Prostaglandins and other arachidonic acid metabolites in the kidney

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1 Kidney international, Vol. 29 (1986), pp Prostaglandins and other arachidonic acid metabolites in the kidney DETLEF SCHLONDORFF and RAYMOND ARDAILLOU Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, and Tenon Hospital, Paris, France This review discusses the metabolism of arachidonic acid to prostaglandins (PG) and other metabolites and the site of physiological action of these products along the nephron. Potential pathophysiological contributions of renal PG will be briefly reviewed. The breakdown of prostaglandins will not be discussed and the reader is referred to several excellent articles on the subject [1, 2]. General principles of prostaglandin synthesis The biosynthetic pathway leading to the formation of the unstable intermediate endoperoxides from arachidonic acid (AA) seems to be identical in all tissues investigated [1]. Subsequent conversion of the endoperoxides follows a tissuespecific pattern resulting in the formation of different PG by different tissues. The endoperoxides are synthesized by a single enzyme which is a glycoprotein with two enzymatic sites, cyclooxygenase and hydroperoxidase [II. The endoperoxides can then be transformed by prostacyclin-synthase to PGI2, by thromboxane synthase to TXA2, by PG isomerases to PGE2 and PGD2, and by endoperoxide reductase to yield PGF2,. (Fig. 1). There is, in addition, also some nonenzymatic decomposition of PGH2 into PGE2 and PGD2 [1]. It remains unclear at this point whether the reduction from PGH2 to PGF2,. is an enzymatic reaction. Most crude homogenates contain enough thiol compounds and hemoproteins to generate significant amounts of PGF2. by nonenzymatic reduction from PGH2 [1]. The different enzymes involved in the formation of the various PUs have specific cofactor requirements (Table 1) so that the pattern of PG production can change depending on the preparation and conditions used and need not at all reflect the pattern of PG formation in intact tissue. For example, the relationship of the different PGs produced by kidney microsomes can be altered depending on the addition of various cofactors [21. Also, the pattern of PG formed may vary with the enzyme/substrate ratio and substrate concentration [2]. Finally, the ratio of cyclooxygenase to isomerase may be different in various tissues so that different results will be obtained depending on whether AA or PGH2 are used as substrate (for example, see [3D. Received for publication June 12, by the International Society of Nephrology Control of PG-synthesis Cyclooxygenase activity. Changes in cell cyclooxygenase activity (half-life 24 hr) may occur slowly under certain conditions and can chronically change the capacity for PG synthesis. Such alterations in total cyclooxygenase activity have been observed, for example, in rats with congenital diabetes insipidus after chronic administration of antidiuretic hormone [4]. A different mechanism may underlie the increase in cyclooxygenase after unilateral ureteral ligation [5 8] or renal venous obstruction [91. In these instances it appears that the increase in enzyme does not occur in the renal cells, themselves, but is instead due to proliferation of inflammatory cells [10]. Substrate availability. Under normal physiological conditions the amount of free intracellular AA, that is available for cyclooxygenase is negligible [1]. Apart from the activity of cyclooxygenase in a given tissue, the major factor controlling PG-synthesis is the availability of free AA. AA is esterified in the 2 position of the phospholipid, predominantly in phosphatidylinositol but also in phosphatidyleholine and phosphatidylethanolamine. Most likely both phospholipase C and phospholipase A2 activation are involved in the release of AA [11 12]. Agreement exists that the enzymatic steps leading to the release of AA are calcium-dependent [1]. Phospholipase A2 in the renal medulla [12 14] may be a calcium-calmodulin-dependent enzyme, while phospholipase C appears to be calmodulin-independent [15, 161. In the isolated kidney [17] and kidney slices [7] and cultured mesangial cells [181, there are specific pools of AA linked to cyclooxygenase activity, while other AA pools are unrelated to PG-synthesis. Furthermore, metabolism of only a small percentage of the AA pool in phospholipids seems to be hormone responsive [7, 181. The amount of membrane-bound AA converted to cyclooxygenase or lipoxygenase products is only a small fraction of the total. Only a few percent of the cellular AA is released even after maximal hormone stimulation, and of this, only a fraction (10 to 40%) is transformed by cyclooxygenase, while the rest may be reincorporated into phospholipids [17]. The fact that the hormone responsive AA pool is small compared to the total phospholipid-bound AA complicates studies which rely on the prelabeling of phospholipids with exogenous AA, because under most conditions the total phospholipid pool is labeled nonspecifically [7]. Prelabeling of the specific hormone responsive pool may be facilitated by prior hormone stimulation [19]. Further complicating matters, different individual phospholipids also have different turnover rates and are represented to 108

