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1 Kidney research Centre, OHRI, Ottawa, ON, Canada
2 Kidney research Centre, OHRI, Ottawa, ON, Canada; Pharmacology, Univ Sao Paulo, Sao Paulo, Brazil
3 Philipps Universitat, Inst. Pharmakologie Toxikologie, Marburg, Germany
* To whom correspondence should be addressed. E-mail: rtouyz{at}uottawa.ca.
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 VSMCs from SHR. Cultured VSMCs from 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 versus 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 versus 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.
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