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Cadmium-induced hypertension is associated with renal myosin light chain phosphatase inhibition via increased T697 phosphorylation and p44 mitogen-activated protein kinase levels

Abstract

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.

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Acknowledgements

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.

Funding

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.

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CRN conceptualized and designed the study and WCC, GM, and CC made some contributions to the methods. Material preparation and data collection and analysis were performed by GM, with western blot assistance from CC. The first draft of the paper was written by GM, and all authors commented on and edited subsequent versions of the paper. All authors contributed to the correction and finalization of the paper. GM and CRN acquired funding for the study. CRN and WCC provided resources for the study. CRN and PDB supervised the entire study. WCC supervised the western blot experiment.

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Correspondence to Garsha McCalla.

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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

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Keywords

  • Cadmium
  • Potassium supplementation
  • MYPT1
  • p44 MAPK

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