From Escherichia coli heat-stable enterotoxin to mammalian endogenous guanylin hormones

The isolation of heat-stable enterotoxin (STa) from Escherichia coli and cholera toxin from Vibrio cholerae has increased our knowledge of specific mechanisms of action that could be used as pharmacological tools to understand the guanylyl cyclase-C and the adenylyl cyclase enzymatic systems. These discoveries have also been instrumental in increasing our understanding of the basic mechanisms that control the electrolyte and water balance in the gut, kidney, and urinary tracts under normal conditions and in disease. Herein, we review the evolution of genes of the guanylin family and STa genes from bacteria to fish and mammals. We also describe new developments and perspectives regarding these novel bacterial compounds and peptide hormones that act in electrolyte and water balance. The available data point toward new therapeutic perspectives for pathological features such as functional gastrointestinal disorders associated with constipation, colorectal cancer, cystic fibrosis, asthma, hypertension, gastrointestinal barrier function damage associated with enteropathy, enteric infection, malnutrition, satiety, food preferences, obesity, metabolic syndrome, and effects on behavior and brain disorders such as attention deficit, hyperactivity disorder, and schizophrenia

Metabolism of diglycine and triglycine by non-filtering kidneys

We have studied the metabolism of diglycine and triglycine in the isolated non-filtering rat kidney. Kidneys from adult male Wistar Kyoto rats weighing 250-350 g were perfused with Krebs-Henseleit solution containing either 1 mM diglycine or triglycine. The analysis of the peptide residues and their components was performed using an amino acid microanalyzer utilizing ion exchange chromatography. Diglycine was degraded to a final concentration of 0.09 mM after 120 min (91%); this degradation occurred predominantly during the first hour, with a 56% reduction of the initial concentration. The metabolism of triglycine occurred similarly, with a final concentration of 0.18 mM (82%); during the first hour there was a 67% reduction of the initial concentration of the tripeptide. Both peptides produced glycine in increasing concentrations, but there was a slightly lower recovery of glycine, suggesting its utilization by the kidney as fuel. The hydrolysis of triglycine also produced diglycine, which was also hydrolyzed to glycine. The results of the present study show the existence of functional endothelial or contraluminal membrane peptidases which may be important during parenteral nutrition

Actions of Crotalus durissus terrificus venom and crotoxin on the isolated rat kidney

Many studies have reported the occurrence of lethal acute renal failure after snakebites. The aim of the present investigation was to determine alterations in renal function produced by Crotalus durissus terrificus venom and crotoxin as well as the histological alterations induced by these venoms. Isolated kidneys from Wistar rats weighing 240 to 280 g were perfused with Krebs-Henseleit solution containing 6 g% of previously dialyzed bovine serum albumin. The effects of Crotalus durissus terrificus venom and crotoxin were studied on glomerular filtration rate (GFR), urinary flow (UF), perfusion pressure (PP) and percentage sodium tubular transport (%TNa+). The infusion of Crotalus durissus terrificus venom (10 µg/ml) and crotoxin (10 µg/ml) increased GFR (control80 = 0.78 ± 0.07, venom80 = 1.1 ± 0.07, crotoxin80 = 2.0 ± 0.05 ml g-1 min-1, P<0.05) and UF (control80 = 0.20 ± 0.02, venom80 = 0.32 ± 0.03, crotoxin80 = 0.70 ± 0.05 ml g-1 min-1, P<0.05), and decreased %TNa+ (control100 = 75.0 ± 2.3, venom100 = 62.9 ± 1.0, crotoxin80 = 69.0 ± 1.0 ml g-1 min-1, P<0.05). The infusion of crude venom tended to reduce PP, although the effect was not significant, whereas with crotoxin PP remained stable during the 100 min of perfusion. The kidneys perfused with crude venom and crotoxin showed abundant protein material in the urinary space and tubules. We conclude that Crotalus durissus terrificus venom and crotoxin, its major component, cause acute nephrotoxicity in the isolated rat kidney. The current experiments demonstrate a direct effect of venom and crotoxin on the perfused isolated kidney

