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The role of phospholipase A2 and cyclooxygenase in renal toxicity A.C.L. Nobrea, G.R. Coeˆlhoa, M.C.M. Coutinhoa, M.M.M. Silvaa, E.V. Angelima, D.B. Menezesb, M.C. Fontelesc, H.S.A. Monteiroa,* aDepartment of Physiology and Pharmacology, Federal University of Ceara, Rua Cel. Nunes de Melo, 1127, 60430-270 Fortaleza, CE, Brazil bDepartment of Pathology and Forensic Medicine, Federal University of Ceara, Rua Monsenhor Furtado, S/N, cCeara State University, Av. Paranjana, 1700, Campus do Itaperi, 60740-000 Fortaleza, CE, Brazil Received 14 February 2000; accepted 12 June 2000 Abstract
We have shown previously that exposure to microcystin-LR (MCLR) causes renal toxic effects in isolated perfused rat kidney. That study was extended further to approach the perspective of pharmacological blockade of renal toxic effects byMCLR through the use of experimental therapeutic agents. An isolated kidney perfusion system was utilized and samples ofurine and perfusate were collected at 10 min intervals to determine the levels of inulin, sodium, potassium and osmolality.
Dexamethasone (20 mg mlϪ1) and indomethacin (10 mg mlϪ1) were administered in the beginning of the perfusion and MCLRwas employed in a dose of 1 mg mlϪ1 after an internal control of 30 min to evaluate the perfusion pressure (PP), renal vascularresistance (RVR), glomerular filtration rate (GFR) and urinary flow (UF). Dexamethasone and indomethacin antagonized thetoxic effects of MCLR on PP, RVR, GFR and UF. Histologic analysis of dexamethasone and indomethacin treated groups didnot show any vascular or interstitial alterations. MCLR potentially impairs the renal function, probably causing vascular andglomerular lesions and, promoting renal alterations through direct or indirect actions. These data seem to indicate that the renalalterations promoted by MCLR involves also phospholipase A2 and arachidonic acid-derived mediators. ᭧ 2000 ElsevierScience Ltd. All rights reserved.
Keywords: Microcistin-LR; Perfused kidney; Dexamethasone; Indomethacin There are few papers in the literature that show the effect the proximal tubular epithelium with slight tubular dilata- of microcystin-LR (MCLR) in the renal system. Radbergh et tion (Hooser et al., 1989) and cellular damage were also al. (1991) have shown degenerative changes in the tubular found in glomeruli and tubules (Radbergh et al., 1991).
epithelial cells, glomeruli and interstitial tissue in kidneys of The utilization of the perfusion system of isolated kidney carps exposed to MCLR, via intraperitoneal. In contrast to permits the study of the direct effect of toxin without what occurs in fish, which presents more severe changes, systemic interference. Our laboratory showed that MCLR renal damages are seldom observed in mice and this can be is capable of changing the kidney functional parameters explained by the survival time to lethal dose. Kotak et al.
(perfusion pressure (PP), renal vascular resistance (RVR), (1996) showed renal lesions in fishes (Oncorhynchus glomerular filtration rate (GFR) and urinary flow (UF)) in mykiss) that consisted of coagulative tubular necrosis and isolated perfused rat kidney (Nobre et al., 1999). The scope dilatation of Bowman’s space. Glomerular capillaries were of this work was to approach the perspective of pharmaco- filled with eosinophilic fibrillary material after nine hours of logical blockade through the use of experimental therapeutic exposure to MCLR. There has been a mild vacuolization of MCLR (Sigma Chemical Co., Saint Louis, MO, USA; Molecular mass 995.2) was used in the current experiments * Corresponding author. Fax: ϩ55-85-2815212.
E-mail address: (H.S.A. Monteiro).
obtained from Microcystis aeruginosa. Adult Wistar rats of 0041-0101/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S 0 0 4 1 - 0 1 0 1 ( 0 0 ) 0 0 1 9 3 - 8 A.C.L. Nobre et al. / Toxicon 39 (2001) 721–724 Table 1Effects of dexamethasone and indomethacin in the renal toxicity caused by MCLR in perfused rat kidney (Results are expressed as means ^SEM of Control kidneys (n ˆ 7) versus MCLR treated kidneys (n ˆ 7) and treated as: MCLR ˆ microcystin-LR (1 mg mlϪ1); Dexa ˆdexamethasona (20 mg mlϪ1); Indo ˆ indomethacin (10 mg mlϪ1). PP ˆ perfusion pressure; RVR ˆ renal vascular resistance; UF ˆ urinaryflow; GFR ˆ glomerular filtration rate. The first 30 min represent the internal control for each group) a Significance in relation to control (p Ͻ 0,05).
b Significance in relation to treated group with MCLR (p Ͻ 0,05), compared by ANOVA (Bonferroni test).
both sexes weighing 250–280 g were anesthetized with pentobarbital sodium (50 mg kgϪ1 body weight ip). Before (10 mg mlϪ1) studies were initiated before an internal the experiment, the animals were fasted for 24 h with access control of 30 min, and MCLR (1 mg mlϪ1) after an internal to water ad libitum. The right renal artery was cannulated as control, and observations were made during the next 90 min.
described by Bahlmann et al. (1967), Nishiitsutji-Uwo et al.