2 Prostaglandins and metabolites in the kidney 109 Phosphoglyceride Triglyceride Cholesterol ester (OOH) OH 5-HET COON Acylhydrolase COON 02 Arachidonic Acid (20:4) 02 (HOO' r0h Cyclo oxgenase 12-Het CHO CH OH PGG2 OOH [H) 6-keto-PGF1 OH OH OH PGD2 PGF2 Fig. 1. Scheme of biologically active compounds derived from arachidonic acid. (Reprinted from [II with permission) differing degrees within the cells. For example, phosphatidylinositol only represent 5 to 10%, while phosphatidylcholine and phosphatidylethanolamine each account for about 30% of the total phospholipids. Thus, small changes in the turnover of phosphatidyicholine and phosphatidylethanolamine may release as much AA as much more marked changes in phosphatidylinositol turnover. For all these reasons, the exact source of AA and the mechanism of its release have yet to be defined fully. Inhibition of phospholipase. An endogenous inhibitor of phospholipase has been described in neutrophils [20 22] and renal medulla [22]. This inhibitor is a protein that is synthetized and released in response to glucocorticoids. It has been called macrocortin [20], lipomodulin [21], orrenocortin [22]. Lipomodulin has been shown to inhibit both phospholipase A2 and C in vitro [21]. Other factors influencing AA availability. In addition to release of AA by phospholipase, factors that influence the AA availability include: (1) Binding of AA to protein. AA avidly binds to both extra and intracellular proteins and as such is no longer available for cyclooxygenase. Thus, not all intracellular AA is "free" and can be utilized for PG synthesis [1]. (2) Reincorporation of AA. AA released from the phospholipids may be reincorporated rapidly into phospholipids [1, 17]. This reaction competes with cyclooxygenase for AA [7, 18]. As the reincorporation into phospholipids requires ATP, the reaction may be slowed during hypoxia, which, in turn, could lead to higher concentrations of nonesterified AA. This Table 1. Some characteristics of enzymes involved in prostaglandin synthesis AA Formation of Location Cofactors Cyclooxygenase PGG2. Hemin Particulate Hydro- PGG2. peroxluase PGH2 Aromatic compounds (for example, tryptophan) as reducing substrate PGE2 Particulate Glutathione PGI2 Particulate None known Thromboxane Particulate None known PGD2 Soluble Glutathione (?) albumin (?) PGF2 Enzymatic (?) Thiol compounds and hemoproteins may be one explanation for increased PG synthesis observed during hypoxia [23 25]. (3) Competition foraa. In addition to cyclooxygenase, AA is also a substrate for lipoxygenase and epoxygenase. This competition for free AA could influence PG-synthesis. Furthermore, the products of these enzymes may in turn influence phospholipases and the cyclooxygenase system. These pathways are only beginning to be explored in the kidney. Lipoxygenase products and the kidney Formation of lipoxygenase products by the kidney. Arachidonic acid can also be metabolized via lipoxygenase pathways

3 110 Schlondorff and Ardaillou (Figs. 1 and 2) [26]. To our knowledge, the formation of small amounts of 12-HETE by guinea pig kidney homogenates was first demonstrated by Hamberg [27]. Recently, Winokur and Morrison [28] demonstrated formation of 12-HETE and 15- HETE (identified by gas chromatography followed by mass spectrometry) by a cytosolic preparation from rabbit renal medulla but not from the cortex. The lipoxygenase activity was increased in hydronephrotic kidneys, a finding similar to the increase in cyclooxygenase activity in hydronephrotic kidneys [5]. In the hydronephrotic kidney, it remains unclear whether these products are truly of renal cell origin or are produced by invading inflammatory cells [10]. The enzyme required calcium and was inhibited by the lipoxygenase inhibitors eicosatetraynoic acid (ETYA) and phenidone, but not by indomethacin [28]. Lipoxygenase products have been identified lately by gas chromatography-mass spectrometry as 12-HETE in rat glomeruli [29, 301 and as 12- and 15-HETE in human glomeruli [30]. It is to be expected that lipoxygenase products will be identified in other renal structures, as more attention is directed toward these products and as analytical detection methods are improving. The physiological significance of these lipoxygenase products in renal function remains to be determined but is certain to attract much interest in the near future. Lately, it has been postulated that lipoxygenase products may play a role in experimental immune injury to the glomerulus [31 33]. Metabolism of leukotrienes in the kidney. To date no evidence exists for 5-HETE formation and subsequent leukotriene production by kidney tissue (Fig. 2). Systemic infusion of leukotrienes, however, does influence renal function [34]. It is therefore reasonable to assume that leukotrienes released from inflammatory cells within the kidneys may influence renal hemodynamics and capillary permeability, as they do in other systems [261. Also, the kidney may be involved in the metabolism of leukotrienes. Transformation of LTC3 to the biologically more active LTD3 by gamma-glutamyltranspeptidase has been demonstrated in the kidney [35]. Conversion of LTD to LTE has also been demonstrated in the porcine kidney [36] and is associated with a tenfold decrease in biological activity. In vivo the kidney may play a role in the metabolism and inactivation of leukotrienes as suggested by total body autoradiography of mice after injection of [3H]-labeled leukotriene C3 [37]. Epoxygenase pathway In addition to cyclooxygenase and lipoxygenase, the kidney contains mixed function oxidases that are involved in the metabolism of fatty acids and also PG [38 41]. Recently, it has been shown that AA can be converted by NADPH-dependent, cytochrome P-450 to oxidation products (Fig. 3); [42 44]. They include dihydroxyeicosatrienoic acids oxidized at the 5,6; the 8,9; the 11, 12 and the 14,15 position as well as 19,20- hydroxyeicosatetraenoic acids, 19-oxoeicosatetraenoic acid, and eicosatetraen-l,20-dioic acid. The formation of these products by renal cortical microsomes depended on the pesence of NADPH which cannot be substituted for NADH. 02 is also necessary for their formation [42 44]. The formation of the 11, 12- and the 14,15-dihydroxyeicosatetraenoic acid occurred probably via the intermediate epoxides 11(12)- and 14(15)- oxido-cis-5,8,14 eicosatrienoic acid. The dihydroxyacids can be metabolized further to trihydroxy acids [44] (Fig. 3). It is HvdrolaS>Z H OH HOH Leukotriene B4 (LTB4) Arachidonic acid I Lipoxygenase HOOH 5-HPETE Dehydrase HOH HETE HO Nonenzymatic Leukotriene A4(LTA4) Glutathione 'S-transferase HOH 5H1 ys-giy c -Glu Leukotriene C4 (LTC4) 1GGp HO H LTD4 c_ Cys-Gly HOH LTE4 H S C5H11 Cys LTF4 H OH OH.OOH C5H11 Cys c -Glu Fig. 2. Formation