Renal Alterations Induced by the Venom of Colombian Scorpion Centruroides Margaritatus

Author(s): J.D. Galíndez-Cerón, R.J.B. Jorge*, M.H. Chavez-Acosta, A.R.C. Jorge, N.T.Q. Alves, M.M.G. Prata, F.A. de Paulo Rodrigues, A. Havt, T.L. Sampaio, A.M.C. Martins, J.A. Guerrero-Vargas, H.S.A. Monteiro, J.T. Beltrán-Vidal.

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 22 , 2019

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Abstract:

Background: Scorpion venom causes renal injury and affects vascular ion-channels function. Centruroides margaritatus scorpion is found in Colombia and is frequently the cause of envenomation accidents; however, its renal impact has never been investigated.

Objective: To evaluate the effects of C. margaritatus venom (CmV) on renal parameters using isolated rat kidney and renal cell culture models.

Methods: Wistar rats (n = 5, weighing 240-300 g) were first perfused with Krebs-Henseleit solution containing 6 g 100 mL-1 bovine serum albumin. After 30 minutes, the kidneys were perfused with CmV to a final concentration of 10 μgmL-1; evaluation was performed by measuring Perfusion Pressure (PP), Renal Vascular Resistance (RVR), Urinary Flow (UF), Glomerular Filtration Rate (GFR), and percentage of electrolyte tubular transport. Moreover, kidney histological analyses and cell cytotoxicity in renal tubule epithelial cells (MDCK) and proximal tubular cells (LLC-MK2) were assessed.

Results: CmV increased PP and RVR 60 min after perfusion. On the other hand, UF, GFR, and the percentages of sodium, potassium and chloride tubular transport decreased after experimental envenomation. UF dropped after 120 min, while GFR and percentage of electrolyte tubular transport diminished after 60, 90 and 120 min. CmV was not toxic to MDCK cell line but reduced the viability of LLC-MK2 cells at concentrations ranging from 6.25 to 200 μgmL-1. Histological analyses disclosed hydropic degeneration, edema, and protein deposits. Flow cytometry disclosed that cell death occurred predominantly by necrosis.

Conclusion: Our results suggest that C. margaritatus venom can trigger renal impairment, mainly in the proximal kidney tubule.

Keywords: Scorpion envenomation, Centruroides margaritatus, Kidney perfusion, Cytotoxicity, Necrosis, Acute kidney injury.

