Dietary intake of the heavy metal cadmium (Cd2+) is implicated in hypertension, but potassium supplementation reportedly mitigates hypertension. This study aims to elucidate the hypertensive mechanism of Cd2+. Vascular reactivity and protein expression were assessed in Cd2+-exposed rats for 8 weeks to determine the calcium-handling effect of Cd2+ and the possible signaling pathways and mechanisms involved. Cd2+ induced hypertension in vivo by significantly (p < 0.001) elevating systolic blood pressure (160 ± 2 and 155 ± 1 vs 120 ± 1 mm Hg), diastolic blood pressure (119 ± 2 and 110 ± 1 vs 81 ± 1 mm Hg), and mean arterial pressure (133 ± 2 and 125 ± 1 vs 94 ± 1 mm Hg) (SBP, DBP, and MAP, respectively), while potassium supplementation protected against elevation of these parameters. The mechanism involved augmentation of the phosphorylation of renal myosin light chain phosphatase targeting subunit 1 (MYPT1) at threonine 697 (T697) (2.58 ± 0.36 vs 1 ± 0) and the expression of p44 mitogen-activated protein kinase (MAPK) (1.78 ± 0.20 vs 1 ± 0). While acetylcholine (ACh)-induced relaxation was unaffected, 5 mg/kg b.w. Cd2+ significantly (p < 0.001) attenuated phenylephrine (Phe)-induced contraction of the aorta, and 2.5 mg/kg b.w. Cd2+ significantly (p < 0.05) augmented sodium nitroprusside (SNP)-induced relaxation of the aorta. These results support the vital role of the kidney in regulating blood pressure changes after Cd2+ exposure, which may be a key drug target for hypertension management. Given the differential response to Cd2+, it is apparent that its hypertensive effects could be mediated by myosin light chain phosphatase (MLCP) inhibition via phosphorylation of renal MYPT1-T697 and p44 MAPK. Further investigation of small arteries and the Rho-kinase/MYPT1 interaction is recommended.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Yoopan N, Watcharasit P, Wongsawatkul O, Piyachaturawat P, Satayavivad J. Attenuation of eNOS expression in cadmium-induced hypertensive rats. Toxicol Lett. 2008;176:157–61.
Marchetti C. Role of calcium channels in heavy metal toxicity. ISRN Toxicol. 2013;2013:184360 https://doi.org/10.1155/2013/184360.
Abarikwu SO, Njoku R, Lawrence CJ, Charles IA, Ikewuchi JC. Rutin ameliorates oxidative stress and preserves hepatic and renal functions following exposure to cadmium and ethanol. Pharm Biol. 2017;55:2161–9. https://doi.org/10.1080/13880209.2017.1387575.
Jackson WF. Potassium channels in regulation of vascular smooth muscle contraction and growth. Adv Pharm. 2017;78:89–144. https://doi.org/10.1016/bs.apha.2016.07.001.
Poorolajal J, Zeraati F, Soltanian AR, Sheikh V, Hooshmand E, Maleki A. Oral potassium supplementation for management of essential hypertension: a meta-analysis of randomized controlled trials. PLoS One. 2017;12:e0174967–83. https://doi.org/10.1371/journal.pone.0174967.
Salihi AB. Activation of inward rectifier potassium channels in high salt impairment of hydrogen sulphide-induced aortic relaxation in rats. Physiol Pharm. 2016;19:263–73.
Nesovic-Ostojic J, Cemerikic D, Dragovic S, Milovanovic A, Milovanovic J. Low micromolar concentrations of cadmium and mercury ions activate peritubular membrane K+ conductance in proximal tubular cells of frog kidney. Comp Biochem Physiol A Mol Integr Physiol. 2008;149:267–74. https://doi.org/10.1016/j.cbpa.2007.12.006.
Ruta LL, Popa VC, Nicolau I, Danet AF, Iordache V, Neagoe AD, et al. Calcium signalling mediates the response to cadmium toxicity in Saccharomyces cerevisiae cells. FEBS Lett. 2014;588:3202–12.
Lopin KV, Thevenod F, Page JC, Jones SW. Cd2+ block and permeation of Cav3.1 (α-1G) T-type Ca2+ channels: candidate mechanism for Cd2+ influx. Mol Pharm. 2012;82:1183–93.
Johnson RP, El-Yazbi AF, Takeya K, Walsh EJ, Walsh MP, Cole WC. Ca2+ sensitization via phosphorylation of myosin phosphatase targeting subunit at threonine-855 by Rho kinase contributes to the arterial myogenic response. J Physiol. 2009;587:2537–53.
Kitazawa T, Somlyo AP. Modulation of Ca2+ sensitivity by agonists in smooth muscle. Adv Exp Med Biol. 1991;304:97–109. https://doi.org/10.1007/978-1-4684-6003-2_10.