of leukotrienes via the 5-lipoxygenase pathway. GGTP is y-glutamyl transpeptidase. (Reprinted from [26] with permission) possible that a cytochrome P-450-linked epoxygenase system is involved in the formation of metabolites that previously were mistaken for cyclooxygenase or lipoxygenase products. An intriguing finding is the production of considerable amounts of AA derivatives by the thick ascending loop of Henle that derive from neither cyclo- nor lipoxygenase pathways and may be epoxygenase products [45 47]. The epoxygenase pathway is certain to attract considerable interest, especially as 5,6 epoxyeicosatrienoic acid, a product of a renal NADPH-dependent monooxygenase pathway, can inhibit sodium transport in isolated collecting tubules [48] and vasopressin's hydroosmotic action in the toad urinary bladder [49]. PG-synthesis in the kidney The kidney, and especially the renal medulla, is one of the most active PG-producing tissues. Homogenates or microsomes from the entire kidney produce PGE2, PGF2, 6 keto PGF1,, TXB2, and PGD2 to varying degrees depending on the conditions used [2]. The isolated perfused kidney produces predominantly PGE2 [5, 50] but also can release PG!2 [51], and under certain circumstances, TXB2 [52, 531. Table 2 lists factors influencing renal PG synthesis. There are marked regional differences in the quantity and pattern of PG production within the kidney. As PGs are locally active agents, the pattern of PGs produced by different nephron

4 / w-oxidation Prostaglandins and metabolites in the kidney 111 Arachidonic acid / \ w6 and w9 Epoxidation (w-1) Oxidation /OH Dehydrogenase 0 I I / /1 HO OH HO OH wand (w-1) Oxidation and (w-1) Oxidation OOH 0r' Dehydrogenase HO OH HO OH OH HO OH HO OH OH HO OH 0 Fig. 3. Tentative pathway of arachidonic acid metabolism leading to trihydroxy metabolites in fortfled rabbit kidney microsomes by the epoxy genase systems. (Reprinted from [44] with permission) Table 2. Factors stimulating PG synthesis by the kidney in vivo or perfused in vitro Stimulating factor Reference Angiotensin II 7, 17, 23, Bradykinin 7, 17, 23, 55, Vasopressin Catecholamines and renal nerve stimulation 50, 60, 64 Converting enzyme inhibitor 65 Mannitol 66 Renal perfusion rate segments is important. PG synthesis increases from cortex to medulla [701 and has been examined recently in isolated glomeruli, different tubular segments, interstitial cells, or cells derived from various nephron segments. Localization of prostaglandin synthase by histochemical or immunofluorescence methods. Localization of prostaglandin synthase activity within the kidney has been performed by histochemical staining for peroxidase activity [71, 72] and indirect immunofluorescence for cyclooxygenase [73]. Both methods have yielded remarkably similar results. In the renal cortex of rabbit, cow, rat, sheep, and guinea pig, positive immunofluorescence for cyclooxygenase was observed in the endothelial cells of arteries and arterioles but not in the capillaries or venous tree [73]. Glomerular epithelial cells of Bowman's capsule stained positive in the rabbit only, whereas in bovine and ovine glomeruli, the fluorescence was present in a mesangial distribution. Proximal tubules, the loop of Henle, and distal convoluted tubules, including the macula densa, were negative by both immunofluorescence and peroxidase methods [71, 72]. It should be considered, however, that the immunofluorescence staining for cyclooxygenase activity gives only a qualitative picture and a negative staining reaction does not rule out cyclooxygenase activity but could just indicate levels below the detection limit. In the renal medulla both histochemical and immunofluorescence methods show strongly positive staining in collecting tubule cells and interstitial cells [71 73]. PG-synthesis by different nephron segments. (1) Renal cortex. To better characterize the source of PG synthesis in renal cortical tissue, isolated nephron segments have been examined for PG synthesis. PG!2 synthesis has been shown to be prominent in microdissected cortical arteries and arterioles [74]. Rat glomeruli produce mainly PGE2 and PGF2,, and less PGI2 and TXB2 [75 78]. Human glomeruli synthesize mainly PGI2 (determined as 6 keto PGF1a,) and also some TXB2, PGE2 and PGF2a [79, 80]. Localization of PG synthesis within the glomerulus has been studied using primary cultures of glomerular cells. Rat cultured mesangial cells synthesize almost exclusively PGE2 [80, 811 while mesangial cells from humans produce predominantly PGI2, [82] similar to the isolated human glomerulus [83]. Rat glomerular epithelial cell cultures seem to have the same profile as mesangial cells but the amount of PGs produced may be smaller [80, 84]. Kreisberg, Karnovsky, and Levine [85] have, however, reported considerable and predominant synthesis of 6 keto-pgf1, by epithelial cells in culture. The problem of actually identifying the cultured cells to be of glomerular visceral epithelial origin makes it difficult to assign an exact PG profile to the epithelial cells. In contrast to isolated glomeruli, cortical tubules, consisting of predominantly proximal tubules, produce very little PG [76 78, 86] consistent with the absence of either peroxidase

