Main Article Content
Aim: There are conflicting reports on the effect of peptides of the Renin Angiotensin System (RAS) on the pathogenesis of malaria infection. Captopril is a common antihypertensive drug that inhibits angiotensin-converting enzyme (ACE), a critical peptide of RAS, and its effect on the pathological process of malaria is just beginning to unfold. This study was carried out to investigate the effect of captopril on parasitemia, ACE, angiotensin II, and angiotensin II type 1 receptor (AT1R) levels in Plasmodium berghei-infected mice.
Methodology: Twenty-five mice divided into: Group 1 (control), Group 2 (Malaria control), Groups 3, 4 and 5 (Treated with 0.03 mg/kg lonart, 0.03 and 0.09 mg/kg captopril, respectively) were treated for 14 days. On the 15th day, they were sacrificed to obtain the blood and kidneys. The concentration of ACE and Ang II in serum and kidneys; and expression of ACE and AT1R in kidneys were assayed using standard protocols.
Results: There was a significant decrease (P<0.05) in parasitemia in all treated mice compared to malaria control mice, and by the 14th day, the parasitemia level in mice given 0.09 mg/kg captopril and 0.03 mg/kg lonart was not different (P>0.05) from control. The ACE and angiotensin II levels in serum and kidneys of malaria-infected mice increased significantly (P<0.05), but decreased (P<0.05) when given 0.03 mg/kg lonart, and both doses of captopril. With respect to gene expression, the ACE and AT1R mRNA were upregulated (P<0.05) in the kidneys of diseased mice, but treatment with captopril resulted in a dose-dependent decrease (P<0.05).
Conclusion: Captopril inhibits Plasmodium parasite; and this may be due to its ability to down-regulate ACE and AT1R expression.
(Accessed April 2018).
World Health Organization. World Malaria Report; 2018.
(Accessed December, 2018).
Skeggs T, Kahn JR, Shumway NP. The preparation and function of the angiotensin- converting enzyme. J Exp Med. 1956;10(3):295-299.
Boulpaep EL, Boron WF. Integration of Salt and Water Balance. Medical Physiology: A Cellular and Molecular Approach. Philadelphia; 2005.
Zhang C, Wu S, D.Xu. Catalytic mechanism of angiotensin-converting enzyme and effects of the chloride ion. J Physiol Chem. 2013;117(22):6635-6645.
Klabunde E. ACE - inhibitors. Cardiovascular pharmacology concepts; 2009.
(Accessed February, 2018).
Silva-Filho JL, Souza MC, Ferreira-DaSilva CT, Silva LS, Costa MFS, Padua TA. Angiotensin II is a new component involved in splenic T lymphocyte responses during Plasmodium berghei ANKA infection. PLoS ONE. 2013;8: e62999.
Iwai N, Inagami T, Ohmichi N, Kinoshita M. Renin is expressed in rat macrophage/ monocyte cells. Hypertension. 1996;27: 399-403.
Bush E, Maeda N, Kuziel WA, Dawson TC, Wilcox JN, De Leon H. Chemokine receptor 2 is required for macrophage infiltration and vascular hypertrophy in angiotensin II-induced hypertension. Hypertension. 2000;36:360-363.
Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, Goronzy J, Weyand C, Harrison DG. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med. 2007;204:2449–2460.
11. Hoch NE, Guzik TJ, Chen W, Deans T, Maalouf SA, Gratze P, Weyand C, Harrison DG. Regulation of T-cell function by endogenously produced angiotensin II. Am. J. Physiol Regul Integr Comp Physiol. 2009;296:208-216.
Silva-Filho JL, Souza MC, Henriques M, Morrot A, Savino W, Nunes MP, Caruso-Nerves C, Pinheiro AA. AT1 receptor-mediated angiotensin II activation and chemotaxis of T lymphocytes. Mol Immunol. 2011;48:1835-1843.
Silva-Filho JL, Souza MC, Henriques MG, Morrot A, Savino W, Caruso-Neves C, Pinheiro AA. Renin-angiotensin system contributes to naive T-cell migration in vivo. Arch Biochem Biophys. 2015;573:1-13.
Maciel C, de Oliveira Junior VX, Fazio MA, Nacif-Pimenta R, Miranda A, Pimenta PF. Anti-plasmodium activity of angiotensin II and related synthetic peptides. PLoS ONE. 2008;3:3296.
Saraiva VB, de Souza Silva L, Ferreira-DaSilva CT, da Silva-Filho JL, Teixeira-Ferreira A, Perale J. Impairment of the Plasmodium falciparum erythrocytic cycle induced by angiotensin peptides. Infect Immun. 2011;10:14-20.
Gallego-Delgado J, Baravian C, Edagha I, Ty MC, Ruiz-Ortega M, Xu W. Angiotensin II moderately decreases Plasmodium infection and experimental cerebral malaria in mice. PLoS ONE. 2015;10: e0138191.