Naϩ and Kϩ were determined by flame photometry (Flame (1967) and Ross (1978). The perfusate was a modified Photometer IL, Model 445), and inulin was analyzed Krebs–Henseleit solution with the following composition according to Walson et al. (1955) as modified by Fonteles in mmol lϪ1: Naϩ 147, Kϩ 5, Caϩϩ 2.5, Mgϩϩ 2, ClϪ 110, et al. (1998). Osmolality of the samples was measured in an Advanced Instruments osmometer (Needham Heights, MA).
urea and 0.075 g inulin. Six grams of bovine serum albumin After the renal perfusion a histologic evaluation of kidneys (BSA fraction V, Sigma) were added to the solution after a was made by optical microscopy. Dexamethasone was previous dialysis for 48 h at 4ЊC in 1.5 l of Krebs. The pH acquired from Merck and CO., Inc (EUA) and indomethacin was then adjusted to 7.4. Total perfusate used per experi- The data were presented as mean ^ S.E.M. At least seven The perfused rat kidney model followed the method of different animals were used for each data point. Data were Bowman (1970) as modified by Fonteles et al. (1983, 1998).
analyzed by ANOVA (Bonferroni test). For statistical The system was calibrated for flow and resistance before purposes, p Ͻ 0:05 was considered significant.
each experiment. The rate of perfusion flow was maintained Previous results showed that infusion of 1 mg mlϪ1 of of 25–35 ml minϪ1 per kidney. The first 30 min of perfusion MCLR after 30 min of internal control caused alterations were considered to be an internal control. Each experiment of renal functional parameters (Nobre et al., 1999).
was divided into four periods of 30 min; these periods were Dexamethasone (20 mg mlϪ1) showed a capacity of further subdivided into equal intervals of 10 min. During reverting the renal changes promoted by MCLR when each 10 min period, samples of perfusate and urine were compared to the control group and internal control collected for determinations of sodium, potassium, inulin (Table 1). The drug was able to antagonize in a significant manner …p Ͻ 0:05† the effect on the PP, RVR, UF and GFR A.C.L. Nobre et al. / Toxicon 39 (2001) 721–724 at 60, 90 and 120 min. Indomethacin at the dose of 1998). In our experiments we have observed that MCLR 10 mg mlϪ1 was able to protect the kidneys from the toxic seems to induce the activation of phospholipase A2 and effects of MCLR as compared with the control group and the cyclooxygenase as its effects were blocked by dexamethasone internal control group (Table 1). A significant reversion of and indomethacin; this mechanism is similar to the hepatic the effects of MCLR on the PP, RVR, UF and GFR at 60, 90 effect. It is supposed that this renal change occurs probably by damaging both vascular and glomerular sites.
Nobre et al. (1999) showed an intense amount of protei- naceous material in the urinary spaces following perfusionwith MCLR. Proteinaceous material was not seen in the Acknowledgements
tubules or urinary space of kidneys pretreated with dexa-methasone and indomethacin, nor were there any abnorm- Acknowledgments are made to Maria Sı´lvia Helena alities in the renal vessels and interstitium, suggesting a Freire Franc¸a and Domingos Barreto Oliveira for technical protective effect of these substances.
assistance. This research was supported by CNPq and Naseem et al. (1990) evaluated the effects of glucocorti- coids in the release of arachidonic acid and its metabolitesinduced by MCLR in rat hepatocytes. They showed thatfluorcinolone, dexamethasone and hydrocortisone suppress References
the release of arachidonic acid, prostacyclin (6-ketoF1a) andTXB Bahlmann, J., Giebish, G., Ochwadt, B., Schoeppe, W., 1967.
2. It is known that microcystins are capable of inducing the cyclooxygenase via the metabolism of arachidonic acid Micropuncture study of isolated perfused rat kidney. Am. J.
Physiol. 212, 77–82.
thus being prone undergoing the action of glucocorticoids.
Bowman, R.H., 1970. Gluconeogenesis in the isolated perfused rat In our experiments, MCLR induces an increase in PP kidney. J. Biol. Chem. 245, 1604–1612.
which was inhibited by indomethacin. The results suggest Braquet, P., 1987. Perspectives in platelet activation factor research.
that this increase in pressure can be related to alterations in the homeostasis of cell calcium. If MCLR induces change in Fonteles, M.C., Cohen, J.J., Black, A.J., Wertheim, S.J., 1983.
the calcium metabolism of smooth muscle cell, this change Support of renal kidney function by long-chain fatty acids in calcium input can be contributing to an arteriolar vaso- derived from renal tissue. Am. J. Physiol 244, 235–246.