[1]
Isbister, G.K.; Bawaskar, H.S. Scorpion envenomation. N. Engl. J. Med., 2014, 371(5), 457-463.
[http://dx.doi.org/10.1056/NEJMra1401108] [PMID: 25075837]
[2]
Chippaux, J.P.; Goyffon, M. Epidemiology of scorpionism: A global appraisal. Acta Trop., 2008, 107(2), 71-79.
[http://dx.doi.org/10.1016/j.actatropica.2008.05.021] [PMID: 18579104]
[3]
Possani, L.D.; Merino, E.; Corona, M.; Bolivar, F.; Becerril, B. Peptides and genes coding for scorpion toxins that affect ion-channels. Biochimie, 2000, 82(9-10), 861-868.
[http://dx.doi.org/10.1016/S0300-9084(00)01167-6] [PMID: 11086216]
[4]
Petricevich, V.L. Scorpion venom and the inflammatory response. Mediators Inflamm., 2010, 2010903295
[http://dx.doi.org/10.1155/2010/903295] [PMID: 20300540]
[5]
Sitprija, V.; Sitprija, S. Renal effects and injury induced by animal toxins. Toxicon, 2012, 60(5), 943-953.
[http://dx.doi.org/10.1016/j.toxicon.2012.06.012] [PMID: 22750531]
[6]
Nunan, E.A.; Moraes, M.F.D.; Cardoso, V.N.; Moraes-Santos, T. Effect of age on body distribution of Tityustoxin from Tityus serrulatus scorpion venom in rats. Life Sci., 2003, 73(3), 319-325.
[http://dx.doi.org/10.1016/S0024-3205(03)00264-9] [PMID: 12757839]
[7]
Santos, M.S.V.; Silva, C.G.L.; Neto, B.S.; Grangeiro Júnior, C.R.P.; Lopes, V.H.G.; Teixeira Júnior, A.G.; Bezerra, D.A.; Luna, J.V.; Cordeiro, J.B.; Júnior, J.G.; Lima, M.A. Clinical and epidemiological aspects of scorpionism in the world: A systematic review. Wilderness Environ. Med., 2016, 27(4), 504-518.
[http://dx.doi.org/10.1016/j.wem.2016.08.003] [PMID: 27912864]
[8]
De Armas, L.; Luna, D.; Flórez, E. Composition of the genus Centruroides Marx, 1890 (Scorpiones: Buthidae) in Colombia, with description of a new species. Bol. SEA, 2012, 50, 105-114.
[9]
Guerrero-Vargas, J.A.; Rodrigues, J.R.B.; Ayerbe, S.; Flórez, E.D.; Beltrán, J.T.V. Scorpionism and Dangerous Species of Colombia. Scorpion Venoms; Gopalakrishnakone, P.; Possani, L.; Schwartz, E.; Rodríguez de la Vega, R., Eds.; Springer: Dordrecht, 2015, Vol. 04, pp. 245-272.
[http://dx.doi.org/10.1007/978-94-007-6404-0_22]
[10]
Escobar, E.; Velásquez, L.; Rivera, C. Separation and identification of some toxins from Centruroides margaritatus venom (Gervais,1841) (Scorpiones: Buthidae). Rev. Peru. Biol., 2003, 10(2), 217-220.
[11]
García-Calvo, M.; Leonard, R.J.; Novick, J.; Stevens, S.P.; Schmalhofer, W.; Kaczorowski, G.J.; Garcia, M.L. Purification, characterization, and biosynthesis of margatoxin, a component of Centruroides margaritatus venom that selectively inhibits voltage-dependent potassium channels. J. Biol. Chem., 1993, 268(25), 18866-18874.
[PMID: 8360176]
[12]
Guerrero-Vargas, J.A. Partial Proteomic Analysis by Venom of Colombian Scorpion's Centruroides margaritatus (Gervais, 1841); Master's Thesis: University of Brasilia: Brasilia, 2008.
[13]
Dueñas Cuellar, R.A.; Kushmerick, C.; Naves, L.A.; Batista, I.F.C.; Guerrero-Vargas, J.A. Pires Jr., O.R.; Fontes, Wagner.; Castro Mariana. Cm38: A new antimicrobial peptide active against klebsiella pneumoniae is homologous to Cn11. Protein Pept. Lett., 2015, 22(2), 164-172.
[http://dx.doi.org/10.2174/092986652202150128143048] [PMID: 25633390]
[14]
Marinkelle, C.J.; Stahnke, H.L. Toxicological and clinical studies on Centruroides margaritatus (Gervais), A common scorpion in western Colombia. J. Med. Entomol., 1965, 2(2), 197-199.
[http://dx.doi.org/10.1093/jmedent/2.2.197] [PMID: 5318265]
[15]