Renal Effects Of Supernatant From Macrophages Activated By Crotalus Durissus Cascavella Venom: The Role Of Phospholipase A2 And Cyclooxygenase

In Brazil, the genus Crotalus is responsible for approximately 1500 cases of snakebite annually. The most common complication in the lethal cases is acute renal failure, although the mechanisms of the damaging effects are not totally understood. In this work, we have examined the renal effects caused by a supernatant of macrophages stimulated by Crotalus durissus cascavella venom as well as the potential role of phospholipase A2 and cyclo-oxygenase. Rat peritoneal macrophages were collected and placed in a RPMI medium and stimulated by crude Crotalus durissus cascavella venom (1, 3 or 10 μg/ml) for 1 hr. They were then washed and kept in a culture for 2 hr. The supernatant (1 ml) was tested in an isolated perfused rat kidney. The first 30 min. of each experiment were used as an internal control, and the supernatant was added to the system after this period. All experiments lasted 120 min. A study of toxic effect on perfusion pressure, glomerular filtration rate, urinary flow, percent of sodium tubular transport and percent of proximal tubular sodium transport was made. The lowest concentration of venom (1 μg/ml) was not statistically different from the control values. The most intense effects were seen at 10 μg/ml for all renal parameters. The infusion of the supernatant of macrophages stimulated with crude venom (3 or 10 μg/ml) increased the perfusion pressure, glomerular filtration rate and urinary flow, decreased the percent of sodium tubular transport and percent of proximal tubular sodium transport. Dexamethasone (10 μM) and quinacrine (10 μM) provided protection against the effect of the venom on glomerular filtration rate, urinary flow, percent of sodium tubular transport, percent of proximal tubular sodium transport and perfusion pressure. Indomethacin (10 μM) and nordiidroguaretic acid (1 μM) reversed almost all functional changes, except those of the perfusion pressure. These results suggest that macrophages stimulated with Crotalus durissus cascavella venom release mediators capable of promoting nephrotoxicity in vitro. Moreover, phospholipase A2 and cyclooxygenase products are involved in these biologic effects.9211420Azar, S., Tobian, T., Ishii, M., Prolonged water diuresis affecting solutes and intersticial cells of renal papilla (1971) Amer. J. Physiol., 221, pp. 75-79Balhlmann, J., Giebisch, G., Ochwadt, B., Micropuncture study of isolated perfused rat kidney (1967) Amer. J. Physiol., 212, pp. 77-82Barnes, P.J., Adcock, I., Anti-inflammatory actions of steroids: Molecular mechanisms (1993) Trends Pharmacol. Sci., 14, pp. 436-441Barraviera, B., Curso sobre acidentes pot animais peçonhentos: Acidentes por serpente do gênero crotalus (1989) Arq. Bras. Med., 64, pp. 14-20Bowman, R.H., Gluconeogenesis in the isolated perfused rat kidney (1970) J. Biol. Chem., 245, pp. 1604-1612Ferreira, S.H., Are macrophages the body's alarme cells? (1980) Agents Actions, 10, pp. 229-230Ferreira, M.L., Moura-da-Silva, A.M., França, F.O.S., Cardoso, J.L., Mota, I., Toxic activities of venoms from nine Bothrops species and their correlation with lethality and necrosis (1992) Toxicon, 30, pp. 1603-1608Fonteles, M.C., Forti, C.A., The effect of indomethacin and reserpine on renal vascular escape (1993) Chem. Pathol. Pharmacol., 81, pp. 103-110Fonteles, M.C., Cohen, J.J., Black, A.J., Wertheim, S.J., Support of renal kidney function by long-chain fatty acids derived from renal tissue (1983) Amer. J. Physiol., 244, pp. 235-246Fonteles, M.C., Greenberg, R.N., Monteiro, H.S.A., Currie, M.G., Forte, L.R., Natriuretic and Kaliuretic activies of guanylin and uroguanylin in the isolated perfused rat kidney (1998) Amer. J. Physiol., 44, pp. 191-197Greg, G.M., Cohen, J.J., Black, A.Y., Espeland, M.A., Feldstain, M.C., Effects of glucose and insulin metabolism and