Downregulation of renal TRPM7 and increased inflammation and fibrosis in aldosterone-infused mice - Effects of magnesium

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 mu g/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.