Galíndez-Cerón, J.D. Analysis of the hemodynamic alterations in rats induced by scorpions venoms In: Centruroides margaritatus, Centruroides limpidus and Centruroides noxius; Master's Thesis, Federal University of Ceará: Fortaleza, 2018.
[16]
Murugesan, S.; Krishna Murthy, K.R.; Noronha, O.; Samuel, A.M. Scorpion Venom: Labelling, Biodistribution and Scintiimaging. J. Venom. Anim. Toxins, 1999, 5, 35-46.
[http://dx.doi.org/10.1590/S0104-79301999000100003]
[17]
Devaux, C.; Jouirou, B.; Naceur Krifi, M.; Clot-Faybesse, O.; El Ayeb, M.; Rochat, H. Quantitative variability in the biodistribution and in toxinokinetic studies of the three main alpha toxins from the Androctonus australis hector scorpion venom. Toxicon, 2004, 43(6), 661-669.
[http://dx.doi.org/10.1016/j.toxicon.2004.02.021] [PMID: 15109887]
[18]
Angsanakul, J.; Sitprija, V. Scorpion venoms, kidney and potassium. Toxicon, 2013, 73, 81-87.
[http://dx.doi.org/10.1016/j.toxicon.2013.06.023] [PMID: 23834919]
[19]
Abdoon, N.A.; Fatani, A.J. Correlation between blood pressure, cytokines and nitric oxide in conscious rabbits injected with Leiurus quinquestriatus quinquestriatus scorpion venom. Toxicon, 2009, 54(4), 471-480.
[http://dx.doi.org/10.1016/j.toxicon.2009.05.009] [PMID: 19467253]
[20]
Sitprija, V.; Sitprija, S. Animal toxins and renal ion transport: Another dimension in tropical nephrology. Nephrology (Carlton), 2016, 21(5), 355-362.
[http://dx.doi.org/10.1111/nep.12633] [PMID: 26421422]
[21]
Bowman, R.H. Gluconeogenesis in the isolated perfused rat kidney. J. Biol. Chem., 1970, 245(7), 1604-1612.
[PMID: 4314592]
[22]
Fonteles, M.C.; Cohen, J.J.; Black, A.J.; Wertheim, S.J. Support of kidney function by long-chain fatty acids derived from renal tissue. Am. J. Physiol., 1983, 244(3), F235-F246.
[PMID: 6829757]
[23]
Walser, M.; Davidson, D.G.; Orloff, J. The renal clearance of alkali-stable inulin. J. Clin. Invest., 1955, 34(10), 1520-1523.
[http://dx.doi.org/10.1172/JCI103204] [PMID: 13263432]
[24]
Cecilio, A.B.; Caldas, S.; Oliveira, R.A.; Santos, A.S.B.; Richardson, M.; Naumann, G.B.; Schneider, F.S.; Alvarenga, V.G.; Estevão-Costa, M.I.; Fuly, A.L.; Eble, J.A.; Sanchez, E.F. Molecular characterization of Lys49 and Asp49 phospholipases A2 from snake venom and their antiviral activities against Dengue virus. Toxins (Basel), 2013, 5(10), 1780-1798.
[http://dx.doi.org/10.3390/toxins5101780] [PMID: 24131891]
[25]
Saidani, C.; Béchohra, L.; Laraba-Djebari, F.; Hammoudi-Triki, D. Kidney inflammation and tissue injury induced by scorpion venom: Comparison with a nephrotoxic model. Toxin Rev., 2018, 0(0), 1-8.
[http://dx.doi.org/10.1080/15569543.2018.1446028]
[26]
Heidarpour, M.; Ennaifer, E.; Ahari, H.; Srairi-Abid, N.; Borchani, L.; Khalili, G.; Amini, H.; Anvar, A.A.; Boubaker, S.; El-Ayeb, M.; Shahbazzadeh, D. Histopathological changes induced by Hemiscorpius lepturus scorpion venom in mice. Toxicon, 2012, 59(3), 373-378.
[http://dx.doi.org/10.1016/j.toxicon.2011.12.011] [PMID: 22230352]
[27]
Viswanathan, S.; Prabhu, C. Scorpion sting nephropathy. NDT Plus, 2011, 4(6), 376-382.
[PMID: 25984198]
[28]
Koeppen, B.M.; Stanton, B.A. Renal Physiology, 5th ed; Elsevier: Amsterdam, 2012.
[29]
Fan, F.; Pabbidi, M.R.; Ge, Y.; Li, L.; Wang, S.; Mims, P.N.; Roman, R.J. Knockdown of Add3 impairs the myogenic response of renal afferent arterioles and middle cerebral arteries. Am. J. Physiol. Renal Physiol., 2017, 312(6), F971-F981.
[http://dx.doi.org/10.1152/ajprenal.00529.2016] [PMID: 27927653]
[30]
