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Metabolism of Prostaglandins in the Kidney

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Metabolism of Prostaglandins in the Kidney View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 19 (1981), pp. 760—770 Metabolism of prostaglandins in the kidney FRANK F. SUN, BRUCE M. TAYLOR, JAMES C. MCGUIRE, and PATRICK Y. K. WONG Department of Experimental Biology, The Upjohn Company, Kalamazoo, Michigan, and Department of Pharmacology, New York Medical College, Valhalla, New York Since the early report of Lee et a! [1] describing a recommend that the reader consult the reviews vasoactive acidic lipid in the rabbit renal medulla, published elsewhere [4—6]. the kidney has been recognized as a major site of prostaglandin metabolism in the body. In fact, the Prostaglandin biosynthesis kidney medulla is one of the richest sources of The renal prostaglandin biosynthesis has been cyclooxygenase activity and, therefore, has been extensively investigated for over a decade [7—9], but widely used for prostaglandin biosynthetic studies. there are still many gray areas of ambiguity. In Many direct and indirect findings have established vitro, the renal papilla and medulla from rat, rabbit, that PG!2 and PGE2 play important roles in the and human [7-46] contain more cyclooxygenase regulation of renal blood flow and maintenance of (prostaglandin endoperoxide synthetase) than the electrolyte balance. Other oxygenated metabolites cortex does. The medullary cyclooxygenase is of arachidonic acid (that is, PGF2a, PGD2, TXB2, membrane bound and can be solubilized and isolat- hydroxyeicosatetraenoic acids, and leucotrienes ed by column chromatography [14]. The solubilized [2]) are reportedly synthesized by the kidney, al- enzyme has a heme-dependent cyclooxygenase ac- though their function remains as yet undefined. tivity that converts arachidonic acid to the hydro- Tissues do not store prostaglandins but generate peroxide PGG2 and a peroxidase activity that con- them from endogenous substrate fatty acids on verts PGG2 to PGH2. The overall process is stimu- demand. Several peptide hormones including bra- lated by phenolic compounds, but is inhibited by dykinin and angiotensin II are able to activate renal nonsteroidal antiinflammatory agents. In vivo, the phospholipase and release arachidonic acid for activity is probably limited by substrate availability prostaglandin synthesis. The action of prostaglan- [17—2 1]. Experiments with cx vivo isolated perfused dins is usually limited to their site of biosynthesis rabbit kidneys [19—21] have shown that bradykinin because powerful prostaglandin dehydrogenases and angiotensin II, which stimulated phospholipase are present, particularly in the lung, that inactivate activity, lead to increased PGE2 release. Similar the PG's before their removal from circulation. experiments with rat papilla slices [17] or isolated The kidney is also an important organ for prosta- renomedullary interstitial cells [18] in vitro or dog glandin excretion. It accumulates exogenous pros- kidney in vivo [221 have yielded similar findings. taglandins above the plasma level [3] and is respon- Anatomically, the cyclooxygenase-containing sible for removing 50 to 80% of the body's prosta- cells in the kidney of several species have been glandins by the urinary route, although very little is located by an immunofluorescence procedure [23— yet known about specific mechanisms. This article 25].In all species, the enzyme was found in the will present a brief review of the recent information epithelial cell of the cortical and medullary collect- on the biosynthesis and metabolism of renal prosta- ing ducts, arterial vascular endothelial cells, and glandins. For a more extensive discussion, we medullary interstitial cells. Other sites containing cyclooxygenase include the parietal layer of Bow- man's capsule in rabbit, mesangial cells in ovine and bovine glomeruli, and the thin limbs of Henle's Received for publication December 11, 1980 ioop in the hydronephrotic rabbit kidney. Some of 0085-2538/81/0019-0760 $02.20 these cells or structures have been isolated and ©1981 by the International Society of Nephrology their PG synthetases studied by biochemical meth- 760 Renal metabolism of prostaglandins 761 ods. In this respect, interstitial cells from rat and strate affinity [39] and cofactor requirements [40]. rabbit [18, 26, 27] have been reported to produce Therefore, any difference in substrate concentra- PGE2 and PGF2,. Terragno, McGiff, and Terragno tion, incubation time, or the presence of cofactors [281 demonstrated that the arteries and arterioles used in each study may lead to differences in isolated from pig kidney cortex by microdissection prostaglandin product distribution. Furthermore, have a high capacity for PG!2 biosynthesis. Bohman prostaglandin endoperoxides are extremely unsta- [29] and Grenier and Smith [30] have reported that ble. If the cyclooxygenase in an enriched tissue the collecting duct epithelial cells isolated from such as kidney medulla is allowed to operate at rabbit renal papilla synthesized 6-keto-PGF1, optimal condition, the