5 112 Schlondorffand Ardaillou Table 3. Factors stimulating PG synthesis in glomeruli Tissue Isolated glorneruli Cultured glomerular mesangial cells Cultured glomerular epithelial cells Stimulating factor A Angiotensin 11 Converting enzyme inhibitor Hydrogen peroxide Mercury chloride A Angiotensin 11 Vasopressin Platelet activating factor Bradykinin Zymosan A Angiotensin II Vasopressin years. The literature is extensive and shall not be reviewed in Reference detail. Several excellent reviews dealing with the physiological and pathophysiological aspects of renal prostaglandins have 16, 77 appeared. The reader is referred to them for a more extensive 76, 80, 87 treatment [I 15 I 17]. At present there is convincing evidence that prostaglandins 89 influence: (1) renal blood flow and glomerular filtration, (2) the 90 release of renin, and (3) the urinary concentrating mechanism. A contribution of prostaglandins to NaCI and perhaps phos ' ' 92 ' 93 phate and hydrogen ion handling by the kidney independent of 82, 83 blood flow is likely, but not fully established. Finally, a role of 83, 94 prostaglandins in the control of renal erythropoeitin production has been postulated. PG and the control of renal blood flow and glomerular 95 filtration. In general the importance of renal prostaglandins for 84 the inaintenancc of blood flow and glomerular filtration can be 95 demonstrated only under conditions where the vasoconstrictor system is activated [ ]. Similar to the vasculature in other organs PGE2 and PGI2 are vasodilators in the kidney medullary tissue [120]. Occasional vasoconstriction observed after PGE2 or PGI2 Table 4. Factor stimulating PG synthesis in renal Tissue Stimulating factor Reference administration may be secondary to an increase in renin release and consequently angiotensin II formation [1211. When the Medullary slices and A ' medullary cell Vasopressin 14, 105, io formation of angiotensin II is blocked, both PGE2 and PG!2 act suspensions Angiotensin II II, 107, 109, 1 io as renal vasodilators. On the other hand, thromboxane is a Bradykinin 110 potent vasoconstrictor that also contracts isolated glomeruli Furosemide [122]. The physiological role of the vasodilatorprostaglandins is Hypertonic medium 14, 110, 112 most likely to counteract the effect of vasoconstrictors. Renal (NaCI, mannitolj Isolated collecting tubules Cultured collecting tubule cells Cultured renomedullary interstitial cells A Vasopressin Bradykinin Vasopressin Bradykinin Angiotensin II Vasopressin Bradykinin Hypertonic medium stain or immunofluorescence for cyclooxygense in this tubular segment. Table 3 summarizes factors known to influence PG synthesis in isolated glomeruli and cultured glomerular cells. (2) Renal medulla. In agreement with the histochemical and immunofluorescent studies, the major sources of PGE2 production within the medulla are collecting tubules and interstitial cells. Both rabbit interstitial cells in culture [96 99] and isolated or cultured [ ] collecting tubule cells very actively produce PG, predominantly PGE2, and to a lesser extent, PGF2. and PG!2. In addition the same pattern of prostaglandin synthesis is observed in microdissected collecting tubules [86, 104, 105]. Other elements of the renal medulla, for example, the loop of Henle, exhibit very little PG production [47, 104]. The thick-ascending loop of Henle may, however, have considerable epoxygenase activity [45, 46]. Table 4 indicates agents that alter PG synthesis in collecting tubules and medullary interstitial cells. Physiological and pathophysiological considerations The physiological role of prostaglandins in modifying various renal functions has become increasingly apparent over the last vasoconstrictors increase synthesis of vasodilatatory prostalos glandins (see Tables 2 to 4) and thus act as a negative feedback. 86, 105 Prostaglandins may affect renal blood flow to varying degrees 105 in different regions of the kidney [123, 124]. Inhibition of 102, 103 endogenous prostaglandin synthesis will preferentially decrease 101, 103 medullary blood flow, possibly indicating that the high renal medullary PG synthesis maintains blood flow to this poorly 98,113 oxygenated and hypertonic region of the kidney. 98 Prostaglandins also play a contributory role in renal autoreg- 98, 114 ulation [125]. As modulators of renal vascular tone and mesangial contraction, prostaglandins also influence glomerular filtration rate (GFR) [117, 121, 122, 125]. They may do so by changing the afferent and efferent arteriolar resistance [121, 125], by influencing the renin-angiotensin system [117, 121, 125], and finally, by directly affecting the glomerular filtration characteristics via changes in mesangial contraction [122]. The glomerulus can decrease its size in response to various vasoactive agents [122, 126], presumably by mesangial cell contraction [82, 83, 94, This contraction is attenuated by concomitant increases in the synthesis of vasodilatory PGs [94, 122], Thus, locally produced prostaglandins may also directly influence the effective glomerular filtration surface. Micropuncture experiments have demonstrated that prostaglandins may also contribute to tubuloglomerular feedback regulation [125]. Indeed, the local production of renin, angiotensin II and prostaglandin and their respective interactions would be suited ideally for regulation of individual glomerular function. The role of intrarenal prostaglandins in the maintenance of renal blood flow and GFR is even more evident in various renal diseases. PG synthesis may contribute to maintain renal function in patients with systemic lupus erythematosus, congestive heart failure, chronic renal failure, liver cirrhosis, diabetes mellitus, volume depletion, diuretics, or old age. (For a corn-

6 plete review of the effects of PG-synthesis inhibitors on renal function refer to [129, 130].) The possibility that imbalances between vasodilatory PG and the vasoconstrictor thromboxane play a role in renal diseases has also been raised based on results with experimental unilateral ureteral obstruction [5, 6, 131], acute renal failure [52, 91, 132], renal transplant rejection [133], and experimental nephrotoxic serum nephritis [134]. Changes in intraglomerular hemodynamics can significantly influence the filtration, deposition, and subsequent handling of macromolecules (for example, proteins and immune complexes) by the glomerulus [135]. Thus, vasoactive agents could hfluence glomerular immune-injury; this process could, in turn, be modulated by intraglomerular production of PGs [94]. PG and the control of renin release. PGs, particularly PGE2 and PGI2, have been demonstrated to enhance plasma renin activity in vivo and directly increase renin release in vitro and thus represent one of the multiple factors controlling renin (for