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Kidney International, Vol. 39 (1991), pp. 438—449

Renal tubular

JOSEPH V. BONVENTRE and RAPHAEL NEMENOFF

Renal and Diabetes Units of the Medical Services, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

Arachidonic acid and its metabolites play important roles infree arachidonic acid are influenced, not only by these release renal tubular function. This overview will review general char-mechanisms, but also by very efficient reacylation processes. acteristics of arachidonic acid metabolism, focus on the char- There are three possible pathways for further metabolism of acterization and regulation of renal acyihydrolases that gener-arachidonic acid. Prostaglandin endoperoxide (PGH2) synthase ate arachidonic acid from phospholipids, examine what iscan transform arachidonic acid into prostaglandins. There are known about the production of arachidonic acid metabolitestwo parts to this enzymatic activity residing in a single protein along the nephron, and explore what the potential roles of these[5]. PGH2 synthase has a component which metabolites are in physiological and pathophysiological states.catalyzes the insertion of two molecules of oxygen into arachi- Due to space limitations it is not possible to review thisdonic acid to form PGG2. The second enzymatic activity is a extensive topic including the glomerulus as well as the rest ofhydroperoxidase-induced two-electron reduction of the 15- the nephron, renal interstitium, and vasculature. Since thishydroperoxy group of PGG2 to yield PGH2. Nonsteroidal monograph is focused upon the tubulointerstitium, we will notantiinflammatory agents inhibit the cyclooxygenase component discuss the various aspects of arachidonic acid metabolism inof PGH2 synthase. This is an 02 consuming process and results the glomerulus but only refer to glomerular cells when ain the generation of reactive oxygen species which may, under mechanism pertinent to the tubulointerstitium is best illustratedcertain circumstances, be toxic to the cell. PGH2 is then by work done on a glomerular cell. converted to the biologically active prostaglandins—PGE2, PGD2, PGF2, PGI2 (prostacyclin) and thromboxane A2 (TxA2). Overview of arachidonic acid metabolism An alternative pathway for arachidonic acid metabolism is the lipoxygenase pathway. This catalyzes a dioxygen- Arachidonic acid, which is taken into the body in the diet orase reduction resulting in the formation of 5,8,12 or 15- can be synthesized from the essential dietary , linoleicHPETE' s (hydroperoxyeicosatetraenoic acids). The leukot- acid (18:2w6), is in large part esterified to the sn-2 position ofrienes are products of further metabolism of 5-HPETE and the phospholipids. The release of free arachidonic acid is believed HETE's (hydroxyeicosatetraenoic acids) are products of 8,12, to be the rate-limiting step in synthesis [1]. Releaseor 15-HPETE. of arachidonic acid can occur as a consequence of a number of A third pathway for arachidonic acid metabolism is the different mechanisms (Fig. 1) including: 1) a direct action ofcytochrome P450 monooxygenase. This system results in the A2 on a phospholipid to produce free arachidonicoxidative transformation of a number of endogenous and exog- acid and lysophospholipid; 2) the sequential action of phospho-enous substrates including saturated fatty acids, , C, resulting in the formation of diacylglycerol, followed prostaglandins, steroids, and hydrocarbons [61. Attesting to the by the release of free fatty acid by diacyiglycerol lipase; 3) therelevance of this system to renal function is the recent obser- sequential action of , diacylglycerol kinase andvation that epoxyeicosatrienoic acids have been isolated from phosphatidic acid specific ; and 4) the sequen-human urine [71. tial action of [2] followed by phosphatidic It is likely that cellular pools of free arachidonic acid are not acid-specific phospholipase A2. In addition triglycerides canhomogeneous. Peptide hormones, for example, may result in serve as a source of arachidonic acid via the action of triglyc-release of arachidonic acid into pools with ready access to eride lipase. This latter mechanism may be of particular impor- that will metabolize the arachidonic acid into specific tance in the inner medullary interstitial cells which have large prostaglandins, lipoxygenase products, or other metabolites [8]. lipid droplets, the content of which decreases with physiologi- The first step in the generation of prostaglandins, lipoxygen- cal states associated with enhanced renal prostaglandin produc-ase, or P450 products is the generation of arachidonic acid by tion [3, 41. In most systems phospholipase A2 is believed to bethe action of acyihydrolases on lipids, primarily phospholipids. the primary effector enzyme for arachidonic acid release [1].We will summarize what is known about renal acyihydrolases. The lipid origin of arachidonic acid varies depending upon the cell type and the agonist used to stimulate release. The levels of Acylhydrolases Phospholipase A2 Phospholipase A2 (PLA2) is a ubiquitous enzyme, which © 1991 by the International Society of Nephrology exists in both secretory and intracellular forms. The secretory

438 Bonventre and Nemenoff: Arachidonic acid metabolism 439

FA AA

Choline or lnositol—P2