function of perfused rat kidney (1978) Amer. J. Physiol., 235, pp. 52-61Gutiérrez, J.M., Lomonte, B., Local tissue damage induced by Bothrops snake venoms (1989) Mem. Inst. Butantan, 51, pp. 211-233Hamilton, R.L., Benny, N.M., Williams, M.C., Severin-Ghaus, E.M.A., Simple and inexpensive membrane "lung" for small or-gan perfusion (1974) J. Lipid. Res., 15, pp. 182-186Hanson, R.W., Ballard, F.S., Citrate, pyruvate and lactate contaminants of commercial serum albumin (1968) J. Lipid. Res., 9, pp. 667-668Korzeniewski, C., Callewaert, D.M., An enzyme-release assay for natural cytotoxicity (1983) J. Immunol. Meth., 64, pp. 313-320Laskin, D.L., Pendino, K.J., Macrophages and anti-inflammatory mediators in tissue injury (1995) Annu. Rev Pharmacol. Toxicol., 35, pp. 655-677Lima, A.A.M., Monteiro, H.S.A., Fonteles, M.C., The effects of Escherichia coli heat-stable enterotoxin in renal sodium tubular transport (1992) Pharmacology & Toxicology, 70, pp. 163-167Mancin, A.C., Soares, A.M., Andriao-Escarso, S.H., Faca, V.M., Greene, L.J., Zuccolotto, S., Pela, I.R., Giglio, J., The analgesic activity of crotamine, a neurotoxin from Crotalus durissus terrificus (South American rattlesnake) venom: A biochemical and pharmacological study (1998) Toxicon, 36, pp. 1927-1937Marshall, J.S., Leal Berumen, I., Nielsen, L., Glibetic, M., Jordana, M., Interleukin (IL)-10 inhibits long-term IL-6 production but not performed mediator release from rat peritoneal mast cell (1996) J. Clin. Invest., 97, pp. 1122-1128Martins, A.M.C., Monteiro, H.S.A., Júnior, E.O.G., Menezes, D.B., Fonteles, M.C., Effects of Crotalus durissus cascavella venom in the isolated rat kidney (1998) Toxicon, 36, pp. 1441-1450Monteiro, H.S.A., Da Silva, I.M.S.C., Martins, A.M.C., Fonteles, M.C., Effects of Crotalus durissus terrificus venom and crotoxin on the isolated rat kidney (2001) Braz. J. Med. Biol. Res., 34, pp. 1347-1352Nancy, G., Ahlstrom, M.D., Luginbuhl, M.D.W., Tisher, M.D.C., Acute anuric renal failure after pygmy rattlesnake bite (1991) South. Med. J., 84, pp. 783-785Nathan, C.F., Secretory products of macrophages (1987) J. Clin. Invest., 79, pp. 319-326Nishiitsutji-Uwo, G.M., Ross, B.D., Krebs, H.A., Metabolic activities of the isolated perfused rat kidney (1967) Biochem. J., 103, pp. 852-862Pegg, D.E., Vascular resistance of the isolated rabbit kidney (1971) Cryobiology, 8, pp. 431-440Ribeiro, L.A., Albuquerque, M.J., De Campos, V.A., Katz, G., Takaoka, N.Y., Lebrao, M.L., Jorge, M.T., Deaths caused by venomous snakes in the State of São Paulo: Evaluation of 43 cases from 1988 to 1993 (1998) Rev Assoc. Med. Bras., 44, pp. 312-318Ribeiro, R.A., Flores, C.A., Cunha, F.Q., Ferreira, S.H., IL-8 causes in vivo neutrophil migration by a cell dependent mechanism (1991) Imunology, 73, pp. 472-477Rocha, M.F.G., Soares, A.M., Flores, C.A., Steiner, T.S., Lyerly, D.M., Guerrant, R.L., Ribeiro, R.A., Lima, A.A.M., Intestinal secretory factor released by macrophages stimulated with Clostridium difficile toxin A: Role of interleukin 1β (1998) Infection and Immunity, 66, pp. 4910-4916Ross, B.D., The isolated perfused rat kidney (1978) Cryobiology, 8, pp. 431-440Santoro, M.C., Sousa-e-Silva, M.C., Gonçalves, R.L., Almeida-Santos, S.M., Cardoso, D.F., Laporta-Ferreira, I.L., Saiki, M., Sano-Martins, I.S., Comparision of the biological activities in venoms from three subspecies of the South American rattlesnake (Crotalus durissus terrificus, C. durissus cascavella and C. durissus collilineatus) (1999) Comp. Biochem. Physiol. C Pharmacol. Toxicol. Endocrinol., 122, pp. 61-73Schlondorff, D.P., Roczniak, S., Satriano, J.A., Folkert, V.W., Prostaglandin synthesis by isolated rat glomeruli: Effect of angiotensin II (1980) Amer. J. Physiol., 239, pp. 486-495Vital Brasil, O., Os venenos ofidios neurotóxicos (1980) Rev. Ass. Med. Braz., 26, pp. 212-218White, J., Bites and stings from venomous animals: A global owerview (2000) Ther. Drug Monit., 22, pp. 65-6