Murahashi T, Fujita A. Kitazawa T. Ca2+ -induced Ca2+ desensitization of myosin light chain phosphorylation and contraction in phasic smooth muscle. Mol Cell Biochem. 1999;190:91–8.
Ashraf MW. Levels of heavy metals in popular cigarette brands and exposure to these metals via smoking. Sci World J. 1–5, 2012. https://doi.org/10.1100/2012/729430.
Almenara CCP, Broseghini-Filho GB, Vescovi MVA, Angeli JK, de Oliveira Faria T, Stefanon I, et al. Chronic cadmium treatment promotes oxidative stress and endothelial damage in isolated rat aorta. PLoS One. 2013;8:e68418.
Nwokocha CR, Baker A, Douglas D, McCalla G, Nwokocha M, Brown PD. Apocynin ameliorates cadmium-induced hypertension through elevation of endothelium nitric oxide synthase. Cardiovasc Toxicol. 2013;13:357–63. https://doi.org/10.1007/s12012-013-9216-0.
Omogbai EK, Ozolua RI, Ebeigbe AB. Effects of potassium adaptation on blood pressure and pressor responses in normotensive and renal hypertensive Wistar rats. Methods Find Exp Clin Pharm. 2005;27:5–10. https://doi.org/10.1358/mf.2005.27.1.875430.
Bautista-Ortega J, Stallone JN, Ruiz-Feria CA. Effects of arginine and antioxidant vitamins on pulmonary artery reactivity to phenylephrine in the broiler chicken. Poult Sci. 2013;92:1062–72. https://doi.org/10.3382/ps.2012-02472.
Angeli JK, Cruz Pereira CA, de Oliveira Faria T, Stefanon I, Padilha AS, Vassallo DV. Cadmium exposure induces vascular injury due to endothelial oxidative stress: the role of local angiotensin II and COX-2. Free Radic Biol Med. 2013;65:838–48.
Ok SH, Lee HL, Yu J, Park J, Shin IW, Lee Y, et al. Lipid emulsion attenuates acetylcholine-induced relaxation in isolated rat aorta. Biomed Res Int. 2015;2015:871545–53. https://doi.org/10.1155/2015/871545.
Dang N, Pang S, Song H, An L, Ma X. Inactivation of mitogen-activated protein kinase signalling pathway reduces caspase-14 expression in impaired keratinocytes. Iran J Basic Med Sci. 2016;19:28–33.
Mulvany MJ, Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res. 1977;41:19–26.
Schutte R, Nawrot T, Richart T, Thijs L, Roels HA, Van Bortel LM, et al. Arterial structure and function and environmental exposure to cadmium. Occup Environ Med. 2008;65:412–9. https://doi.org/10.1136/oem.2007.035576.
Assmann G, Cullen P, Evers T, Petzinna D, Schulte H. Importance of arterial pulse pressure as a predictor of coronary heart disease risk in PROCAM. Eur Heart J. 2005;26:2120–6. https://doi.org/10.1093/eurheartj/ehi467.
Reymond P, Westerhof N, Stergiopulos N. Systolic hypertension mechanisms: effect of global and local proximal aorta stiffening on pulse pressure. Ann Biomed Eng. 2012;40:742–9. https://doi.org/10.1007/s10439-011-0443-x.
Kim DH, Yoo JY, Lee SY, Kim YJ, Lee SR, Park SY. Effects of pulse pressure alterations on cardiac output measurements derived from analysis of arterial pressure waveform. Anesth Pain Med. 2016;11:280–4. https://doi.org/10.17085/apm.2016.11.3.280.
Ozturk IM, Buyukakilli B, Balli E, Burak C, Gunes S, Semra Erdogan S. Determination of acute and chronic effects of cadmium on the cardiovascular system of rats. Toxicol Mech Methods. 2009;19:308–17.
Crestani S, Webb RC, da Silva-Santos JE. High-salt intake augments the activity of the RhoA/ROCK pathway and reduces intracellular calcium in arteries from rats. Am J Hypertens. 2017;30:389–99. https://doi.org/10.1093/ajh/hpw20.
Cho YE, Ahn DE, Morgan KG, Lee YH. Enhanced contractility and myosin phosphorylation induced by Ca2+-independent MLCK activity in hypertensive rats. Cardiovasc Res. 2011;91:162–70. https://doi.org/10.1093/cvr/cvr043.
Mita M, Tanaka H, Yanagihara H, Nakagawa J, Hishinuma S, Sutherland C, et al. Membrane depolarization-induced RhoA/Rho-associated kinase activation and sustained contraction of rat caudal arterial smooth muscle involves genistein-sensitive tyrosine phosphorylation. J Smooth Muscle Res. 2013;49:26–45. https://doi.org/10.1540/jsmr.49.26.