[PLA2] Choline [DAG.ki] PA Lyso-PC Fig. 1. Pathways for generation of free Lvso-Pl arachidonic acid (AA) and the subsequent metabolism of arachidonic acid. Arachidonic acid can be cleaved from the sn-2 position of phospholipids such as phosphatidyicholine and phosphatidylinositol by the action of phospholipase A2 (PLA2) leaving L yso-PA lysophosphatidylcholine (Lyso-PC) or lysophosphatidylinositol (Lyso-PI). AA Alternatively free arachidonic acid can be generated by the sequential activity of phospholipase C (PLC), producing diacyiglycerol (DAG), which is then metabolized by DAG-lipase, thus generating free arachidonic acid and monoacylglycerol (MAG). Phosphatidic acid (PA), which can be produced directly from phospholipids by the action of phospholipase D (PLD), or indirectly due to the phosphorylation of diacylglycerol by DAG-kinase can serve as a substrate for phosphatidic acid-specific-phospholipase A2 (PA-PLA2), generating free arachidonic acid and lysophosphatidic acid (lyso-PA). Once free arachidonic acid is liberated it can be Prostag landi ns F-1PETES E ETS metabolized via the cyclooxygenase, Thromboxanes HETES Vicinal Diols lipoxygenase, or cytochrome P450 mixed- Leukotrienes HETES function oxidase systems, as described in the w-hydroxylated FAs text. Abbreviation FA is fatty acid. forms of the enzyme are prominent components of snake and The regulation of PLA2 is multifaceted (Fig. 2). Inner med- insect venoms, as well as pancreatic extracts. These enzymesullary slices labelled with '4C-arachidonic acid release 14C- are generally small proteins (molecular wt -l2,000 to 18,000arachidonic acid in response to increased levels of Ca2 and daltons), which depend upon calcium for activity and have veryA23 187 in the buffer [141. This is associated with corresponding high specific activities (>100 tmol/min/mg) [9].Manyof thesereductions in amount of '4C-arachidonic acid in phosphatidyl- enzymes have been purified and their amino acid sequencescholine, phosphatidylethanolamine, and phosphatidylinositol. determined [10]. In general, much less is known about intra-W-7, a calmodulin inhibitor, inhibited the arachidonic acid cellular forms of PLA2, which are involved in the hormonalrelease. When the 100,000 xg particulate fraction was incu- regulation of arachidonic acid release. It was generally believedbated with exogenous 14C-arachidonic acid-phosphatidyicho- that intracellular forms of the enzyme were also Ca2 requiringline there was a Ca2 dependent release of '4C-arachidonic acid enzymes. More recently, both Ca2 dependent and indepen-from the phospholipid. PLA2 activity was observed at 100 IIM dent forms of the enzyme have been identified, and somecalculated free Ca2 concentration, and was increased five- to intracellular forms have specific activities approaching those ofninefold over Ca2-free conditions when the buffer Ca2 con- the secretory forms of PLA2 [11]. It is also apparent that thesecentration was 5 msi. W-7 inhibited this activity [141. The pH intracellular enzymes represent distinct proteins. Antibodiesoptimum was 9.0 when pH was tested over a range of 5to9. raised against intracellular mitochondrial PLA2, for example,Urea, at 800 mOsm, suppressed PLA2 activity while NaCI, at fail to cross react with a variety of secretory forms of PLA2equivalent osmolarity, had no effect. [121, and even fail to recognize other intracellular forms of the When mesangial cells were rendered permeable with digito- enzyme. As has become clear in the study of other phospholi-nm and exposed to levels of free calcium concentration mea- pases such as inositol-specific phospholipase C [13], PLA2sured in the intact cells stimulated with vasopressin, there was constitutes a family of proteins. enhanced arachidonic acid release and PGE2 synthesis when 440 Bonventreand Nemenoff: Arachidonic acid metabolism

PMA was added to permeabilized cells clamped at 500 to 2200 nM [Ca2 ],therewas a marked increase in PGE2 production. PMA alone had no effect upon PGE2 production after 10 minutes of stimulation of intact cells or in cells permeabilized under conditions where [Ca2] was clamped at levels less than 200 flM [153. Thus we concluded that protein kinase C modu- Ca" lates the Ca2 dependent activation of PLA2 and suggested that this effect may be mediated by phosphorylation of PLA2 itself or PLA2 modulatory proteins. In Madin Darby canine kidney DAG (MDCK) cells PMA alone has been reported to increase ara- chidonic acid release, but this requires longer periods of expo- sure to the phorbol ester [22]. P1CC Increased arachidonic acid release is also seen following t stimulation of mesangial cells with epidermal growth factor 9, (EGF) which does not in itself cause an activation of phospho- Modulat lipase C or rise in intracellular free Ca2 levels [23, 24]. When S. S. mesangial cells were stimulated with platelet derived growth 'O S. factor (PDGF), increases in arachidonic acid release were 'I,' observed prior to detectable increase in cytosolic [Ca211 and S. inositol trisphosphate levels, suggesting that PLA2 activity was increased prior to a significant increase in phospholipase C /E activity [25]. Interleukin I enhances arachidonic acid release from papillary collecting duct cells in culture [26]. Since recom- binant IL-i does not increase phosphatidylinositol-specific phospholipase C activity in cells where this has been examined [27], it is probable that this activation of arachidonic acid Fig. 2. Schematic representation of various forms of regulation ofrelease is also [Ca2] independent. phospholipase A2 as derived from experiments in our laboratories on In many studies changes in PLA2 activity have been inferred the renal mesangial cell. The dotted lines represent pathways which are from observed changes in arachidonic acid release [28—30]. To less well understood. Agonists such as vasopressin (AVP), which activate phospholipase C (PLC), likely via a G protein (Go), increase directly examine PLA2 enzymatic activity we have recently cytosolic free calcium concentration (Ca2) due to inositol trisphos-developed a cell-free assay to measure PLA2 activity with phate (1P3)-induced release of calcium from intracellular stores. Cal- exogenous phospholipid substrate. Employing this assay, a cium activates phospholipase A2 (PLA2) directly and also mediates the hormonally regulated form of PLA2 has been identified [31, 32, translocation of the enzyme to the cell membrane. The diacylglycerolNote added in proof A]. Treatment of mesangial cells with formed as a result of PLC activation will activate protein kinase C (PKC) which enhances the calcium dependent activation of PLA2. This PMA, AVP or EGF results in a stable modification of enzymatic potentiation of PLA2 activity by protein kinase C could occur either by activity, which is detected at saturating Ca2 concentrations, direct phosphorylation of the enzyme or indirectly by phosphorylationand survives fractionation of the enzyme on several columns of a PLA2 modulatory protein. Epidermal growth factor (EGF), by[23, 311. Pretreatment