeutic benefit of COX-2-specific drugs in these patient populations will need to be resolved with clinical investigations. Pharmacology of cyclooxygenase-2 inhibition in the kidney. Cyclooxygenase (COX) exists as two unique isoforms (that is, COX-1 and COX-2) which are poorly understood with regard to their roles in renal function. The renal effects of conventional non-steroidal anti-inflammatory drugs (NSAIDs) are believed to result from the inhibition of one or both isoforms. Drugs that selectively inhibit COX-2 provide useful pharmacological tools for discerning the effects associated with the inhibition of the individual isoforms, and may help clarify the renal roles of COX-1 and COX-2. This review summarizes the current data on the renal expression of COX isoforms and their potential roles in renal function, and reviews the studies that have attempted to correlate renal functional changes with selective isoform inhibition. Since there are significant differences in the expression of COX isoforms in the kidneys of laboratory animals and humans, this review also examines the correlation of the results of COX inhibition in experimental studies in laboratory animals with clinical data. Because of potential interspecies differences in the roles of COX isoforms in renal function, animal models may have limited predictive value for patients, particularly those with renal risk factors. Accordingly, any uncertainty concerning the safety or therapeutic benefit of COX-2-specific drugs in these patient populations will need to be resolved with clinical investigations. In the early 1970s, Vane hypothesized that the therapeutic action and toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) were based on the inhibition of the enzyme cyclooxygenase (COX) that catalyzes the committed step in the synthesis of prostaglandins (PGs)1.Vane J.R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.Nat New Biol. 1971; 231: 232-235Crossref PubMed Scopus (7076) Google Scholar. Almost two decades later, an accumulation of in vitro and in vivo evidence supported a new hypothesis: that two distinct isoforms of COX exist, including one that is induced selectively by pro-inflammatory stimuli2.Needleman P. Isakson P.C. The discovery and function of COX-2.J Rheumatol. 1997; 24: 6-8PubMed Google Scholar. Several laboratories confirmed the existence of two genes that encode distinct isoforms of COX (COX-1 and COX-2) in 19913.Kujubu D.A. Fletcher B.S. Varnum B.C. et al.TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue.J Biol Chem. 1991; 266: 12866-12872Abstract Full Text PDF PubMed Google Scholar,4.Xie W.Q. Rothblum L.I. Rapid, small-scale RNA isolation from tissue culture cells.Biotechniques. 1991; 11: 324-327PubMed Google Scholar. The COX-1 isoform is constitutive in many organs and cells and catalyzes the PG synthesis believed to support physiologic functions, including gastric mucosal defense and platelet aggregation. The COX-2 isoform also is constitutive in some tissues, but unlike COX-1, this isozyme is markedly induced by bacterial endotoxins, cytokines and growth factors, and catalyzes the synthesis of pro-inflammatory PGs. The antagonism of inflammation and pain by NSAIDs is believed to result from the inhibition of COX-2, while the antagonism of gastric mucosal defense and platelet aggregation are the results of COX-1 inhibition5.Masferrer J.L. Zweifel B.S. Manning P.T. et al.Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic.Proc Natl Acad Sci USA. 1994; 91: 3228-3232Crossref PubMed Scopus (1250) Google Scholar, 6.Warner T.D. Giuliano F. 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Thus, therapeutic use of these rather useful drugs is limited by significant clinical toxicity, including gastrointestinal (GI) ulceration, perforation, obstruction, and bleeding. Drugs that selectively inhibit COX-2 now are available, including celecoxib (Celebrex®), valdecoxib (Bextra®), and rofecoxib (Vioxx®). These possess anti-inflammatory properties similar to naproxen, ibuprofen, and diclofenac; but unlike conventional non-selective NSAIDs, they spare COX-1 at clinical doses. This greatly mitigates the adverse effects in the GI tract as well as bleeding secondary to diminished platelet function. Now it is known that the biological role of COX-2 extends beyond inflammation and pain Figure 1. Early female reproductive function (for example, ovulation, implantation and decidualization) is dependent on COX-2. Numerous reports suggest that certain forms of pre-cancerous lesions and cancer, including renal and bladder cancer, over-express COX-214.Sirois J. Richards J.S. 