de Sousa Alves, R.; do Nascimento, N.R.F.; Barbosa, P.S.F.; Kerntopf, M.R.; Lessa, L.M.A.; de Sousa, C.M.; Martins, R.D.; Sousa, D.F.; de Queiroz, M.G.; Toyama, M.H.; Fonteles, M.C.; Martins, A.M.; Monteiro, H.S. Renal effects and vascular reactivity induced by Tityus serrulatus venom. Toxicon, 2005, 46(3), 271-276.
[http://dx.doi.org/10.1016/j.toxicon.2005.04.013] [PMID: 16011841]
[31]
Catterall, W.A.; Cestèle, S.; Yarov-Yarovoy, V.; Yu, F.H.; Konoki, K.; Scheuer, T. Voltage-gated ion channels and gating modifier toxins. Toxicon, 2007, 49(2), 124-141.
[http://dx.doi.org/10.1016/j.toxicon.2006.09.022] [PMID: 17239913]
[32]
He, Y.; Zou, X.; Li, X.; Chen, J.; Jin, L.; Zhang, F.; Yu, B.; Cao, Z. Activation of sodium channels by α-scorpion toxin, BmK NT1, produced neurotoxicity in cerebellar granule cells: an association with intracellular Ca2+ overloading. Arch. Toxicol., 2017, 91(2), 935-948.
[http://dx.doi.org/10.1007/s00204-016-1755-2] [PMID: 27318804]
[33]
Alves, R.S.; Ximenes, R.M.; Jorge, A.R.C.; Nascimento, N.R.F.; Martins, R.D.; Rabello, M.M.; Hernandes, M.Z.; Toyama, D.O.; Toyama, M.H.; Martins, A.M.; Havt, A.; Monteiro, H.S. Isolation, homology modeling and renal effects of a C-type natriuretic peptide from the venom of the Brazilian yellow scorpion (Tityus serrulatus). Toxicon, 2013, 74, 19-26.
[http://dx.doi.org/10.1016/j.toxicon.2013.07.016] [PMID: 23911732]
[34]
Silva, N.A.; Albuquerque, C.M.R.; Marinho, A.D.; Jorge, R.J.B.; Silva, A.G.; Monteiro, H.S.; Silva, T.D.; Silva, M.V.; Correia, M.T.; Pereira, T.P.; Martins, A.M.; Menezes, D.B.; Ximenes, R.M.; Martins, R.D. Effects of Tityus stigmurus (Thorell 1876) (Scorpiones: Buthidae) venom in isolated perfused rat kidneys. An. Acad. Bras. Cienc., 2016, 88(Suppl. 1), 665-675.
[http://dx.doi.org/10.1590/0001-3765201620150253] [PMID: 27142547]
[35]
Pipelzadeh, M.H.; Jalali, A.; Taraz, M.; Pourabbas, R.; Zaremirakabadi, A. An epidemiological and a clinical study on scorpionism by the Iranian scorpion Hemiscorpius lepturus. Toxicon, 2007, 50(7), 984-992.
[http://dx.doi.org/10.1016/j.toxicon.2007.07.018] [PMID: 17854855]
[36]
Rodríguez de la Vega, R.C.; Schwartz, E.F.; Possani, L.D. Mining on scorpion venom biodiversity. Toxicon, 2010, 56(7), 1155-1161.
[http://dx.doi.org/10.1016/j.toxicon.2009.11.010] [PMID: 19931296]
[37]
Wu, R.S.; Marx, S.O. The BK potassium channel in the vascular smooth muscle and kidney: α- and β-subunits. Kidney Int., 2010, 78(10), 963-974.
[http://dx.doi.org/10.1038/ki.2010.325] [PMID: 20861815]
[38]
Quintero-Hernández, V.; Jiménez-Vargas, J.M.; Gurrola, G.B.; Valdivia, H.H.; Possani, L.D. Scorpion venom components that affect ion-channels function. Toxicon, 2013, 76, 328-342.
[http://dx.doi.org/10.1016/j.toxicon.2013.07.012] [PMID: 23891887]
[39]
Jalali, A.; Pipelzadeh, M.H.; Sayedian, R.; Rowan, E.G. A review of epidemiological, clinical and in vitro physiological studies of envenomation by the scorpion Hemiscorpius lepturus (Hemiscorpiidae) in Iran. Toxicon, 2010, 55(2-3), 173-179.
[http://dx.doi.org/10.1016/j.toxicon.2009.09.012] [PMID: 19799924]
[40]
de Morais, I.C.O.; Torres, A.F.C.; Pereira, G.J.D.S.; Pereira, T.P.; Pessoa Bezerra de Menezes, R.R.D.P.; Mello, C.P.; Coelho Jorge, A.R.; Bindá, A.H.; Toyama, M.H.; Monteiro, H.S.A.; Smaili, S.S.; Martins, A.M.C. Bothrops leucurus venom induces nephrotoxicity in the isolated perfused kidney and cultured renal tubular epithelia. Toxicon, 2013, 61, 38-46.
[http://dx.doi.org/10.1016/j.toxicon.2012.10.005] [PMID: 23127898]
[41]