of mesangial cells with a high concentra- contrast, activates PLA2 by a mechanism that does not require antion of PMA, which results in down-regulation of protein kinase activation of PLC or associated activation of protein kinase C or increases in cytosolic free calcium concentration. This activation is not C, abolishes the AVP stimulation, suggesting that it is mediated well understood. It may involve G proteins (Go') but, if so, not athrough activation of protein kinase C. EGF stimulation, on the pertussis toxin-inhibitable G protein. Since EGF activation is known to other hand, remains unaffected, arguing for a protein kinase C be associated with tyrosine kinase activation, tyrosine kinase substrates independent mechanism of regulation. This enzyme is distinct may be involved. from many of the previously characterized forms of PLA2. It is a large soluble protein which appears to associate with mem- brane fractions in a Ca2 dependent manner [31, 33]. Hormone- compared with permeabilized cells exposed to calcium concen-induced increases in intracellular Ca2 will presumably cause tration ([Ca2]) measured in resting cells (<100 nM) [15]. Thusthe enzyme to translocate to the membrane. This may represent the intracellular PLA2 is Ca2-dependent over the "physiolog-an additional form of regulation. ical range" of [Ca2i variation. In addition, distinct isoforms of This enzyme is the major soluble form of PLA2 in extracts PLA2 appear to be regulated by guanine nucleotide bindingfrom whole kidney. Purification of the enzyme from kidney proteins (G-proteins) [16, 171, activation of protein kinase Chas shown it to be a 110 kDa protein (Note added in proof A). [15], Na/H exchange activity [18], membrane potential [19],The enzyme has a requirement for Ca2, and is activated at and perhaps specific PLA2 regulatory proteins [20, 211. physiologic concentrations of Ca2t It has a specificity for In renal cells activation of protein kinase C may play anunsaturated fatty acid side chains of phosphatidyicholine and important role in the regulation of PLA2 activity. In glomerularphosphatidylethanolamine, with low activity towards phospha- mesangial cells we demonstrated that when PMA (phorboltidylinositol. A similar enzyme has been partially characterized myristate acetate) was added to intact cells along with the Ca2in a macrophage cell line RAW 264.7 [34] and peritoneal ionophore, A23 187, there was a marked potentiation of themacrophages [35]. To determine the specific role this enzyme effect of A23187 on arachidonic acid release. Likewise, whenplays in arachidonic acid metabolism, it will be necessary to Bonventre and Nemenoff: Arachidonic acid metabolism 441 develop specific antibodies and clone the gene encoding for this Phosphatidic acid specific phospholipase A2 protein in order to examine its regulation. Craven and De Rubertis [14] found that phosphatidic acid Kidney extracts also contain a smaller molecular weight form of PLA2. A small (Mr 14 kDa) form is enriched in mitochon-specific PLA2 activity in the renal medulla was also Ca2 drial fractions, and is only activated at micromolar levels ofdependent with optimal stimulation occurring at 25 M Ca2 Ca2. Both the cytosolic large form and mitochondrial smallerconcentration. Eighty-nine to 96% of total homogenate activity form are increased in activity with ischemia and reperfusion inwas in the particulate fraction. The pH optimum was in the range of 7 to 7.5. Activity was measured against phosphatidic the rat kidney (unpublished observations). Mitochondrial PLA2 activity is also enhanced in vitro by exposure of isolated renalacid under pH and Ca2 conditions where there was no mitochondria to Ca2 and reactive oxygen species using aacyihydrolase activity against phosphatidyleholine or phospha- model we have developed to stimulate ischemia and reperfusiontidylethanolamine suggesting specificity of the enzymatic activ- in vivo [36, 37]. ity, although not precluding the possibility that the greater In non-renal tissues other intracellular forms of PLA2 havesolubility of phosphatidic acid might enhance substrate avail- been purified. Sheep platelets contain a soluble PLA2 which isability to the enzymatic activity. W-7 had no effect on this activity. Urea (800 mOsm) inhibited the activity. In contrast to activated at physiologic Ca2 (<1 LM) [38]. Spleen contains both membrane associated and soluble forms of the enzyme,other acylhydrolases 400 or 800 mOsm NaC1 markedly inhibited both of which are small molecular weight forms requiring highthe activity of the phosphatidic acid specific PLA2. Ca2* concentrations for maximal activity [39, 40]. The soluble form appears to be identical to pancreatic secretory PLA2. Kidney acyihydrolases and hypertension Another membrane associated form of the enzyme has been Dunn [50] and Limas and Limas [51, 52] found that prosta- isolated from P388D1 macrophages [41]. This is also a lowglandin synthetase activity was greater in adult spontaneously molecular weight form. Finally Ca2 independent forms ofhypertensive rats (SHR) than in the WKY control rats. Limas PLA2 have been partially purified from cytosolic fractions [11].and Limas also found that enhanced PGE2 synthesis by SHR kidney renomedullary microsomes and tissue slices could be PLA2 modulatory proteins found when 2-[ 1- '4C1 arachidonyl phosphatidylcholine was Much attention has recently been focused on a family ofused as substrate and suggested that there was enhanced Ca2-phospholipid binding proteins called "lipocortins", "lipo-microsomal phospholipase activity in SHR animals. Further modulins", or "renocortins" [42—44]. These proteins wereevidence that this activity represented PLA2 was provided by shown to be PLA2 inhibitors in vitro. Data that these proteinsdata indicating that '4C-arachidonic acid incorporated primarily were secreted in response to glucocorticoids, provided aninto phosphatidyicholine was released after exogenous PLA2 attractive mechanism for PLA2 regulation. Rat renomedullaryaddition or exposure to bradykinin or angiotensin II. Mepa- interstitial cells in culture produce two proteins in response tocrine, a PLA2 inhibitor, decreased the release of