review, see [1361). In vitro studies showed that locally produced PGs act on renin secretion by renal cortical preparations [1361. Stimulation of renin release also occurs in isolated glomeruli superfused with arachidonic acid PGE2 or PG!2 [137], and this is blocked by PG synthesis inhibition. The mechanism of action of PGs on renin release seems to involve cyclic AMP as second messenger [138] and both PGE2 and PGI2 stimulate cyclic AMP generation in rat [139] and human glomeruli [140]. PG in the urinary concentrating mechanism. Ever since the original observation that PGE1 inhibits the effect of antidiuretic hormone in the toad urinary bladder [1411 and in the mammalian collecting tubule [142], the interaction of ADH with PG has attracted much interest. Multiple studies have confirmed that PGE1 and PGE2 antagonize the antidiuretic action of ADH both in vitro and in vivo. [ Two major questions that have attracted considerable interest are: (1) How does PG interfere with the renal concentrating mechanism? (2) Does ADH directly enhance the synthesis of prostaglandins in its target organ closing a negative feedback loop? Concerning the first question, several possible mechanisms exist. PG could interfere with the renal concentrating mechanism by increasing renal medullary blood flow leading to the washout of solute and dissipation of the osmotic gradient required for water reabsorption. PG may also influence medullary solute composition by decreasing sodium transport and urea accumulation in the medulla. Both of these effects could be independent of ADH. Consistent with this formulation, medullary NaCI concentration increases after inhibition of PG synthesis and decreases after administration of PGE2 [146, 147]. Thus, PG could influence medullary solute composition and hence urinary concentrating ability even in the absence of ADH [148]. Also, urea permeability of the toad urinary bladder [149] and the mammalian collecting tubule [150] increases after inhibition of PG synthesis while exogenous PG decreases urea permeability. It has been shown that vasopressin stimulates adenylate cyclase and enhances NaCI reabsorption via cyclic AMP in the medullary thick ascending limb of Henle. Moreover, two laboratories independently have shown that PGE2 inhibits adenylate cyclase and NaCI reabsorption in this nephron segment in a dose-dependent manner in response to vasopressin [151, 152]. Since NaCI reabsorption in this nephron Prostaglandins and metabolites in the kidney 113 segment is central to the generation and maintenance of the medullary hypertonicity, these data suggest that PGE2 can also affect the urinary concentration mechanism by modifying the action of vasopressin in the thick ascending limb of Henle's loop. The major effect of PG in the concentrating mechanism is its interference with the cellular mechanism of action of ADH. Studies in the toad urinary bladder [153, 154] in segments of the thick ascending loop of Henle and in isolated collecting tubules [151, 152, 155, 1561, and in vivo [157] have shown that PGE2 interferes with the ADH-induced cyclic AMP generation probably via an inhibitory subunit of the adenylate cyclase. While this effect can be shown in intact tissue, an inhibitory action of PG on ADH-stimulated adenylate cyclase in broken cell preparations has not been uniformly found [1581. Furthermore, PGE2 at concentrations of 10-6 M and upward may even increase cellular cyclic AMP concentrations [14, 153, Therefore, the possibility of an additional inhibitory action of PG at a site distal to the generation of cyclic AMP has been postulated [154]. Finally, it has been proposed that thromboxane may directly enhance vasopressin's action [159] though these findings remain controversial [160]. The second question, that is, whether ADH directly enhances the synthesis of prostaglandins in its target organ thereby closing a negative feedback loop as originally proposed by Zusman, Keiser, and Handler [161], has resulted in some seemingly contradictory answers. In the toad urinary bladder stimulation of PGE2 and thromboxane synthesis after ADH has been reported [159, 161]. Other groups were unable to detect a significant effect of ADH on PGE2 synthesis in the toad bladder or toad bladder epithelial cells [ ]. At present it appears that the reason for the differences may in part relate to differences in the preparation of the tissue [165, 166]. In studies with mammalian tissue, interstitial cells in culture, medullary slices and cell suspensions, collecting tubule cells in culture, and microdissected collecting tubules have been used. In medullary slices and cell suspensions ADH usually stimulates PGE2 synthesis to some extent (see Table 4). These preparations do, however, contain both interstitial and collecting tubule cells, and thus, do not allow one to attribute the increase in PGE2 synthesis to a specific cell. In primary cultures of medullary collecting tubule cells ADH increased cyclic AMP concentration but did not stimulate PGE2 synthesis [101]. On the other hand, in cultures of cortical collecting tubules ADH increased PGE2 synthesis [102, 103]. Similarly, ADH and DD AVP were found to increase PGE synthesis in isolated cortical collecting tubules [86]. Studies carried out in our laboratory indicate that some of the differences may be due to the in vitro incubation conditions and that, under certain conditions, ADH can increase PGE2 synthesis in both cortical and medullary collecting tubules [105]. A number of points have to be considered to explain these discrepant results. For example, PGE2 synthesis by toad urinary bladder, medullary slices, and isolated collecting tubules decreases progressively with incubation time [14, 105, 163]. The absence of a stable baseline makes it difficult to unequivocably demonstrate stimulation, unless this occurs to a very marked degree. Demonstration of ADH-induced PGE2 synthesis may be complicated further by the fact that cyclic AMP can decrease PG production probably by inhibiting phospholipase activity.