Saidani, C.; Hammoudi-Triki, D.; Laraba-Djebari, F.; Taub, M. In vitro studies with renal proximal tubule cells show direct cytotoxicity of Androctonus australis hector scorpion venom triggered by oxidative stress, caspase activation and apoptosis. Toxicon, 2016, 120, 29-37.
[http://dx.doi.org/10.1016/j.toxicon.2016.07.012] [PMID: 27470530]
[42]
Hebert, S.C.; Desir, G.; Giebisch, G.; Wang, W. Molecular diversity and regulation of renal potassium channels. Physiol. Rev., 2005, 85(1), 319-371.
[http://dx.doi.org/10.1152/physrev.00051.2003] [PMID: 15618483]
[43]
Lee, Y.J.; Kim, M.O.; Ryu, J.M.; Han, H.J. Regulation of SGLT expression and localization through Epac/PKA-dependent caveolin-1 and F-actin activation in renal proximal tubule cells. Biochim. Biophys. Acta, 2012, 1823(4), 971-982.
[http://dx.doi.org/10.1016/j.bbamcr.2011.12.011] [PMID: 22230192]
[44]
Ortiz, E.; Gurrola, G.B.; Schwartz, E.F.; Possani, L.D. Scorpion venom components as potential candidates for drug development. Toxicon, 2015, 93, 125-135.
[http://dx.doi.org/10.1016/j.toxicon.2014.11.233] [PMID: 25432067]
[45]
Koç, E.; Çelik-Uzuner, S.; Uzuner, U.; Çakmak, R. The detailed comparison of cell death detected by annexin V-PI counterstain using fluorescence microscope, flow cytometry and automated cell counter in mammalian and microalgae cells. J. Fluoresc., 2018, 28(6), 1393-1404.
[http://dx.doi.org/10.1007/s10895-018-2306-4] [PMID: 30343360]
[46]
Rigoni, V.L.S.; Kwasniewski, F.H.; Vieira, R.P.; Linhares, I.S.; da Silva, J.L.V.; Nogueira-Pedro, A.; Zamuner, S.R. Human bronchial epithelial cells injury and cytokine production induced by Tityus serrulatus scorpion venom: An in vitro study. Toxicon, 2016, 120, 22-28.
[http://dx.doi.org/10.1016/j.toxicon.2016.07.013] [PMID: 27452928]
[47]
Das Gupta, S.; Debnath, A.; Saha, A.; Giri, B.; Tripathi, G.; Vedasiromoni, J.R.; Gomes, A.; Gomes, A. Indian black scorpion (Heterometrus bengalensis Koch) venom induced antiproliferative and apoptogenic activity against human leukemic cell lines U937 and K562. Leuk. Res., 2007, 31(6), 817-825.
[http://dx.doi.org/10.1016/j.leukres.2006.06.004] [PMID: 16876244]
[48]
Vanden Berghe, T.; Grootjans, S.; Goossens, V.; Dondelinger, Y.; Krysko, D.V.; Takahashi, N.; Vandenabeele, P. Determination of apoptotic and necrotic cell death in vitro and in vivo. Methods, 2013, 61(2), 117-129.
[http://dx.doi.org/10.1016/j.ymeth.2013.02.011] [PMID: 23473780]
[49]
Boujrad, H.; Gubkina, O.; Robert, N.; Krantic, S.; Susin, S.A. AIF-mediated programmed necrosis: A highly regulated way to die. Cell Cycle, 2007, 6(21), 2612-2619.
[http://dx.doi.org/10.4161/cc.6.21.4842] [PMID: 17912035]
[50]
Krysko, D.V.; Kaczmarek, A.; Krysko, O.; Heyndrickx, L.; Woznicki, J.; Bogaert, P.; Cauwels, A.; Takahashi, N.; Magez, S.; Bachert, C.; Vandenabeele, P. TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation. Cell Death Differ., 2011, 18(8), 1316-1325.
[http://dx.doi.org/10.1038/cdd.2011.4] [PMID: 21311566]
[51]
Rodríguez de la Vega, R.C.; Possani, L.D. Current views on scorpion toxins specific for K+-channels. Toxicon, 2004, 43(8), 865-875.
[http://dx.doi.org/10.1016/j.toxicon.2004.03.022] [PMID: 15208019]
[52]
Jang, S.H.; Choi, S.Y.; Ryu, P.D.; Lee, S.Y. Anti-proliferative effect of Kv1.3 blockers in A549 human lung adenocarcinoma in vitro and in vivo. Eur. J. Pharmacol., 2011, 651(1-3), 26-32.
[http://dx.doi.org/10.1016/j.ejphar.2010.10.066] [PMID: 21087602]


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