arachidonic dexamethasone which have PLA2-inhibitory action in an assayacid. Kawaguchi and Yasuda found that enhanced PLA2 activ- in vitro, where substrate was limiting, and reduce PGE2 pro-ity was found in cortical and medullary microsomes from stroke duction in intact control cells [42]. Lipocortin land II have beenprone SHR rats when compared with WKY controls [53]. This purified and cloned [45], and we have found these proteins, asactivity increased with age (and blood pressure) in the SHR well as the mRNA's encoding for them, to be present in largeanimals but not in controls. Phosphatidylethanolamine was the amounts in mesangial cells [46]. More recently it has beenpreferred substrate and maximal activity was achieved at a shown that lipocortin inhibition of PLA2 occurs by sequestra-Ca2 concentration of 5 mri. The authors suggested that the tion of phospholipid substrate, and not a direct interaction withenhanced PLA2 activity in the SHR animals was related to the enzyme [47]. Nevertheless, a role for PLA2 modulatoryincreases in intramicrosomal Ca2 in these animals. In a proteins in cellular PLA2 regulation remains a distinct possibil-subsequent study this group found that enhanced phospholipase ity [48]. In fact, a modulatory protein which activates PLA2 hasC activity was found in the cortical and medullary cytosolic been characterized and purified [49]. This protein appears to befractions from the stroke-prone SHR animals. Furthermore, immunologically related to mellitin, a substance with knownthey found enhanced lipase activity in the microso- PLA2 stimulatory characteristics. Identification of isoforms ofmal fractions from the SHR animals [54]. PLA2 involved in arachidonic acid metabolism will facilitate the search for PLA2 modulatory proteins. Cyclooxygenase products Diacyiglycerol lipase While it is generally believed that the levels of free arachi- Craven and DeRubertis [14] measured diacyiglycerol lipasedonic acid are rate limiting for prostaglandin synthesis it has activity in the 100,000 xg particulate fraction from the renalbeen demonstrated that PGH2 synthase, as well as some of the medulla. They found that ['4C]-arachidonic acid release fromenzymes which convert PGH2 to various prostaglandins and ['4C]-arachidonic acid-diglyceride in the presence of the partic-thromboxanes, may also be regulated. PGH2 synthase has been ulate fraction was enhanced by Ca2 with the optimal Ca2 cloned from sheep vesicular gland (Note added in proof B). The concentration being approximately 100 /LM. The pH optimum ofmolecular weight of the unglycosylated enzyme, lacking the 24 the enzyme was 7.0 to 7.5. Eighty-five to 95% of the homoge-amino acid signal sequence, is 65,621. The enzyme is a glyco- nate diacylglycerol lipase activity was found in the particulateprotein. A serine, that is acetylated by , is at position fraction. The activity was not inhibited by W-7, but was530, close to the carboxyl terminus. Most prostaglandin syn- inhibited by 800 mOsm urea. thase activity in the kidney is found in the papilla with decreas- 442 Bonventre and Nemenoff. Arachidonic acid metabolism ing amounts proceeding through medulla and cortex [50, 55].POE2 synthesis in cortical collecting ducts, the V2 agonist, This activity is found primarily in the microsomal fraction [51].dDAVP, exerted a very weak response. This weak response to Ureteral and venous obstruction have been reported todDAVP is contrary to the results of Kirschenbaum et al [61] and enhance cyclooxygenase activity and ureteral obstruction in-has been taken as evidence that the AVP-induced PGE2 re- creases thromboxane synthase activity [56—58]. In human kid-sponse is mediated by a V1 vasopressin . neys immunohistochemical staining with antiserum to PGH2 A number of investigators have examined the control of synthase is localized to collecting duct, thin ascending limbprostaglandin synthesis in collecting duct cells in culture. Using epithelial cells, and possibly mesangial cells [59]. Staining withthis preparation the following agonists and manipulations have antiserum to is localized to the peritubu-been found to enhance prostaglandin production: AVP [68, 69], lar capillaries, renal interstitial cells and glomerular mesangialbradykinin [68], angiotensin II [68], and hypertonicity [68, 69]. cells. While PGH2 synthase staining is comparable to normalTeitelbaum, Mansour and Berl have reported that cAMP inhib- kidneys in renal tissue from patients with acute tubular necro-its PGE2 production, possibly by an effect on phospholipase A2 sis, tubulointerstitial nephritis, or liver disease without the[70]. Medullary interstitial cells in culture produce prostaglan- hepatorenal syndrome, staining is markedly suppressed indins in response to AVP, angiotensin II and bradykinin [65]. kidneys from patients with hepatorenal syndrome [59]. The investigators who reported these findings suggested that the Actions of cyclooxygenase products in the kidney reduced medullary PGH2 synthase activity may explain the Cyclooxygenase products have many actions on the renal reduced prostaglandin E2 excretion observed with the hepato-tubular cell directly and on the renal vasculature supplying the renal syndrome and may relate in an important way to thetubular cells [71]. In this review it is not possible to give an pathophysiology of the syndrome. adequate overview of these multiple effects which are the topics With the exception of PGI2 [60], prostaglandin synthesis isof many recent reviews [72]. We will, however briefly summa- greater in the renal medulla than it is in the cortex. Corticalrize primary actions of these that may be relevant tubule production of prostaglandins is very low [61—63]. Byto tubulointerstitial physiology and pathophysiology. contrast there is significant production in the glomerulus, outer Renal blood flow. In general PGI2, PGF2, and PGA2 are medulla and inner medulla [61—65]. Kirschenbaum et al [611vasodilators and TxA2 a vasoconstrictor in the kidney [71—73]. found that isolated rabbit cortical collecting tubules produceUnder normal conditions prostaglandins likely play a minimal prostaglandins. Schlondorff, Satriano and Schwartz [631 re-role in blood flow