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; 267: 6382-6388Abstract Full Text PDF PubMed Google Scholar, 15.Khan K.N. Masferrer J.L. Woerner B.M. et al.Enhanced cyclooxygenase-2 expression in sporadic and familial adenomatous polyposis of the human colon.Scand J Gastroenterol. 2001; 36: 865-869Crossref PubMed Scopus (67) Google Scholar, 16.Stanfield K.S. Khan K.N.M. Gralinski M.R. Localization of cyclooxygenase isozymes in cardiovascular tissues of dogs treated with naproxen.Vet Immuno. 2001; 80: 309-314Crossref PubMed Scopus (17) Google Scholar, 17.Kauffman W.E. Andreasson K.I. Isakson P.C. Worley P.F. Cyclooxygenases and the central nervous system.Prostaglandins. 1997; 54: 601-624https://doi.org/10.1016/s0090-6980(97)001287Crossref PubMed Google Scholar, 18.Lim R.W. Paria B.C. Das S.K. et al.Multiple female reproductive failures in cyclooxygenase-2-deficient mice.Cell. 1997; 9: 1197-1208Google Scholar, 19.Kniss D.A. Cyclooxygenases in reproductive medicine and biology.J Soc Gynecol Investig. 1999; 6: 285-292Crossref PubMed Scopus (107) Google Scholar, 20.Mohammad S.I. Bostwick D.G. Foster R.S. et al.Expression of cyclooxygenase-2 in human invasive transitional cell carcinoma of the urinary bladder.Cancer Res. 1999; 59: 5647-5650PubMed Google Scholar. Therefore, it is likely that research will continue to identify potential roles for COX-2 in disease and normal physiology, as well as discover new therapeutic applications of COX-2-specific drugs. Renal physiology is partially COX-dependent, and PGs are active in regulating vascular tone and salt and water homeostasis by modulating glomerular hemodynamics and regulating distal nephron function21.Currie M.G. Needleman P. Renal arachidonic acid metabolism.Annu Rev Physiol. 1984; 46: 327-341Crossref PubMed Scopus (40) Google Scholar,22.Dunn M. The role of arachidonic acid metabolites in renal homeostasis. Non-steroidal anti-inflammatory drugs renal function and biochemical, histological and clinical effects and drug interactions.Drugs. 1987; 33: 56-66Crossref PubMed Scopus (44) Google Scholar. Therefore, some consequence of the inhibition of COX activity in the kidney is not unexpected. In fact, COX inhibition is believed to be the basis of some adverse renal effects of NSAIDs, including acute ischemic renal failure, fluid and electrolyte disturbances, and, possibly, renal papillary necrosis (RPN)23.Nies A.S. Renal effects of nonsteroidal anti-inflammatory drugs.Agents Actions. 1988; Suppl 24: 95-106Google Scholar, 24.Whelton A. Hamilton C.W. Nonsteroidal anti-inflammatory drugs: Effects on kidney function.J Clin Pharmacol. 1991; 31: 588-598Crossref PubMed Scopus (286) Google Scholar, 25.Pugliese F. Cinotti G.A. Nonsteroidal anti-inflammatory drugs (NSAIDs) and the kidney.Nephrol Dial Transplant. 1997; 12: 386-388Crossref PubMed Scopus (18) Google Scholar. Given the propensity of NSAIDs to cause renal side effects, there is keen interest in the renal safety of COX-2-specific drugs. Recently, a large body of data has been published on the renal expression of COX-1 and COX-2 and the renal effects of non-selective NSAIDs versus COX-2 selective agents. This review provides a perspective on the current data relating to cyclooxygenase inhibition in the kidney, particularly with anti-inflammatory therapeutic agents that are based on COX inhibition. Unlike the GI tract and platelet, in which physiological function is dependent on COX-1, the kidneys of both laboratory species (rat and dog) and primates (cynomolgus monkeys and humans) constitutively express both COX-1 and COX-216.Stanfield K.S. Khan K.N.M. Gralinski M.R. Localization of cyclooxygenase isozymes in cardiovascular tissues of dogs treated with naproxen.Vet Immuno. 2001; 80: 309-314Crossref PubMed Scopus (17) Google Scholar, 26.Harris R.C. McKanna J.A. Akai Y. et al.Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction.J Clin Invest. 1994; 94: 2504-2510Crossref PubMed Scopus (804) Google Scholar, 27.Smith W.L. Bell T.G. Immunohistochemical localization of the prostaglandin-forming cyclooxygenase in renal cortex.Am J Physiol. 