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Cardiovascular-Kidney Interactions in Health and Disease

Differential regulation of transient receptor potential melastatin 6 and 7 cation channels by ANG II in vascular smooth muscle cells from spontaneously hypertensive rats

¹Kidney Research Centre, University of Ottawa, Ontario, Canada; ² Department of Pharmacology, University of Sâo Paulo, Sâo Paulo, Brazil, ³ Institut Pharmakologie Toxikologie, Philipps Universität, Marburg, Germany

Submitted 19 July 2005 ; accepted in final form 16 August 2005

Intracellular Mg²⁺ depletion has been implicated in vascular dysfunction in hypertension. We demonstrated that transient receptor potential melastatin 7 (TRPM7) cation channels mediate Mg²⁺ influx in VSMCs. Whether this plays a role in [Mg²⁺]_i deficiency in hypertension is unclear. Here, we tested the hypothesis that downregulation of TRPM7 and its homologue TRPM6 is associated with reduced [Mg²⁺]_i and that ANG II negatively regulates TRPM6/7 in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR). Cultured VSMCs from Wistar Kyoto (WKY) and SHR were studied. mRNA and protein expression of TRPM6 and TRPM7 were assessed by RT-PCR and immunoblotting, respectively. Translocation of annexin-1, specific TRPM7 substrate, was measured as an index of TRPM7 activation. [Mg²⁺]_i was determined using mag fura-2. VSMCs from WKY and SHR express TRPM6 and TRPM7. Basal TRPM6 expression was similar in WKY and SHR, but basal TRPM7 content was lower in VSMCs from SHR vs. WKY. This was associated with significantly reduced [Mg²⁺]_i in SHR cells (P < 0.01). ANG II time-dependently increased TRPM6 expression, with similar responses in WKY and SHR. ANG II significantly increased TRPM7 expression in WKY (P < 0.05), but not in SHR. Annexin-1 translocation was reduced 1.5–2-fold in SHR vs. WKY. Our findings demonstrate that TRPM6 and TRPM7 are differentially regulated in VSMCs from SHR and WKY. Whereas TRPM6 is unaltered in SHR, expression of TRPM7 is blunted. This was associated with attenuated annexin-1 translocation and decreased VSMC [Mg²⁺]_i in SHR. Downregulation of TRPM7, but not TRPM6, may play a role in altered Mg²⁺ homeostasis in VSMCs from SHR.

magnesium; hypertension; mesenteric arteries; ion transport

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