endoperoxide generated may PGF2a, PGE2, and PGD2. Other groups [3 1—33] be more than its isomerases can consume. The have shown that the isolated glomeruli from rat excess will randomly decompose to PGF2a, PGE2, kidney cortex have the capacity for synthesis of and PGD2. Our in vitro study described below best PGF2a, PGE2, 6-keto-PGF1a, thromboxane B2, and illustrates this situation. PGD2. The mesangial cells [34] and the epithelial When a piece of rabbit inner medulla was homog- cells [351 are the site of prostaglandin E2 biosynthe- enized with '4C-arachidonate and incubated for 5 sis, and the arterioles probably produce PGI2, mm, the formation of radioactive prostaglandin whereas the cortical tubule fragments [311 contain products varied with the substrate concentration much lower activity than do the glomeruli. (Fig. 1). If the exogenous arachidonic acid was The literature shows qualitative and quantitative sufficiently low (2 pM) the product was almost inconsistencies in prostaglandins produced in dif- exclusively PGE2. If larger amounts (0.1 #.LM) of ferent regions of the kidney. Whorton et al [15] substrate were added or the cyclooxygenase was demonstrated clear evidence that rabbit kidney stimulated by phenolic compounds, the products cortex microsomes synthesized both PGI2 and were PGE2, PGF2a, and PGD2. Addition of reduced PGE2 from arachidonic acid and PG endoperoxide, glutathione increased PGE2 at the expense of PGF2a whereas the medullary microsomes synthesized ex- and PGD2. These results suggest that the enzymatic clusively PGE2. Similar experiments with rat inner product in the medulla is PGE2, and the rate- medullary slices [36] or rabbit medulla microsomes limiting step is the PGE2 isomerase. When the [14] agreed with these results. New evidences, cyclooxygenase is artificially stimulated, any ex- however, extended these observations and showed cess endoperoxide decomposes into a variety of that the medulla also had the capacity of synthesiz- mixed prostaglandin products. But if the isomerase ing PG!2. Silberbauer and Sinzinger [37] found that is stabilized with reduced glutathione, the enzyme both cortex and medulla of rat generated prostacy- can handle additional amounts of endoperoxide. din-like activity blocking platelet aggregation and Throughout this study, the formation of 6-keto- that the medulla was significantly more active than PGF1, was not detected. the cortex. With a gas chromatography mass spec- A small amount of 1 l-hydroxyeicosatetraenoic trometry method, Oliw et al [38] found high levels acid (1 1-HETE) was detected in the extract and its of 6-keto-PGF1a accumulated in cortex, medulla, identity was confirmed by GCMS analysis. This and papilla of postmortem rabbit kidney. Although confirmed a similar finding of Hamberg [7]. The 11- the papilla 6-keto-PGF1a level was the highest, the HETE was not a product of lipoxygenase because cortex contained five times more 6-keto-PGF1a than its formation can be inhibited by indomethacin. It is did PGE2 and PGF2a. Very recently, Hassid and probably a side product of the cyclooxygenase as Dunn [16] reported that microsomes prepared from suggested by Porter et al [411. both cortex and medulla of human kidney convert- Similar experiments with cortex slices yielded ed arachidonic acid to PGF2a, 6-keto-PGF1a, TXB2, smaller amounts of prostaglandins. With either low and PGE2 and that the relative abundances were or high substrate concentration, the cortex pro- similar in both regions. They concluded that there duced four times less prostaglandins than did the was no compartmentalization of PG!2 synthetase in medulla. PGE2 and PGF2a were the main products, the cortex. and very little 6-keto-PGF1a was detected. We feel these inconsistencies arose from differ- Although these results agreed with earlier report- ences in the in vitro experimental conditions. The ed work, we suspected that the PG!2 synthetase in medulla cortex and papilla probably contain isomer- our preparation was being inactivated by the organ- ases for the production of PGE2 and PG!2. The two ic peroxides generated during vigorous tissue ho- enzymes, however, have wider differences in sub- mogenation in air. Therefore, we prepared washed 762 Sunet a! Medulla Medulla 2 nmole AA 1000 nmole AA F 6KF 6KF Cortex b Medulla d 2 nmole AA 1000 nmole AA + glutathione E 6KF 6KF Fig. 1. Radiochromatogram of the extract from the conversion of'C-arachidonic acid to prostaglandins by rabbit kidney homogenate: a medulla 1.0 g of tissue and 2 LMAA,b cortex 1.0 g of tissue and 2 I.LM AA, cmedulla0.1 g of tissue and 100 IJ.M AA, and d medulla 0.1 g of tissue, 100 ILM AA, and I m reduced glutathione. microsomes from both rabbit cortex and medulla suggesting that the Km values for the two enzymes under an argon atmosphere. Indomethacin was also are different. At all substrate concentrations, the added to stop PG biosynthesis. These microsomes yield of 6-keto-PGF1a from medullary microsome were incubated with various concentrations of '4C- was three to four times greater than the cortex PGH2, and the products were analyzed by thin- microsome was.
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