1978; 235: F451-F457PubMed Google Scholar, 28.Komhoff M. Jeck N.D. Seyberth H.W. et al.Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome.Kidney Int. 2000; 58: 2420-2424Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 29.Tomasoni S. Noris M. Zappella S. et al.Upregulation of renal and systemic cyclooxygenase-2 in patients with active lupus nephritis.J Am Soc Nephrol. 1998; 9: 1202-1212PubMed Google Scholar, 30.Komhoff M. Grone H.J. Klein T. et al.Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: implication for renal function.Am J Physiol. 1997; 272: F460-F468PubMed Google Scholar, 31.Khan K.N. Venturini C.M. Bunch R.T. et al.Interspecies differences in renal localization of cyclooxygenase isoforms: Implications in nonsteroidal antiinflammatory drug-related nephrotoxicity.Toxicol Pathol. 1998; 26: 612-620Crossref PubMed Google Scholar. COX-1 immunoreactivity is abundant and appears uniformly across species in the collecting ducts, renal vasculature, glomeruli, and papillary interstitial cells Figure 2. In contrast, basal COX-2 immunoreactivity in kidney is less intense and exhibits some interspecies differences in localization. The intrarenal distribution of COX-2 in rats and dogs includes the macula densa Figure 2, thick ascending limbs of loop of Henle (TAL), and papillary interstitial cells. COX-2 immunoreactivity also has been reported in the intercalated cells of the cortical collecting duct in the mouse32.Ferguson S. Herbert R.L. Laneuville O. NS-398 upregulates constitutive cyclooxygenase-2 expression in the M-1 cortical collecting duct cell line.J Am Soc Nephrol. 1999; 10: 2261-2271Crossref PubMed Google Scholar. In normal humans and non-human primates, COX-2 is co-localized with COX-1 in glomeruli and small blood vessels of the kidney but is not detectable in the macula densa29.Tomasoni S. Noris M. Zappella S. et al.Upregulation of renal and systemic cyclooxygenase-2 in patients with active lupus nephritis.J Am Soc Nephrol. 1998; 9: 1202-1212PubMed Google Scholar, 30.Komhoff M. Grone H.J. Klein T. et al.Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: implication for renal function.Am J Physiol. 1997; 272: F460-F468PubMed Google Scholar, 31.Khan K.N. Venturini C.M. Bunch R.T. et al.Interspecies differences in renal localization of cyclooxygenase isoforms: Implications in nonsteroidal antiinflammatory drug-related nephrotoxicity.Toxicol Pathol. 1998; 26: 612-620Crossref PubMed Google Scholar. Recently, it was shown that COX-2 is detectable in the macula densa in elderly humans (>60 years of age)33.Nantel F. Meadows E. Denis D. et al.Immunolocalization of cyclooxygenase-2 in the macula densa of human elderly.FEBS Lett. 1999; 457: 475-477Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar. These authors suggested that this COX-2 expression in elderly subjects may be secondary to decreased basal renin production associated with aging. In summary, it may be inferred from these observations that: (1) COX-1 may fulfill similar roles in renal function across species; (2) basal COX-1 and COX-2 activities may be redundant in kidneys of higher species, including humans; and, (3) COX-1 and COX-2 may support different aspects of renal function in lower species. Based on immunoreactivity data, the renal consequence of COX-1 inhibition might be expected to be similar across species, while COX-2 inhibition may have different consequences in the kidneys of lower animals compared with humans. In any case, the significant differences in COX expression between laboratory animals and humans suggest that extrapolation of findings with COX inhibitors in animals to humans may not be simple. The kidney is a target of NSAIDs and the renal activity observed with these drugs reflects multiple points of drug action along the nephron. Local PG synthesis in the kidney supports important roles in the regulation of renal function and homeostasis Table 1. Therefore, these effects likely reflect pharmacological inhibition of renal COX-1 and/or COX-2. Currently, the relationship of specific COX isoforms to renal function is not well understood34.Schneider A. Harendza S. Zahner G. et al.Cyclooxygenase metabolites mediate glomerular monocyte chemoattractant protein-1 