Seko T, Ito M, Kureishi Y, Okamoto R, Moriki N, Onishi K, et al. Activation of RhoA and inhibition of myosin phosphatase as important components in hypertension in vascular smooth muscle. Circ Res. 2003;92:411–8. https://doi.org/10.1161/01.RES.0000059987.90200.44.
Seok YM, Baek I, Kim YH, Jeong YS, Lee IJ, Shin DH, et al. Isoflavone attenuates vascular contraction through inhibition of the RhoA/Rho-kinase signalling pathway. J Pharm Exp Ther. 2008;326:991–8. https://doi.org/10.1124/jpet.108.138529.
Seok YM, Azam MA, Okamoto Y, Sato A, Yoshioka K, Maeda M, et al. Enhanced Ca2+-dependent activation of phosphoinositide-3-kinase class IIα isoform-Rho axis in blood vessels of spontaneously hypertensive rats. Hypertension. 2010;56:934–41. https://doi.org/10.1161/HYPERTENSIONAHA.110.160853.
Kim S, Cheon HS, Kim SY, Juhnn YS, Kim YY. Cadmium induces neuronal cell death through reactive oxygen species activated by GADD153. BMC Cell Biol. 2013;14:4–12. https://doi.org/10.1186/1471-2121-14-4.
Adi PJ, Burra SP, Vataparti AR, Matcha B. Calcium, zinc and vitamin E ameliorate cadmium-induced renal oxidative damage in albino Wistar rats. Toxicol Rep. 2016;3:591–7. https://doi.org/10.1016/j.toxrep.2016.07.005.
Scott AJ, O’Dea KP, O’Callaghan D, Williams L, Dokpesi JO, Tatton L, et al. Reactive oxygen species and p38 mitogen-activated protein kinase mediate tumour necrosis factor α-converting enzyme (TACE/ADAM-17) activation in primary human monocytes. J Biol Chem. 2011;286:35466–76. https://doi.org/10.1074/jbc.M111.277434.
Aikawa R, Komuro I, Yamazaki T, Zou Y, Kudoh S, Tanaka M, et al. Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats. J Clin Invest. 1997;100:1813–21. https://doi.org/10.1172/JCI119709.
Nowak G, Clifton GL, Godwin ML, Bakajsova D. Activation of ERK1/2 pathway mediates oxidant-induced decreases in mitochondrial function in renal cells. Am J Physiol Ren Physiol. 2006;291:F840–55. https://doi.org/10.1152/ajprenal.00219.2005.
Parenti A, Cui XL, Hopfer U, Ziche M, Douglas JG. Activation of MAPKs in proximal tubule cells from spontaneously hypertensive and control Wistar-Kyoto rats. Hypertension. 2000;35:1160–6.
Thind GS. Role of cadmium in human and experimental hypertension. J Air Pollut Control Assoc. 1972;22:267–70. https://doi.org/10.1080/00022470.1972.10469637.
Eum K-D, Lee M-S, Paek D. Cadmium in blood and hypertension. Sci Total Environ. 2008;407:147–53. https://doi.org/10.1016/j.scitotenv.2008.08.037.
Staessen JA, Kuznetsova T, Roels HA, Emelianov D, Fagard R. Exposure to cadmium and conventional and ambulatory blood pressures in a prospective population study. Public health and environmental exposure to cadmium study group. Am J Hypertens. 2000;13:146–56. https://doi.org/10.1016/s0895-7061(99)00187-9.
Satarug S, Nishijo M, Lasker JM, Edwards RJ, Moore MR. Kidney dysfunction and hypertension: role for cadmium, P450 and haem oxygenases? Tohoku J Exp Med. 208: 179–202. https://doi.org/10.1620/tjem.208.179.
Broseghini-Filho GB, Almenara CC, Vescovi MV, Faria Tde O, Vassallo DV, Angeli JK, et al. Acute Cadmium exposure reduces the local angiotensin I converting enzyme activity and increases the tissue metal content. Biol Trace Elem Res. 2015;166:149–56. https://doi.org/10.1007/s12011-015-0250-6.
Nakagawa H, Nishijo M. Environmental cadmium exposure, hypertension and cardiovascular risk. J Cardiovasc Risk. 1996;3:11–7. https://doi.org/10.1177/174182679600300103.
Aoshima K. Itai-itai disease: renal tubular osteomalacia induced by environmental exposure to cadmium—historical review and perspectives. Soil Sci Plant Nutr. 2016;62:319–26. https://doi.org/10.1080/00380768.2016.1159116.
Lalor GC, Rattray R, Williams N, Wright P. Cadmium levels in kidney and liver of Jamaicans at autopsy. West Indian Med J. 2004;53:76–80.