7 114 Schlendorffand Ardaillou Based on the observation that 8 bromo cyclic AMP can inhibit PGE2 synthesis in renal medullary cells and toad bladder epithelial cells under basal and ADH-stimulated conditions, it has been proposed recently that ADH and PGE2 may interact in a dual feedback loop [1661. In this scheme ADH would increase PGE2 synthesis by activating phospholipases in a cyclic AMPindependent manner as originally proposed by Zusman, Keiser, and Handler [161]. The resulting increase ofpge2 will, in turn, inhibit ADH's hydroosmotic effect, to a large extent by interfering with cyclic AMP generation. On the other hand, the increase in cyclic AMP could inhibit phospholipase activation and the resulting synthesis of PGE2, representing a second feedback loop that would tend to prevent an overshoot of both the ADH and PGE2 effect in either direction. Contribution of PG to renal NaC1 excretion. Despite a considerable amount of experimental data from both in vivo and in vitro studies, the evidence for a blood-flow independent role for prostaglandins in renal NaCI excretion remains controversial. In vivo, depending on the experimental conditions (for example, prior NaCI content of diet, volume status, water diuresis, or antidiuresis, awake or anesthesia, and so forth), intrarenal administration of PGE or inhibition of renal PG production has provided results that indicate: (1) renal PG do not influence renal NaCI excretion; (2) PG inhibit NaCI excretion, or (3) PG increase renal NaCI excretion [115, 116, These conflicting results are not overly surprising as the physiological status of the animal can alter the effect of prostaglandins on renal blood flow and its distribution. Though some studies attempt to minimize or exclude changes in blood flow, it remains doubtful whether this factor can ever be eliminated adequately during in vivo studies. Studies using urinary PGE2 excretion as an index of renal PG synthesis have occasionally, but not always, shown a correlation between urinary PG and NaCI excretion. Studies using the isolated perfused tubule have resulted similarly in conflicting results [1671. While several groups have shown inhibition of NaCI transport by PGE2 or PGI2 in the cortical collecting tubule [ ] or the thick ascending loop of Henle [171] from rabbits, another group has been unable to show such an effect [172, 173]. The reason for these discrepancies remains unclear and cannot be explained easily by differences in hormonal status, basal NaCI transport, or buffers used. If PGE2 produced by the collecting tubule inhibits NaCl transport, it remains unclear why inhibition of collecting tubular PG synthesis does not result in enhancement of NaCI transport. Holt and Lechene [1741 did, however, report that PG-inhibition prevented the vasopressin-induced changes in Na-transport in cortical collecting tubules. Studies using simultaneous measurements of NaCI transport and PGE2 synthesis by isolated collecting tubules might be helpful in resolving the role of PGE2 in NaCI transport by this segment. Also, it is possible that noncyclooxygenase products of arachidonic acid influence NaCI transport. For example, PGE2 has been postulated to inhibit NaCl transport in the thick ascending limb of Henle's loop [171]. The thick ascending loop of Henle, however, produces only very small amounts of prostaglandins [104, 122, 125]. On the other hand, cells from this segment seem to have a high capacity to metabolize arachidonic acid to noncyclooxygenase products possibly via the epoxygenase pathway [45, 661. The possibility that such products influence NaCI transport has been reported [48] and will have to be examined further. Conceivably, the effect of PGE2 on NaCI transport observed in isolated tubules may be an indirect one secondary to an influence of the added PGE2 on the formation of noncyclooxygenase products. Role of PG in renal phosphate excretion. Published reports on the effects of PGs on renal phosphate transport are also conflicting. Beck et al [175] showed that PGE1 alone was mildly antiphosphaturic but that it markedly inhibited the phosphaturic response to PTH in intact dogs. In contrast, Strandhoy et al [1761 reported that PGE1 increased the fractional excretion of phosphate in intact dogs whereas PGE2 was inactive. In further studies Fragola et al [177] confirmed that PGE2 by itself had no effect on phosphate excretion in thyroparathyroidectomized dogs, but abolished the phosphaturic action of PTH in vivo. This effect occurred only if PGE2 infusion preceded the administration of PTH. More recently, the same group using the microperfusion technique showed a dual role for PGE2. PGE2, like PTH, inhibited phosphate transport in the proximal straight segment of the rabbit nephron, but also antagonized the effect of PTH [178]. Taken together, these results could suggest that the interaction of PTH and PGE in vivo could represent tubular desensitization to PTH by PGE2. In rabbit cortical collecting tubules, Holt and Lechene [174] demonstrated that ADH inhibited calcium and phosphorus reabsorption and that pretreatment with meclofenamate blocked this effect of ADH whereas PGE2 mimicked the effect. From these studies, the authors concluded that phosphate reabsorption in the cortical collecting tubule may be decreased by PGE2 synthesized in response to ADH. In summary some evidence supports a role for PG to inhibit tubular phosphate transport. It should be recalled however, that the proximal tubule, the major site of phosphate transport, has very little capacity to produce PG [76, 77, 86]. Also to date, no unequivocal effect of PG inhibition on proximal tubular phosphate transport has been demonstrated. Role of PG in renal erythropoeitin production. A role