regulation, as reflected by the fact that ported that PGE2 synthesis increases when moving from thesystemic treatment with nonsteroidal antiinflammatory agents branched connecting tubule to the cortical and medullaryhas little effect on renal blood flow or GFR. By contrast, with a collecting tubules. A23 187 induced enhanced synthesis in eachcompromised circulation, as occurs with hemorrhage, conges- segment to an extent predicted by the basal levels of PGE2tive heart failure, or cirrhosis, inhibition of cylooxygenase synthesis. causes marked decreases in renal blood flow and GFR [74, 75]. Farman, Pradelles and Bonvalet [64] examined the profile ofThis is presumed to be due to the inhibition of the production of PGE2 and PGF2 synthesis along the nephron of the rabbit byvasodilatory prostaglandins. Prostaglandins act to counteract preparing isolated nephron segments and incubating them withthe vasoconstrictive tendencies of angiotensin II and vasopres- arachidonic acid. PGE2 was the primary prostaglandin pro-sin which are present in large amounts in these pathophysiolog- duced in every tubular segment. A progressive increase inical states. The effects of prostaglandins on renal blood flow prostaglandin synthesis occurred along the distal nephron. Thecounterbalance vasoconstrictive influences, such as the stimu- major site of PGE2 and PGF2 synthesis was the collectinglated sympathetic nervous system, even when the renin-angio- tubule, especially the medullary collecting tubule. Of the moretensin system has been suppressed [76]. Prostaglandins may proximal nephron segments the thin descending limb was thealso affect GFR via their action on the mesangial cell. Agents only segment with significant prostaglandin production. PGF2such as AVP and angiotensin II increase cytosolic [Ca2] in synthesis was 50 to 100 times lower than that of PGE2 in eachmesangial cells [77] and cause mesangial cell contraction which segment except for the glomerulus where they were approxi-may result in a reduction in Kf. This effect is counteracted by mately equivalent. Synthesis of 6-keto-PGF1 was extensive invasodilatory prostaglandins which are produced by the mesan- the medullary collecting duct but even greater in the glomeru-gial cells [15] in response to these agonists and which cause lus. The rate of thromboxane B2 synthesis was also greatest inrelaxation of the mesangial cells [78]. the glomerulus with the cortical and medullary collecting duct Renin secretion. Prostaglandins are potent stimuli of renal also active producers of TxB2. Medullary interstitial cellsrenin release. Arachidonic acid infusion into the kidney results produce PGE2 and PGF2 in vitro [28, 651, and likely contributein enhanced renin production that is inhibited by indomethacin. in an important way to the papillary prostaglandin production.Renin production from both filtering and nonfiltering kidneys is Modulation of prostaglandin production. Yasopressin in-also enhanced by prostaglandin infusion in vivo [79]. Whorton creases cortical collecting duct prostaglandin production [61,et al. found that P012, PGE2, PGF2, and PGE1 released renin 631 and the prostaglandins inhibit the antidiuretic action offrom rabbit cortical slices with PGE2 and POE1 being the most vasopressin [61]. Schlondorff et al [63] found that bradykinineffective agents [801. Beierwaltes et al found PGI2 to be most enhanced PGE2 synthesis in cortical and medullary collectingeffective in stimulating renin release from isolated glomeruli tubules from adult rabbits. Schuster, Kokko and Jacobson [66][81]. j3-adrenergic stimulation of renin release occurs, in large showed that bradykinin inhibited the hydroosmotic effect ofpart, by a prostaglandin-independent mechanism [79, 82, 83] vasopressin via a prostaglandin-dependent mechanism. although there is some evidence to suggest involvement of the Jaisser et al [67] have reported that, whereas AVP increasespro staglandin system in this process [84]. Prostaglandins also Bonventre and Nemenoff: Arachidonicacid metabolism 443 appear to be important for the renin release which occursabout the lipoxygenase enzymes comes from other tissues. The secondary to changes in macula densa NaC1 delivery 185]. human leukocyte 15-lipoxygenase has been purified to homo- Sodiumexcretion. When PGE2 is infused intravenously orgeneity [105]. Based on partial N-terminus protein sequence directly into the renal artery of animals that are salt repletedata there was 71% homology with rabbit reticulocyte 15- there is a marked natriuresis [861. This natriuresis is likely duelipoxygenase and 36% homology with rat basophilic leukemia in part to the above described effects on renal blood flow but5-lipoxygenase [106]. The l5-lipoxygenase is activated by cal- part of the natriuresis is likely also related to direct effects oncium in crude homogenates but the purified enzyme is indepen- tubular sodium transport. Furthermore, cyclooxygenase inhib-dent of calcium, suggesting the possible presence of a calcium- itors markedly reduce the natriuresis associated with volumedependent activator. Recently a membrane protein which is expansion [87]. necessary for synthesis in intact cells has been PGE2, the predominant prostaglandin formed in the kidney,isolated and cloned [106—108]. This protein has been named alters transport characteristics in the thick ascending limb andfive-lipoxygenase activating protein (FLAP) and its presence collecting duct and possibly in the proximal tubule. Kinoshita,indicates that the regulation of the various lipoxygenases will Romero and Knox [88] have recently shown that interstitiallikely be as diverse as the above described regulation of the infusion of PGE2 increases, whereas PG!2 decreases, proximalacylhydrolases. tubule sodium reabsorption in rats. PGE2 inhibits NaCI reab- To date there is no evidence for 5-lipoxygenase activity and sorption from the ADH- or DOCA-stimulated ascending limbsubsequent leukotriene production by renal tissue. Hamberg [89—911. Another group [92], however, was unable to find anfound that 12-HETE (12-hydroxyeicosatetraenoic acid) was inhibitory effect of PGE2. Miyanoshita, Terada and Endou [931generated by guinea pig kidney