Thalidomide and pentoxifylline block the renal effects of supernatants of macrophages activated with Crotalus durissus cascavella venom

Because thalidomide and pentoxifylline inhibit the synthesis and release of tumor necrosis factor-alpha (TNF-alpha), we determined the effect of these drugs on the renal damage induced by supernatants of macrophages activated with Crotalus durissus cascavella venom in order to identify the role of TNF-alpha in the process. Rat peritoneal macrophages were collected with RPMI medium and stimulated in vitro with C.d. cascavella venom (10 µg/ml) in the absence and presence of thalidomide (15 µM) or pentoxifylline (500 µM) for 1 h and washed and kept in culture for 2 h. Supernatant (1 ml) was tested on an isolated perfused rat kidney (N = 6 for each group). The first 30 min of each experiment were used as control. The supernatant was added to the perfusion system. All experiments lasted 120 min. The toxic effect of the preparation of venom-stimulated macrophages on renal parameters was determined. At 120 min, thalidomide (Thalid) and pentoxifylline (Ptx) inhibited (P < 0.05) the increase in perfusion pressure caused by the venom (control = 114.0 ± 1.3; venom = 137.1 ± 1.5; Thalid = 121.0 ± 2.5; Ptx = 121.4 ± 4.0 mmHg), renal vascular resistance (control = 4.5 ± 0.2; venom = 7.3 ± 0.6; Thalid = 4.5 ± 0.9; Ptx = 4.8 ± 0.6 mmHg/ml g-1 min-1), urinary flow (control = 0.23 ± 0.001; venom = 0.44 ± 0.01; Thalid = 0.22 ± 0.007; Ptx = 0.21 ± 0.009 ml g-1 min-1), glomerular filtration rate (control = 0.72 ± 0.06; venom = 1.91 ± 0.11; Thalid = 0.75 ± 0.04; Ptx = 0.77 ± 0.05 ml g-1 min-1) and the decrease in percent tubular sodium transport (control = 77.0 ± 0.9; venom = 73.9 ± 0.66; Thalid = 76.6 ± 1.1; Ptx = 81.8 ± 2.0%), percent tubular chloride transport (control = 77.1 ± 1.2; venom = 71.4 ± 1.1; Thalid = 77.6 ± 1.7; Ptx = 76.8 ± 1.2%), and percent tubular potassium transport (control = 72.7 ± 1.1; venom = 63.0 ± 1.1; Thalid = 72.6 ± 1.0; Ptx = 74.8 ± 1.0%), 30 min before and during the stimulation of macrophages with C.d. cascavella venom. These data suggest the participation of TNF-alpha in the renal effects induced by supernatant of macrophages activated with C.d. cascavella venom