for renal PG in the production and release of erythropoeitin by the kidney has been postulated based on some indirect experimental evidence [179, 180]. Unfortunately, our knowledge of the synthesis of erythropoeitin by the kidney and its control is too scanty at this point to allow a critical evaluation of this issue. Role of prostaglandins in various renal diseases Because of the multiple contributions of prostaglandins to various renal functions, it is not surprising that abnormal prostaglandin synthesis has been invoked to contribute to a variety of disease states. In cases of threatened renal function, the enhanced PG synthesis may help to maintain renal blood flow and glomerular filtration (see Renal blood flow above). The possible role of prostaglandins in systemic hypertension of various etiologies continues to attract considerable interest. Changes in renal PG synthesis have been described in several models of hypertension, Again, it remains unclear whether the changes in PG synthesis represent a primary contributing factor or a secondary reaction [1811. Surprisingly, a possible contributory role of inhibition of prostaglandin synthesis to the etiology of analgesic nephropathy has not been investigated extensively. Nonsteroidal antiinflammatory drugs, all of which are PG-synthesis inhibi-

8 Prostaglandins and metabolites in the kidney 115 tors, are, however, associated With a variety of abnormalities of renal function [129, 130]. Abnormalities of renal PG synthesis have also been observed in experimental hypokalemia [ ], experimental hypercalcemia [185], and hypothyroidism [186] and were related to the associated inability to maximally concentrate urine. However, these findings have been questioned [187, 188] and the urinary concentrating defect appears independent of changes in PG synthesis [189, 190]. Also, a contributory role of enhanced prostaglandin synthesis in Bartter syndrome has been discussed [191]. Summary This very brief summary of the various possible contributions of PG to normal and abnormal renal function should highlight the problem of assigning a specific role to PG in overall renal physiology and pathophysiology. PG produced in specific segments of the nephron will affect specific functions occurring in this segment. These effects need not necessarily be reflected in the overall renal function. Also in some cases, the determinant may not be prostaglandins, that is, cyclooxygenase derivatives of AA, but perhaps lipoxygenase or epoxygenase products that influence the functional parameters of the specific segment. Despite the multitude of renal functions that may be influenced by PG, we would like to propose a teleological hypothesis for an overall role of PG in the kidney, that is, that of cytoprotective agents. Renal vasodilatatory prostaglandins will maintain renal blood flow when the latter is challenged, thus, preventing hypoxic injury to the tissue. Endogenous prostaglandins may also protect tubular cells from extreme environmental changes as may occur on both the luminal and contraluminal sides. For example, tubular cells may be exposed to luminal fluid that may vary from hypotonic to hypertonic, from alkaline to acid, and so forth. Similarly, the interstitial fluid osmolality and solute composition is subject to considerable variations which may be opposite to those existing on the urinary side. The role of PG might be to maintain the internal milieu of the cells exposed to such extreme changes in environment. This could be accomplished by changing the permeability characteristics of the membranes and the function of pumps. Thus, specific PGs could dampen the hormonal response to protect the specific nephron segment, which might otherwise suffer injury. This hypothesis might also help to explain why the effect of PG administration or inhibition of PG synthesis may vary considerably depending on the overall physiological state of the subject: Maintenance of a local internal milieu may require different responses from those required for total body homeostasis. Acknowledgments Supported by a grant from the National Institute of Health AM (Schiondorif) and by the Institut National de Ia Sante et de la Recherche Medicale (Ardaillou) and by a North Atlantic Treaty Organization grant for international collaboration in research (Schlondorff and Ardaillou). We thank Mrs. G. O'Sullivan for secretarial assistance. Reprint requests to Dr. D. Schlondorff, Room 615 UI/mann, Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA References I. LANDS WEM: The biosynthesis and metabolism of prostaglandins. Ann Rev Physiol 41: , SUN FF, TAYLOR BM, MCGLFF JC, WONG PK: Metabolism of prostaglandins in the kidney. Kidney mt 19: , SHENG WY, WYCHE A, LYSZ T, NEEDLEMAN P: Prostaglandin endoperoxide E2 isomerase is dissociated from prostaglandin endoperoxide synthetase in the renal cortex. J Biol Chem 257: , BECK TR, HA55ID A, DUNN Mi: Desamino-D-Arginine Vasopressin induces fatty acid cyclooxygenase activity in the renal medulla of diabetes insipidus rats. J Pharmacol Exp Ther 221: , Nisi-iiw.s. K, MORRISON A, NEEDLEMAN P: Exaggerated prostaglandin biosynthesis and its influence on renal resistance in the isolated hydronephrotic rabbit kidney. J Clin Invest 59: , MORRISON AR, MORITZ H, NEEDLEMAN P: Mechanism of enhanced renal prostaglandin biosynthesis in ureter obstruction. Role of de novo protein synthesis. J Biol Chem 253: , SCHWARTZMAN M, LIBERMAN E, RAZ A: Bradykinin and angiotensin IL activation of arachidonic acid deacylation and prostaglandin E2 formation in rabbit kidney. Hormone-sensitive versus hormone-insensitive lipid pools of arachidonic acid. J Biol Chem 256: , SHENG WY, LYSz TA, WYCHE A, NEEDLEMAN P: Kinetic comparison and regulation of the cascade of microsomal enzymes involved in renal arachidonate and endoperoxide metabolism. 