homogenates. Winokur and have reported that furosemide, ethacrynic acid and bumetanideMorrison [109] reported the production of 12- and 15-HETE by significantly increase PGE2 production in the thick ascendingsoluble fractions of rabbit medullary homogenates. Jim et al limb and the effects of PGE2 on this nephron segment may[110] found lipoxygenase activity in the cortex of rat kidney. facilitate the diuretic action of these diuretics. l2-HETE was produced by homogenized glomeruli, glomerular In the collecting duct PGE2 inhibits sodium reabsorptionepithelial cells in culture and cortical tubules, although it was [94—96]. Stokes [97] has argued that PGE2 acts to inhibit apicalnot clear whether this cortical tubule activity was due to Na entry into the cells of the isolated collecting duct since itcortical epithelial cells, glomeruli or vascular structures which indirectly increases lumen-to-bath K movement in a mannercontaminated the tubule preparation. 12- and l5-HETE have similar to amiloride, rather than decreases K permeation asbeen reported to be produced by mesangial cells in culture seen with ouabain. Jabs, Zeidel and Silva [98], however, found[111]. In a recent study Gordon, Figard and Spector [112] that PGE2 inhibited ouabain-sensitive oxygen consumption andshowed that MDCK cells could convert 12-HETE to a more 86Rb uptake in freshly isolated inner medullary collecting ductpolar metabolite: 8- hydroxyhexadecatrienoic acid by a process cells, and NaKATPase activity in inner medullary mem-that does not involve the lipoxygenase, cytochrome P450 or branes. mitochondrial /3-oxidation pathways. Water excretion. Prostaglandins alter the concentrating abil- Lipoxygenase products may affect transmembrane transport ity of the kidney in a number of ways. Since prostaglandins alterby effects on channels. The /3y-subunits of G-proteins have thick ascending limb Na reabsorption, they would be expectedbeen reported to activate potassium channels in atrial cells by to alter the medullary concentration gradient and hence freestimulating production of lipoxygenase intermediates [113]. A water reabsorption. Enhanced medullary blood flow mediatedsimilar phenomena has been described in epithelial cells with by local prostaglandin synthesis results in partial wash-out oflipoxygenase intermediates involved in Na channel regulation the medullary solute gradient [99]. Agents which inhibit pros-[114]. Lipoxygenase products may affect other components of taglandin synthesis decrease vasa recta blood flow [99]. It hasarachidonate metabolism. In the platelet and neutrophil the been known for some time that prostaglandins of the E classmonoHETEs inhibit PLA2 activity [115]. In MDCK cells 12- inhibit AVP-induced water flux across the toad bladder [1001HETE inhibits the formation of PGE2, the primary prostaglan- and isolated collecting tubule [101]. This inhibition occurs, atdin product of these cells [116]. least in part, because of inhibition of the generation of cAMP by While PGE2 and prostacyclin enhance renin secretion from AVP [102]. Thus, AVP, by promoting the formation of pros-juxtaglomerular cells [100], 12-HETE and 15-HETE and their taglandins, inhibits its own action on water permeability. Pros-precursors 12- and 15-HPETE (12 and l5-hydroperoxyeico- taglandins also reduce urea reabsorption from the collectingsatetraenoic acids) inhibit renin secretion from rat cortical duct [103] and this effect may interfere with "urea recycling,"slices [117]. By contrast, 5-HPETE and leukotrienes had no which is important for maintenance of medullary solute con-effect upon renin secretion. centrations. Nonsteroidal antiinflammatory agents, which in- hibit prostaglandin production, increase concentrating ability Cytochrome P450 monooxygenase products [104]. In addition to these effects of prostaglandins on free Cytochrome P450 monooxygenases represent a family of water reabsorption these agents would be expected to inhibitenzymes [118]. Mixed function oxidase activity involves the free water excretion also due to their inhibition of thick ascend-hemoprotein, cytochrome P450, together with a flavoprotein ing limb Na reabsorption. reductase (NADPH cytochrome P450 reductase) and phos- phatidylcholine [118]. This enzyme system results in the gener- Lipooxygenase products ation of a number of different epoxyeicosatrienoic acids Little is known about the generation of non-cyclooxygenase(EET's) which can then be rapidly converted to dihydroxyeico- products of arachidonic acid in the kidney. Most informationsatrienoic acids (DHET's). 444 Bonventre and Nemenoff: Arachidonic acid metabolism

Oliw et al [1191 in 1981, incubated arachidonic acid withintracellular stores that appear to be distinct from those stores rabbit renal cortical supernatants and microsomes and reportedsensitive to inositol trisphosphate [132]. Arachidonic acid has the formation of 11, 12-dihydroxy-5,8, 14-eicosatrienoic acid andbeen reported to play a pivotal role in the mediation of the 14,15-dihydroxy-5,8,ll-eicosatrienoic acid, as well as 19- andinterleukin 2 signal for y interferon production [133—135]. 20-hydroxyeicosatrienoic acid, 1 9-oxoeicosatetraenoic acid and eicosatetraen- 1 ,20-dioic acid. Role of arachidonic acid products in renal tubulointerstitial At the same time, Winokur and Morrison [109] and Morrison disease processes and Pascoe [120] reported that the renal cortex contained an active NADPH-dependent monooxygenase that converted ara- Arachidonic acid and its metabolites may be involved in chidonic acid into I 9-hydroxy- and 20-hydroxy arachidonic acidtubulointerstitial inflammatory processes in a number of dif- as well as 19-ketoarachidonate and dicarboxylic acid. Bothferent ways. Interstitial cell infiltration is an almost invariant groups of investigators proposed that the enzymatic conver-essential component of tubulointerstitial disease. Most of the sions of arachidonic acid were due to the presence of amononuclear cells in the interstitium are T cells and many have cytochrome P-450 monooxygenase. the appearance and carry markers of activated lymphocytes. In When Schwartzman et al [1211 incubated isolated thickacute interstitial nephritis of