Fonteles, M.C., Greenberg, R.N., Monteiro, H.S.A., Currie, M.G., Calcium plays an important role in the activation of phos- Forte, L.R., 1998. Natriuretic and Kaliuretic activities of guany- lin and uroguanylin in the isolated perfused rat kidney. Am. J.
2. If MCLR influences the activity of calcium, it Physiol. 275, F191–F197 (Renal Physiol 44).
is possible that it also intensifies the activation of this Haystead, C.M., Gailly, P., Somlyo, A.V., Haystead, T.A., 1995.
enzyme. On the other hand MCLR is an inhibitor of protein Molecular cloning and functional expression of a recombinant phosphatases what favors hyperphosphorilation, that is an 72.5 kDa fragment of the 110 kDa regulatory subunit of smooth increased response to protein kinases. Protein kinase C muscle protein phosphatase 1M. FEBS Lett. 377 (2), 123–127.
which is responsible for the activation of phospholipase Hooser, S.B., Beasley, V.R., Lovell, R.A., Carmichael, W.W., A2 (Braquet, 1987) could be increased by the action of Haschek, W.M., 1989. Toxicity of microcystin-LR, a cyclic MCLR. The arachidonic acid inhibits L-type calcium heptapeptide hepatotoxin from Microcystis aeruginosa, to rats current, via a mechanism which involves, in part, stimula- and mice. Vet. Pathol. 26, 246–252.
tion of protein phosphatase activity. On the other hand, Kotak, B.G., Semalulu, S., Fritz, D.L., Prepas, E.E., Hrudey, S.E., dexamethasone and indomethacin inhibit arachidonic acid Coppock, R.W., 1996. Hepatic and renal pathology of intraper-itoneally administered microcystin-LR in Rainbow Trout metabolism, what favors an inhibition of activity in these (Oncorhynchus Mykiss). Toxicon 34, 517–525.
protein (Petit-Jacques and Hartzell, 1996). With the use of Kuroda, N., Hayashi, Y., Matozaki, T., Hanioka, K., Gotoh, A., indomethacin and dexamethasone we raise the possibility of Wang, W., Uchida, H., Hashimoto, K., Iwai, Y., Kawasaki, the participation of prostaglandin and of calcium, and phos- K., Imai, Y., Kasuga, M., Itoh, H., 1998. Differential expression pholipase A2, respectably, in the alterations triggered by of SHP2, a protein-tyrosine phosphatase with SRC homology-2 domains, in various types of renal tumour. Virchows Arch. 433 According to the literature MCLR affects two types of cells: hepatocytes and macrophages. In the hepatocytes the toxin Naseem, S.M., Hines, H.B., Creasia, D., 1990. A inhibition of acts as an inhibitor of protein phosphatases and an activator microcystin-induced release of cyclooxygenase products from rat hepatocytes by anti-inflammatory steroids. Proc. Soc. Exp.
the toxin induces TNFa and IL-1 (Rocha et al., 2000). Cyto- Nishiitsutji-Uwo, G.M., Ross, B.D., Krebs, H.A., 1967. Metabolic kines induce the production of PAF, and the activation of activities of the isolated perfused rat kidney. Biochem. J. 103, prostaglandin which seem to be involved in the shock caused by MCLR. Microcystin specifically and potently inhibits Nobre, A.C.L., Jorge, M.C.M., Menezes, D.B., Fonteles, M.C., protein phosphatase 1 and 2A. M110 and SHP2 that are Monteiro, H.S.A., 1999. Effects of microcystin-LR in isolated expressed in kidney. (Haystead et al., 1995; Kuroda et al., perfused rat kidney. Brazilian J. Med. Biol. Res. 32, 985–988.
A.C.L. Nobre et al. / Toxicon 39 (2001) 721–724 Petit-Jacques, J., Hartzell, H.C., 1996. Effect of arachidonic acid on Guerrant, R.L., Ribeiro, R.A., Lima, A.A.M., 2000. Superna- the L-type calcium current in frog cardiac myocytes. J. Physiol.
tants from macrophages stimulated with microcystin-LR induce electrogenic intestinal response in rabbit ileum. Pharmacology Radbergh, C.M.I., Bylund, G., Eriksson, J.E., 1991. Histological effects of microcystin-LR, a cyclic peptide toxin from the cyano- Ross, B.D., 1978. The isolated perfused rat kidney. Clinical Sci.
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Walson, M., Davidson, D.G., Orloff, J., 1955. The renal clearance of Rocha, M.F.G., Sidrim, J.J.C., Soares, A.M., Jimenez, G.C., alkali-stable inulin. J. Clin. Invest. 34, 1520–1523.


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