formation and monocyte recruitment in experimental glomerulonephritis.Kidney Int. 1999; 55: 430-441https://doi.org/10.1046/j.1523-1755.1999.00265.xAbstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar; however, the available immunoreactivity data does suggest that simple relationships are not likely, and that COX isoforms may support a region-specific, and even redundant, function in the kidney (abstract; Stanfield et al, Vet Pathol 37:558, 2000)31.Khan K.N. Venturini C.M. Bunch R.T. et al.Interspecies differences in renal localization of cyclooxygenase isoforms: Implications in nonsteroidal antiinflammatory drug-related nephrotoxicity.Toxicol Pathol. 1998; 26: 612-620Crossref PubMed Google Scholar, 35.Whelton A. Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor.Am J Ther. 1999; 7: 159-175Crossref Scopus (171) Google Scholar, 36.Vio C.P. Cespedes C. Gallardo P. Masferrer J.L. Renal identification of cyclooxygenase-2 in a subset of thick ascending limb cells.Hypertens. 1997; 30: 687-692Crossref PubMed Scopus (132) Google Scholar, 37.Khan K.N. Alden C.L. Gleissner S.E. et al.Effect of papillotoxic agents on expression of cyclooxygenase isoforms in the rat kidney.Toxicol Pathol. 1998; 26: 137-142Crossref PubMed Scopus (22) Google Scholar. Studies that have attempted to characterize the functional consequences of inhibition of specific COX isoforms are summarized in this review.Table 1Constitutive expression of cyclooxygenase inhibition in the kidneyLocationCOX-1COX-2ProstaglandinsPossible functionsGlomerulus++PGE2, PGI2Podocyte contractility and maintenance of GFRThick ascending limb of loop of Henle-+aNot seen in normal human and non-human primates, but seen in elderly humansPGE2Enhance excretion of sodium and chlorideMacula densa-+aNot seen in normal human and non-human primates, but seen in elderly humansPGE2Regulation of renin release; mediates tubuloglomerular feedbackCollecting ducts++bObserved in mouse onlyPGE2Enhance excretion of sodium, chloride, and waterPapillary interstitial cells++PGE2, TXA2Enhance vasodilatation and natriuresisRenal vasculature++PGE2, PGI2, TXA2Regulation of regional blood flow, antagonism of angiotensin II-induced vasoconstrictionSources:16.Stanfield K.S. Khan K.N.M. Gralinski M.R. Localization of cyclooxygenase isozymes in cardiovascular tissues of dogs treated with naproxen.Vet Immuno. 2001; 80: 309-314Crossref PubMed Scopus (17) Google Scholar, 26.Harris R.C. McKanna J.A. Akai Y. et al.Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction.J Clin Invest. 1994; 94: 2504-2510Crossref PubMed Scopus (804) Google Scholar, 28.Komhoff M. Jeck N.D. Seyberth H.W. et al.Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome.Kidney Int. 2000; 58: 2420-2424Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 30.Komhoff M. Grone H.J. Klein T. et al.Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: implication for renal function.Am J Physiol. 1997; 272: F460-F468PubMed Google Scholar, 31.Khan K.N. Venturini C.M. Bunch R.T. et al.Interspecies differences in renal localization of cyclooxygenase isoforms: Implications in nonsteroidal antiinflammatory drug-related nephrotoxicity.Toxicol Pathol. 1998; 26: 612-620Crossref PubMed Google Scholar, 32.Ferguson S. Herbert R.L. Laneuville O. NS-398 upregulates constitutive cyclooxygenase-2 expression in the M-1 cortical collecting duct cell line.J Am Soc Nephrol. 1999; 10: 2261-2271Crossref PubMed Google Scholar, 33.Nantel F. Meadows E. Denis D. et al.Immunolocalization of cyclooxygenase-2 in the macula densa of human elderly.FEBS Lett. 1999; 457: 475-477Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 35.Whelton A. Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor.Am J Ther. 1999; 7: 159-175Crossref Scopus (171) Google Scholar, 55.Clive D.M. Stoff J.S. Renal syndromes associated with nonsteroidal antiinflammatory drugs.N Engl J Med. 1984; 310: 563-572Crossref PubMed Scopus (944) Google Scholar, 56.Delmas P.D. Non-steroidal anti-inflammatory drugs and renal function.Br J Rheumatol. 1995; 34: 25-28Crossref PubMed Scopus (45) Google Scholar, 58.Murray M.D. Brater D.C. Renal toxicity of the nonsteroidal anti-inflammatory drugs.Annu Rev Pharmacol Toxicol. 