various etiologies there are abun- ascending limb cells from the rabbit outer medulla with 14C-dant numbers of T4+ (T helper cells) and T8÷ (suppressor! arachidonic acid, two oxygenated peaks were identified oncytotoxic cells) lymphocytes with various ratios of cell popula- HPLC which differed in retention time from lipoxygenasetions reported [136]. products, were inhibited by SKF-525A, an inhibitor of lipoxy- In the rejecting transplant there is a heavy infiltrate of cells genase and P450 systems, and were increased when the cy-bearing the T8 phenotype of cytotoxic T cells [137—1391. As tochrome P450 system was induced. The same group also foundrejection becomes more severe there is a marked infiltration of that one of these products inhibited the (NaK) ATPase andmacrophages [140]. It is possible that arachidonic acid itself the other relaxed vascular smooth muscle [122]. Formation ofmay activate protein kinase C in T-cells, thus providing one of these products by medullary thick ascending limb cells wasthe signals necessary to activate the T cell to generate IL-2, enhanced by vasopressin and calcitonin [122] and in cellsalthough this has not been shown. It is known that phorbol isolated from rabbits previously made hypertensive due toesters (activators of protein kinase C) are more potent stimuli aortic coarctation [123]. Drugge, Carroll and McGiff [124]than interleukin I (IL-l) of T cell IL-2 production. IL-2 results characterized arachidonic acid metabolism in medullary thickin clonal proliferation and continued viability of activated T ascending limb cells in culture. Cultured cells did not producecells. IL-2 stimulates phospholipid turnover and arachidonic the two P450 peaks seen in freshly isolated cells. The cellsacid release from IL-2 dependent cell lines [141] and arachi- could, however, be induced with hemin and epidermal growthdonic acid and its lipoxygenase products may play a central role factor to produce two different arachidonate products thatin y-interferon production [133, 134]. Gamma-interferon upreg- migrated by thin layer chromatography in the region of cy-ulates MHC class II antigens [142—144], which are expressed on tochrome P450 products. Only one of these products, however,proximal tubular cells in various inflammatory states [145—147]. was NADPH-dependent when studied in broken cell prepara- Prostaglandin E1 has been found to be immunosuppressive in tions. a murine model of interstitial nephritis. This suppressive effect Effects of P450 products on renal function. Besides thewas associated with a reduction in spleen cell-product-induced actions of P450 products to inhibit (NaK) ATPase and relaxeffector Lyt2+ T cells [148]. blood vessels as described above, other physiological roles for Products of arachidonic acid may affect macrophage function these products have been proposed. Schlondorff et al [125]and hence alter the inflammatory response. Tumor necrosis found that each of three epoxyeicosatrienoic acids (5,6-, 11,12-factor (TN F), also called cachectin, is a polypeptide cytokine and 14,l5-EET) inhibited vasopressin-stimulated osmotic waterproduced primarily by monocytes and macrophages in response flow across the toad urinary bladder. The vicinal diol hydrolysisto endotoxin or other immune and inflammatory stimuli [149]. products of these compounds, the dihydroxyeicosatrienoic ac-PGE2 reduces TNF production by stimulated macrophages ids, had effects similar to the EET's. Both 5,6-EET and[144] and HL-60 promyelocytic leukemic cells [150] by an 11,1 2-EET prevented the AVP-induced increase in intracellularaction which occurs at the level of TNF-gene transcription. cAMP levels. ll,12-DHET inhibited AVP-induced stimulationThere is also evidence in the HL-60 cells that non-cyclooxyge- of adenylate cyclase in broken cell preparations. nase metabolites of arachidonic acid may be involved in the We have reported [126] that antagonists of the P450 systemcontrol of TNF gene transcription, since phorbol ester-induced markedly inhibit mesangial cell proliferation and mRNA levelsenhancement of TNF gene expression is inhibited by ketocono- of the immediate early genes, Egr-1 and c-fos. These datazole but not indomethacin. Furthermore, leukotriene B4 increases suggest a role for endogenous cytochrome P450 products ofTNF mRNA levels [150]. TNF stimulates IL-l production by arachidonic acid in the regulation of renal cell growth. macrophages, increases neutrophil-mediated antibody-dependent cytotoxicity [151], phagocytosis [152], and superoxide produc- Arachidonic acid as an intracellular messenger tion [153], and also induces class II antigen expression. Arachi- Free arachidonic acid has been shown to regulate the activ-donic acid plays an important role in the mitogenic and cyto- ities of several enzymes involved in intracellular signalling,toxic effects of TNF in a number of different cell types including protein kinase C [127—129], phospholipase C [130] and[154—156]. Ca2-calmodulin dependent protein kinase [1311. It has also Mangino et al [157] reported that the canine cortex, but not been reported that arachidonic acid can release Ca2 frommedulla, of kidneys undergoing rejection, synthesizes signifi- Bonventre and Nemenoff: Arachidonic acid metabolism 445

cantly greater quantities of 12-HETE than normal or autotrans-DK38452, DK38165, DK 39902, and NS 10828. Joseph V. Bonventre is planted control renal cortex. Production of LTB4 was signifi- an Established Investigator of the American Heart Association. cantly greater in the rejecting cortex compared with control renal cortex. The histological appearance of tissue destruction Reprint requests to Joseph V. Bonventre, M.D., Ph.D., Renal Unit, Jackson 8, Massachusetts General Hospital, Fruit Street, Boston, and cellular infiltration correlated with the amount of 12-HETEMassachusetts 02144, USA. found in the allograft. The dual cyclooxygenase/lipoxygenase inhibitor (BW 755C) reduced levels of 12-HETE and LTB4 as Notes added in proof well as cellular infiltration and tissue damage in rejecting renal allografts [1581. Selective cyclooxygenase inhibition with indo- A. GR0NIcH JH, BONVENTREJV,NEMENOFF RA: Purification of a methacin did