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(Hypertension. 2008;51:915.)
© 2008 American Heart Association, Inc.

Original Articles

Downregulation of Renal TRPM7 and Increased Inflammation and Fibrosis in Aldosterone-Infused Mice

Effects of Magnesium

From the Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, Ontario, Canada.

Correspondence to Rhian M. Touyz, MD, PhD, Kidney Research Centre, University of Ottawa/Ottawa Health Research Institute, 451 Smyth Rd, Ottawa, ON, KIH 8M5. E-mail rtouyz{at}uottawa.ca

Hyperaldosteronism is associated with hypertension, cardiovascular fibrosis, and electrolyte disturbances, including hypomagnesemia. Mechanisms underlying aldosterone-mediated Mg²⁺ changes are unclear, but the novel Mg²⁺ transporters TRPM6 and TRPM7 may be important. We examined whether aldosterone influences renal TRPM6/7 and the TRPM7 downstream target annexin-1 and tested the hypothesis that Mg²⁺ administration ameliorates aldosterone-induced cardiovascular and renal injury and prevents aldosterone-associated hypertension. C57B6 mice were studied (12 weeks, n=8 to 9/group); (1) control group (0.2% dietary Mg²⁺), (2) Mg²⁺ group (0.75% dietary Mg²⁺), (3) aldosterone group (Aldo, 400 µg/kg/min and 0.9% NaCl drinking water), and (4) Aldo+Mg²⁺ group. Blood pressure was unaltered by aldosterone and was similar in all groups throughout the experiment. Serum Na⁺ was increased and serum K⁺ and Mg²⁺ decreased in the Aldo group. Aldo mice had hypomagnesuria and proteinuria, and renal, cardiac, and aortic fibrosis, which were normalized by Mg²⁺ supplementation. Renal and cardiovascular expression of interleukin-6, VCAM1 and COX2 was increased in the Aldo group. Magnesium attenuated renal and cardiac interleukin-6 content and decreased renal VCAM1 and cardiac COX2 expression (P<0.05). Aldosterone decreased expression of renal TRPM7 and the downstream target annexin-1 (P<0.05) without effect on TRPM6. Whereas Mg²⁺ increased mRNA expression of TRPM6 and TRPM7, it had no effect on TRPM7 and annexin-1 protein content. Our data demonstrate that aldosterone mediates blood pressure–independent renal and cardiovascular fibrosis and inflammation through Mg²⁺-sensitive pathways. We suggest that altered Mg²⁺ metabolism in hyperaldosteronism may relate to TRPM7 downregulation and that Mg²⁺ protects against cardiovascular and renal damaging actions of aldosterone.

Key Words: TRP channels • cations • cardiovascular remodeling • blood pressure • vascular cell adhesion molecule • COX2 • annexin-1