1993; 33: 435-465Crossref PubMed Scopus (266) Google Scholar.a Not seen in normal human and non-human primates, but seen in elderly humansb Observed in mouse only Open table in a new tab Sources:16.Stanfield K.S. Khan K.N.M. Gralinski M.R. Localization of cyclooxygenase isozymes in cardiovascular tissues of dogs treated with naproxen.Vet Immuno. 2001; 80: 309-314Crossref PubMed Scopus (17) Google Scholar, 26.Harris R.C. McKanna J.A. Akai Y. et al.Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction.J Clin Invest. 1994; 94: 2504-2510Crossref PubMed Scopus (804) Google Scholar, 28.Komhoff M. Jeck N.D. Seyberth H.W. et al.Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome.Kidney Int. 2000; 58: 2420-2424Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 30.Komhoff M. Grone H.J. Klein T. et al.Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: implication for renal function.Am J Physiol. 1997; 272: F460-F468PubMed Google Scholar, 31.Khan K.N. Venturini C.M. Bunch R.T. et al.Interspecies differences in renal localization of cyclooxygenase isoforms: Implications in nonsteroidal antiinflammatory drug-related nephrotoxicity.Toxicol Pathol. 1998; 26: 612-620Crossref PubMed Google Scholar, 32.Ferguson S. Herbert R.L. Laneuville O. NS-398 upregulates constitutive cyclooxygenase-2 expression in the M-1 cortical collecting duct cell line.J Am Soc Nephrol. 1999; 10: 2261-2271Crossref PubMed Google Scholar, 33.Nantel F. Meadows E. Denis D. et al.Immunolocalization of cyclooxygenase-2 in the macula densa of human elderly.FEBS Lett. 1999; 457: 475-477Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 35.Whelton A. Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor.Am J Ther. 1999; 7: 159-175Crossref Scopus (171) Google Scholar, 55.Clive D.M. Stoff J.S. Renal syndromes associated with nonsteroidal antiinflammatory drugs.N Engl J Med. 1984; 310: 563-572Crossref PubMed Scopus (944) Google Scholar, 56.Delmas P.D. Non-steroidal anti-inflammatory drugs and renal function.Br J Rheumatol. 1995; 34: 25-28Crossref PubMed Scopus (45) Google Scholar, 58.Murray M.D. Brater D.C. Renal toxicity of the nonsteroidal anti-inflammatory drugs.Annu Rev Pharmacol Toxicol. 1993; 33: 435-465Crossref PubMed Scopus (266) Google Scholar. Natriuresis, or sodium excretion, is stimulated by increases in renal interstitial volume and is PG-dependent38.Haas J.A. Knox F.G. Effect of meclofenamate or ketoconazole on the natriuretic response to increased pressure.J Lab Clin Med. 1996; 128: 202-207Abstract Full Text PDF PubMed Scopus (6) Google Scholar. Sodium retention (antinatriuresis) is a consequence of NSAID use in some patients24.Whelton A. Hamilton C.W. Nonsteroidal anti-inflammatory drugs: Effects on kidney function.J Clin Pharmacol. 1991; 31: 588-598Crossref PubMed Scopus (286) Google Scholar. COX-1 is highly expressed in the collecting ducts of both laboratory animals and humans, an area of the nephron that is active in the regulation of sodium excretion21.Currie M.G. Needleman P. Renal arachidonic acid metabolism.Annu Rev Physiol. 1984; 46: 327-341Crossref PubMed Scopus (40) Google Scholar. In addition, COX-2 is co-localized with Na+,K+-ATPase in the thick ascending limb of the rat nephron, further suggesting a role in sodium regulation in that species36.Vio C.P. Cespedes C. Gallardo P. Masferrer J.L. Renal identification of cyclooxygenase-2 in a subset of thick ascending limb cells.Hypertens. 1997; 30: 687-692Crossref PubMed Scopus (132) Google Scholar. Studies included in the preclinical safety database for celecoxib reported transient antinatriuresis in rats up through six weeks of treatment at systemic exposures that were within the index of COX-2 selectivity. Prostaglandin E2 (PGE2) concentrations in renal tissue, but not urine, concomitantly were decreased at these exposures suggesting that the antinatriuretic effect might partly be related to inhibition of COX-2-dependent PGs. The lack of effect of celecoxib on basal urine PGE2 concentrations may represent sparing of a COX-1-dependent PG pool. Gross, Dwyer and Knox have shown a sparing of sodium excretion with COX-2-selective inhibitors during forced diuresis39.Gross J.M. Dwyer J.E. Knox F.G. Natriuretic response to increased pressure is preserved with COX-2 inhibitors.Hypertens. 