Chamlian M, Bastos EL, Maciel C, Capurro ML, Miranda A, Silva AF. A study of the anti-plasmodium activity of angiotensin II analogs. J. Pep. Sci. 2013;19:575-580.
Silva A, Bastos EL, Torres MD, Costa-da-Silva AL, Ioshino RS, Capurro ML, Alves FL, Miranda A, deFreitas, Fischer Vieira R, Oliveira VX. Antiplasmodial activity study of angiotensin II via Ala scan analogs. J.Pep. Sci. 2014,20:640-648.
Silva AF, de Souza, SL, Alves FL, Der Torossian TM, de SáPinheiro AA, Miranda A. Effects of the angiotensin II Ala-scan analogs in erythrocytic cycle of Plasmodium falciparum (in vitro) and Plasmodium gallinaceum (ex vivo). Exp Parasitol. 2015;153:1-7.
Silva LS, Peruchetti DB, Silva CTF, Ferreira-Da Silva AT, Perales J, Caruso-Nerves C, Pinheiro AAS. Interaction between bradykinin B2 and Ang-(1–7) Mas receptors regulates erythrocyte invasion by Plasmodium falciparum. Biochim Biophys Acta. 2016a;2438-2444.
Silva LS, Silva-Filho JL, Caruso-Neves C, Pinheiro AAS. New concepts in malaria pathogenesis: The role of the Renin-Angiotensin system. Front Cell Infect Microbiol. 2016b;5:103.
Silva-Filho JL, Caruso-Neves C, Pinheiro AAS. Angiotensin II type-1 receptor (AT1R) regulates expansion, differentiation, and functional capacity of antigen-specific CD8+ T cells. Sci Rep. 2016;6:35997.
Gallego-Delgado J, Rodriguez A. Malaria and hypertension. Another co-evolutionary adaptation? Front Cell Infect Microbiol. 2014;4:121.
Gallego-Delgado J, Basu-Roy U, Ty M, Alique M, Fernandez-Arias C, Alexandru M, et al. Angiotensin receptors and ß-catenin regulate brain endothelial integrity in malaria. J Clin Investig. 2016;126:4016-4029.
Silva-Filho JL, Caruso-Neves C, Pinheiro AAS. Targeting angiotensin II Type-1 receptor (AT1R) inhibits the harmful phenotype of Plasmodium-Specific CD8+ T Cells during Blood-Stage Malaria. Front Cell Infect Microbiol. 2017;7:42.
Grau GE, Piguet PF, Engers HD, Louis JA, Vassalli P, Lambert PH. L3T4+ T lymphocytes play a major role in the pathogenesis of murine cerebral malaria. J Immunol. 1986;137:2348-2354.
Cheesbrough M, District Laboratory Practice in Tropical Countries, Part 1, Cambridge University Press: Cambridge, United Kingdom; 2005.
Cushman DW, Cheung HS. Spectro-photometric assay and properties of angiotensin converting enzyme from rabbit lungs. Biochem Pharmacol. 1971;20:1637.
Kobayashi T, Matsumota T, Kamata K. Mecahanisms underlying the chronic pravastatin treatment-induced improve-ment in the unpaired endothelium-dependent aortic relaxation seen in streptozotocin-induced diabetic rats. Br J.Pharmacol. 2000;131:231.
World Health Organization. Word malaria report, Geneva, Switzerland; 2005.
(Accessed April 2018).
Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature. 2002; 419:498–511.
Holt RA, Subramanian GM, Halpem A, Sutton GG, Charlab R. The genome sequence of the malaria mosquito Anopheles gambiae. Science. 2002;298: 129-149.
Schneider DS, James AA. Bridging the gaps in vector biology. Workshop on the molecular and population biology of mosquitoes and other disease vectors. EMBO Rep. 2006;7:259-262.
Leung PS. Role of the renin-angiotensin system and its blockade in pancreatic inflammation. Int J Biochem Cell Biol. 2004;37:237-238.
Dhangadamajhi G, Mohapatra BN, Kar SK, Ranjit M. Gene polymorphisms in angiotensin I converting enzyme (ACE I/D) and angiotensin II converting enzyme (ACE2 C–>T) protect against cerebral malaria in Indian adults. Infect Genet Evol. 2010;10:337-341.
Abdulazeez, AM, Ya'u M, Kurfi B. Association of hypertension and activity of angiotensin converting enzyme in malaria patients attending Sheik Muhammad Jidda General Hospital, Kano State, Nigeria. Niger J Basic Clin Sci. 2017;14: 121-126.
Torres MD, Silva AF, de Souza SL, de SáPinheiro AA, Oliveira VX. Angiotensin II restricted analogs with biological activity in the erythrocytic cycle of Plasmodium falciparum. J Pep Sci. 2015;21:24-28.