not improve allograft function [1581. Thus lipoxy-high-molecular-mass form of phospholipase A2 from rat kidney acti- vated at physiological calcium concentration. Biochem J 271:37—43, genase products may be important for allograft rejection. It is 1990. B. DEWITT DL, SMITH WL: Primary structure of prostaglandin not clear from these studies, however, whether the lipoxygen- GIH synthase from sheep vesicular gland determined from the compli- ase products were derived from the infiltrating cells or from thementary DNA sequence. Proc Nat! Acad Sci USA 85:1412—1416, 1988 renal cells themselves. With various infectious processes there is enhanced renal References blood flow and natriuresis [159—1611. These changes in renal blood flow and sodium excretion may be mediated by pros- 1. FLOWER RG, BLACKWELL GJ: The importance of phospholipase A2 in prostaglandin synthesis. Biochem Pharmacol 25:285—291, taglandins [162]. Many of the physiological changes associated 1976 with infection are believed to be secondary to IL-i [163]. This 2. LOFFELHOLz K: Receptor regulation of choline phospholipid cytokine, when injected into the rat, causes a marked natriure- hydrolysis. A novel source of diacylglycerol and phosphatidic sis and associated enhanced PGE2 excretion [73]. Indomethacin acid. Biochem Pharmacol 38:1543—1549, 1989 3. BOHMAN S-O, JENSEN PKA: Morphometric studies on the lipid completely abolished the IL-i induced natriuresis. It was con- droplets of the interstitial cells of the renal medulla in different sequently proposed that IL-i is an important stimulus for PGE2 states of diuresis. J Ultrastruct Res 55:182—192, 1976 synthesis in the kidney during infection and POE2 mediates the 4. TOBIAN L, O'DONNELL: Renal prostaglandins in relation to so- natriuresis [73]. This effect of IL-l may be mediated by en- dium regulation and hypertension. Fed Proc 35:2388—2392, 1976 5.SAMUELSSONB, GOLDYNEM,GRANSTROM E, HAMBERGM, hanced PGE2 production by the papillary collecting duct [26]. HAMMER5TROM S, MALMSTEN C: Prostaglandins and thrombox- Hydronephrosis results in renal tubulointerstitial inflamma- anes. Ann Rev Biochem 47:997—1029, 1978 tion and is characterized by marked stimulation of renal arachi- 6. CONNEY AH: Pharmacological implications of microsomal en- donic acid metabolism. Needleman and colleagues have used zyme induction. Pharmaco! Rev 19:317—366, 1967 the hydronephrotic kidney as a model to explore the role of 7. Tow R, SIDDHANTA A, MANNA 5, PRAMANIK B, FALCK JR, CAPDEVILA J: Arachidonic acid epoxygenase: Detection of epoxy arachidonic acid metabolism in monocytic infiltration into renal eicosatrienoic acids in human urine. Biochem Biophys Acta 919: parenchyma and proliferation of fibroblast-like interstitial cells 132—139, 1987 [159]. The mononuclear cells are critical for the enhanced 8. SCHWARTzMAN M, LIBERMAN E, RAz A: Bradykinin and angio- prostaglandin and thromboxane release observed with endo- tensin 11 activation of arachidonic acid deacylation and prostaglan- toxin and bradykinin infusion in this model [159]. Whereas the din E2 formation in rabbit kidney. Hormone-sensitive versus hormone-intensive pools of arachidonic acid. J Biol Chem 256: inflammatory cell agonist fMLP has no effect upon leukotriene 2329—2333, 1981 synthesis in the normal kidney, it enhances leukotriene B4 and 9. WAITE M: Approaches to the study of mammalian cellular phos- C4 in the hydronephrotic kidney, presumably by acting upon pholipases. J Lipid Res 26:1379—1388, 1985 the monocytes. Albrightson et al [164] have proposed that 10. WAITE M: The . New York, Plenum Press, 1987, pp. 332 leukotriene-induced thromboxane synthesis may represent an 11. PIERIK AJ, NussEN JG, AARSMAN AJ, VAN DEN Boscu H: important vasoconstrictive influence in renal inflammation. In a Calcium-independent phospholipase A2 in rat tissue cytosols. recent study [1651 this group proposed that an eicosanoid, Biochim Biophys Acta 962:345—353, 1988 possibly a leukotriene, but not thromboxane A2, mediated the 12. DE JONG JGN, AME5z H, AARSMAN AJ, LENTING HBM, VAN inflammatory cell infiltration. DEN BOSCH H: Monoclonal antibodies against an intracellular phospholipase A2 from rat liver and their cross-reactivity with Conclusions other phospholipase A2. Eur J Biochem 164:129—135, 1987 In this overview we have briefly outlined various aspects of 13. RHEE SG, SUH PG, RYu SH, LEE SY: Studies of inositol phospholipid-specific phospholipase C. Science 244:546—550, 1986 arachidonic acid metabolism and the multiple ways in which 14. CRAVEN PA, DERUBERTIS: Ca2 calmodulin-dependent release of arachidonic acid and its metabolites influence renal function. In arachidonic acid for renal medullary prostaglandin synthesis. J the coming years we will undoubtedly learn more about the Biol Chem 258:4814—4823, 1983 regulation of the various metabolic pathways and recognize 15. BONVENTRE JV, SWIDLER M: Calcium dependency of prostaglan- din E2 production in rat glomerular mesangial cells. J Clin Invest additional roles played by the various metabolites in renal 82:168—176, 1988 function. In particular, we suspect that the noncyclooxygenase 16. JEL5EMA CL, AXELROD J: Stimulation of phospholipase A2 activ- products of arachidonic acid will be recognized as playing ity in bovine rod outer segments by the /3ysubunitof transducin prominent roles in intracellular signalling and control of prolif- and its inhibition by a subunit. Proc Nat! Acad Sci USA 84:3623— eration, as well as cell-cell interactions in a number of physio- 3627, 1987 17. BLOCK DB, BONVENTRE JV, NEER EJ, SEIDMAN JG: A G protein logical and pathophysiological states. a0 subunit alters morphology, growth kinetics, and phospholipid metabolism of somatic cells. Mol Cell Biol 9:5434—5439, 1989 Acknowledgments 18. SWEATT JD, BLAIRIA,CRAGOE EJ, LIMBIRD LE: Evidence that The work presented that was carried out in the authors' laboratories Na47H exchange regulates receptor-mediated phospholipase A2 was supported by National Institutes of Health grants DK39773, activation in human platelets. J Biol Chem 261:8660—8666, 1986 446 Bonventreand Nemenoff: Arachidonic acid metabolism

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