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9 116 Schlondorffand Ardaillou 23. MCGIEF JC, CROWSHAW K, TERRAGNO NA, LONIGRO AJ, STRA JC, WILLIAMSON GA, LEE JB, Na KKF: Prostaglandin-like substances appearing in canine renal venous blood during renal ischemia (abstract). Circ Res 27:765, HERMAN CA, ZENSER TV, DAVIS BB: Prostaglandin E2 production by renal inner inedullary tissue slices, effect of metabolic inhibitors. Prostaglandins 14: , ZIPSER R, SPECKARET P. HAt-IN J, BOSWELL W, HORTON R: Release of immunoassayable POE by the human ischaemic kidney. J C/in Endocrinol Metab 47: , SAMUELSSON B: Leukotrienes, mediators of immediate hypersensitivity reactions and inflammation. Science 220: , HAMBERG M: On the formation of thromboxane B2 and 12 L-hydrox-5,8,lO,l4 eicosatetraenoic acid in tissues from the guinea pig. Biochem Biophys Acta 431: , WIN0KuR TS, MORRISON AR: Regional synthesis of monohydroxy eicosanoids by the kidney. J Biol Chem 256: , JIM K, HASSID A, SUN F, DUNN MJ: Lipoxygenase activity in rat kidney glomeruli and glomerular epithelial cells. J Bio/ Chem 257: , SRAER J, RIGAUD M, BENS M, RABINOVITCH H, ARDAILLOU R: Metabolism of arachidonic acid via the lipoxygenase pathway in human and murine glomeruli. J Bio/ Chem 258:4325, LIAN0S EA, DUNN Mi: Glomerular arachidonate lipoxygenation in nephrotoxic serum nephritis (abstract). Kidney mt 23:186A, SRAER J, BAUD L, BENS M, PODJARNY E, SCHLONDORFF D, ARDAILLOU R, SRAER JD: Glomeruli cooperate with macrophages in converting arachidonic acid to prostaglandins and hydroxyeicosatetraenoic acids. Prostagi, Leukotr Med 13:67 74, BAUD L, HAGEGE J, SRAFR J, RONDEAU E, PEREZ J, ARDAILLOU R: Reactive oxygen production by cultured rat glomerular mesangial cells during phagocytosis is associated with stimulation of lipoxygenase. J Exp Med 158: , BADR KF, BAYLIS C, PFEFFER JM, PFEFFER MA, SOBERMAN Ri, LEWIS RA, AUSTEN KF, COREY EJ, BRENNER BM: Renal and systemic hemodynamic responses to intravenous infusion of leukotriene C4 in the rat. Circ Res 54: , HAMMARSTROM S: Metabolism of leukotriene C3 in the guinea pig. J Biol Chem 256: , BERNSTROM K, HAMMARSTROM S: Metabolism of leukotriene D by porcine kidney. J Biol Chein 256: , APPELGREN LE, HAMMARSTROM 5: Distribution and metabolism of 3H-labeled leukotriene C3 in the mouse. J Biol Chem 257: , ELLIN A, JAKOBSSON SV, SCHENKMAN JB, ORRENIUS S: Cytochrome P450K of rat kidney microsomes, its involvement in fatty acid W- and (W-l)-hydroxylation. Arch Biochem Biophys 150:64 71, ICHIHARA K, KUSUNOSE E, KUSUNOSE M: A fatty acid W- hydroxylation system solubilized from porcine kidney cortex microsomes. Biochem Biophys Acta 239: , ZENSER TV, MATTAMMAL MB, DAVIS BB: Differential distribution of the mixed-function oxidase activities in rabbit kidneys. J Pharmacol Exp Ther 207: , NAVARO J, PIccoLo DE, KUPFER D: Hydroxylation of prostaglandin E1 by kidney cortex microsomol monooxygenase in the guinea pig. Arch Biochim Biophys 191: , MORRIsON AR, PASCOE N: Metabolism of arachidonic acid through NADPH-dependent oxygenase of renal cortex. Proc Nail Acad Sci USA 78: , MANN S. FALCK JR. CHACOS N, CAPDEVLLA J: Synthesis of arachidonic acid metabolites produced by purified kidney cortex microsomal cytochrome P-450. Tetra Let 24:33 36, OLIw EH, OATES JA: Rabbit renal cortical microsomes metabolize arachidonic acid to trihydroxyeicosatrienoic acids. Prostaglandins 22: , FERRERI NR, SCHWARTZMAN M, EBRAHAN NG, CHENDER DN, MCGIFF JC: Arachidonic acid metabolism in a cell suspension isolated from rabbit renal outer medulla. J Pharm Exp Therap 231: , SCHWARTZMAN M, FERRaRI NR, CARROL MA, SONGU MIZE E, MCGIFF JC: Vasopressin stimulates cytochrome P450-related arachidonic acid metabolism in renal medullary cells. Nature 314: , SCHLONDORFF D, ZANGER R, SATRIANO JA, FOLKERT VW, EVELOFF J: Prostaglandin synthesis by isolated cells from the outer medulla and from the thick ascending loopof Henle of rabbit kidney. J Pharmacol Exp Ther 233: , JAcoBsoN HR. CORONA S. CAPDEVILLA J, CHACOS N, MANNA S. WOMACK A, FALCK JR: 5, 6 epoxyicosatrienoic acid inhibits sodium absorption and potassium secretion in rabbit cortical collecting tubule (abstract). Kidney ml 25:330, SCHLONDORFI' D, PETTY E, OATES J, LEVINE SD: Effects of 5,6-epoxyeicosatrienoic acid on osmotic water flow in toad urinary bladder (abstract). C/in Res 33:588A, MCGIFF JC, TERRANONO NA, MALIK KU, L0NIGR0 AJ: Release of a prostaglandin E-like substance from canine kidney by bradykinin. Circ Res 31:36 42, NEEDLEMAN P, BRONSON SD, WYCHE A, SIVAKOFF M, NICOLAOU KC: Cardiac and renal prostaglandin 12, biosynthesis and biological effects in isolated perfused rabbit tissues. J C/in Invest 61: , BENABE JE, KLAHR 5, HOFFMAN MK, MORRISON AR: Production of thromboxane A2 by the kidney in glycerol-induced acute renal failure in the rabbit. Prostag/andins 19: , MYERS SI, ZIPSER R, NEEDLEMAN P: Peptide-induced prostaglandin biosynthesis in the renal-vein-constricted kidney. Biochim J 198: , Au JW, VANE JR: Intrarenal prostaglandin release attenuates the renal vasoconstrictor activity of angiotensin. J Pharmacol Exp Ther 184: , FROHLICHJC, WILSON TW, SWEETMAN BJ, SMIGEL M, NIES AS, CARR KJ, WATSON JT, OATES JA: Urinary prostaglandins: identification and origin. J Cl/n In vest 55: , NEEDLEMAN P. KAUFFMAN AH, DOUGLAS JR J, JOHNSON EM JR. MARSHALL OR: Specific stimulation and inhibition of renal prostaglandin release by angiotensin analogs. Am J Physio/ 224: , DUNN Mi, LIARD JF, DRAY F: Basal and stimulated rates of renal secretion and excretion of prostaglandins E2, F2, and 13, 14 dihydro-15-keto F2 in the dog. 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