1999; 34: 1163-1167Crossref PubMed Scopus (33) Google Scholar. Other studies suggest that COX-2 is up-regulated in response to increased salt load and volume overload. Yang and co-workers characterized the COX-2 expression in the kidneys of rats subjected to either high or low salt dietary intake for seven days40.Yang T. Singh I. Pham H. et al.Regulation of cyclooxygenase expression in the kidney by dietary salt intake.Am J Physiol. 1998; 274: F481-F489PubMed Google Scholar. COX-2 mRNA was increased up to 4.5-fold in the inner medulla by high salt diet whereas no change in COX-2 mRNA was observed with the low salt diet. In contrast, cortical COX-2 mRNA was altered by both high and low salt dietary regimens: a 2.9-fold decrease was observed with the high salt diet, whereas a 3.3-fold increase was observed with the low salt diet. COX-1 mRNA was not affected in any region of the kidney with either diet. The expression of COX-2 was localized primarily in the macula densa and cortical TAL, and medullary interstitial cells. The authors suggest that the increased expression of COX-2 in the medullary interstitium may promote excretion of excess sodium in response to increased pressure (that is, stretch) and volume overload in the medullary interstitium. The up-regulation of COX-2 expression observed in the cortex under conditions of low salt intake was noted by Yang and his co-workers40.Yang T. Singh I. Pham H. et al.Regulation of cyclooxygenase expression in the kidney by dietary salt intake.Am J Physiol. 1998; 274: F481-F489PubMed Google Scholar to be consistent with a role for COX-2 in the preservation of cortical circulation in the volume-contracted state. This role of COX-2 in volume contraction is discussed in greater detail elsewhere in this review. Clearly, their study's results illustrate the potential for multiplicity of PG function and regulation in various regions of the kidney. The reciprocal decrease in COX-2 expression in the cortex provides evidence that COX-2 is regulated differentially in specific regions of the kidney in response to changes in functional demands on the kidney. A few studies tried to elucidate the roles of COX isoforms in renal blood flow in normal animals. For example, Brooks and co-workers studied the effects of indomethacin, a potent non-selective NSAID, 6-MNA (the active metabolite of nabumetone), and celecoxib on renal blood flow in normal conscious dogs following intravenous administration41.Brooks D.P. DePalma P.D. Pullen M. et al.SB 234551, a novel endothelin—A receptor antagonist, unmasks endothelin-induced renal vasodilatation in the dog.J Cardiovasc Pharmacol. 1998; 31: S339-S341Crossref PubMed Scopus (19) Google Scholar. Only celecoxib was reported to decrease renal blood flow, which was attributed to its COX-2-selective action. The data for this study, however, raise some questions. Failure to control for vehicle effect of the organic solvent used for intravascular delivery of celecoxib, and the unexplained lack of effect with the positive control, indomethacin, limit the conclusions regarding pharmacological inhibition of COX. In contrast, SC-046, a COX-2–selective inhibitor closely related to celecoxib, given orally to normal conscious dogs produced no diminution of renal blood flow at doses that produced plasma concentrations adequate for maximal and selective inhibition of COX-2 (abstract; Freeman et al,FASEB J, 13:A722, 1999). These results were corroborated by a study using another COX-2-selective agent, nimesulide42.Rodriguez F. Llinas M.T. Gonzalez J.D. et al.Renal changes induced by a cyclooxygenase-2 inhibitor during normal and low sodium intake.Hypertens. 2000; 36: 276-281Crossref PubMed Scopus (86) Google Scholar. COX-2 selective doses of this agent, confirmed by the absence of an effect on platelet aggregation, were found to produce no effect on mean arterial blood pressure, glomerular filtration, or renal blood flow in normal dogs. Decreases in sodium excretion, urine volume, and lithium excretion were observed with nimesulide, which were considered as tubular effects. Collectively, these two studies suggest that COX-2 does not govern basal renal blood flow in laboratory animals. Prostaglandins appear to be active in volume homeostasis through two mechanisms. First, as part of the renin-angiotensin-aldosterone (RAA) axis, PGs promote the release of renin from the kidney in response
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