Nishijo M, Nakagawa H, Suwazono Y, Nogawa K, Kido T. Causes of death in patients with Itai-itai disease suffering from severe chronic cadmium poisoning: a nested case-control analysis of a follow-up study in Japan. BMJ Open. 2017;7:e015694 https://doi.org/10.1136/bmjopen-2016-015694.
Wright PR, Rattray R, Lalor G, Hanson R. Minimal health impact from exposure to diet-sourced cadmium on a population in central Jamaica. Environ Geochem Health. 2010;32:567–81. https://doi.org/10.1007/s10653-010-9318-6.
Shirran SL, Barran PE. The use of ESI-MS to probe the binding of divalent cations to calmodulin. J Am Soc Mass Spectrom. 2009;20:1159–71. https://doi.org/10.1016/j.jasms.2009.02.008.
Osol G, Brekke JF, McElroy-Yaggy K, Gokina NI. Myogenic tone, reactivity, and forced dilatation: a three-phase model of in vitro arterial myogenic behaviour. Am J Physiol Heart Circ Physiol. 2002;283:H2260–7. https://doi.org/10.1152/ajpheart.00634.2002.
Moreno-Domínguez A, El-Yazbi AF, Zhu HL, Colinas O, Zhong XZ, Walsh EJ, et al. Cytoskeletal reorganization evoked by Rho-associated kinase- and protein kinase C-catalyzed phosphorylation of cofilin and heat shock protein 27, respectively, contributes to myogenic constriction of rat cerebral arteries. J Biol Chem. 2014;289:20939–52. https://doi.org/10.1074/jbc.M114.553743.
El-Yazbi AF, Abd-Elrahman KS. ROK and arteriolar myogenic tone generation: molecular evidence in health and disease. Front Pharm. 2017;8:87. https://doi.org/10.3389/fphar.2017.00087.
Moreno-Domínguez A, Colinas O, El-Yazbi A, Walsh EJ, Hill MA, Walsh MP, et al. Ca2+ sensitization due to myosin light chain phosphatase inhibition and cytoskeletal reorganization in the myogenic response of skeletal muscle resistance arteries. J Physiol. 2013;591:1235–50. https://doi.org/10.1113/jphysiol.2012.243576.
European Food Safety Authority (EFSA) Panel on Contaminants in the Food Chain (CONTAM). Scientific opinion on tolerable weekly intake for cadmium. EFSA J. 2011;9:1975–93. https://doi.org/10.2903/j.efsa.2011.1975.
World Health Organization. Safety evaluation of certain contaminants in foods: cadmium-impact assessment of different maximum limits. Prepared by the Sixty-fourth meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). WHO Food Additives Series 55. 2006;82:156–203.
Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for cadmium. ATSDR/U.S. Public Health Service, ATSDR/TP-88/08, Atlanta, US 1989.
Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological Profile for Cadmium. Draft for public comment. US Department of Health and Human Services. Atlanta, US, 2008.
Xu Q, Liu Y, Gorospe M, Udelsman R, Holbrook NJ. Acute hypertension activates mitogen-activated protein kinases in arterial wall. J Clin Invest. 1996;97:508–14.
Chrissobolis S, Sobey CG. Evidence that Rho-kinase activity contributes to cerebral vascular tone in vivo and is enhanced during chronic hypertension: comparison with protein kinase C. Circ Res. 2001;88:774–9.
González J, Valls N, Brito R, Rodrigo R. Essential hypertension and oxidative stress: new insights. World J Cardiol. 2014;6:353–66. https://doi.org/10.4330/wjc.v6.i6.353.
Sutherland C, MacDonald JA, Walsh MP. Analysis of phosphorylation of the myosin-targeting subunit of myosin light chain phosphatase by Phos-tag SDS-PAGE. Am J Physiol Cell Physiol. 2016;310:C681–91. https://doi.org/10.1152/ajpcell.00327.2015.
Karaki H, Urakawa N, Kutsky P. Potassium-induced contraction in smooth muscle. Jpn J Smooth Muscle Res. 1984;20:427–44.
The authors would like to express gratitude to Cindy Sutherland, Aaron Cull, Drs. Ryan Mills, Alejandro Moreno-Domínguez, Olaia Colinas, Emma Walsh, Hai-Lei Zhu, and Anthony Liwa for assistance with western blotting and members of Basic Medical Sciences, UWI, for technical assistance and help with the organ bath experiment.
This work was funded by grants obtained from the Mona Campus Committee for Research and Publications and Graduate Awards of the School for Graduate Studies and Research, University of the West Indies.
Conflict of interest
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
McCalla, G., Brown, P.D., Cole, W.C. et al. Cadmium-induced hypertension is associated with renal myosin light chain phosphatase inhibition via increased T697 phosphorylation and p44 mitogen-activated protein kinase levels. Hypertens Res (2021). https://doi.org/10.1038/s41440-021-00662-w
- Potassium supplementation
- p44 MAPK