title: Downregulation of renal TRPM7 and increased inflammation and fibrosis in aldosterone-infused mice: effects of magnesium.
abstract: Hyperaldosteronism is associated with hypertension, cardiovascular fibrosis, and electrolyte disturbances, including hypomagnesemia. Mechanisms underlying aldosterone-mediated Mg(2+) changes are unclear, but the novel Mg(2+) 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 Mg(2+) 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 Mg(2+)), (2) Mg(2+) group (0.75% dietary Mg(2+)), (3) aldosterone group (Aldo, 400 microg/kg/min and 0.9% NaCl drinking water), and (4) Aldo+Mg(2+) group. Blood pressure was unaltered by aldosterone and was similar in all groups throughout the experiment. Serum Na(+) was increased and serum K(+) and Mg(2+) decreased in the Aldo group. Aldo mice had hypomagnesuria and proteinuria, and renal, cardiac, and aortic fibrosis, which were normalized by Mg(2+) 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 Mg(2+) 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 Mg(2+)-sensitive pathways. We suggest that altered Mg(2+) metabolism in hyperaldosteronism may relate to TRPM7 downregulation and that Mg(2+) protects against cardiovascular and renal damaging actions of aldosterone.
authors.affiliation: Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, Ontario, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sontia
authors.forename: Augusto C I
authors.initials: AC
authors.lastname: Montezano
authors.forename: Tamara
authors.initials: T
authors.lastname: Paravicini
authors.forename: Fatiha
authors.initials: F
authors.lastname: Tabet
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D006929:Hyperaldosteronism / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D007668:Kidney / Q000276:immunology / Q000473:pathology*; D008274:Magnesium / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009393:Nephritis / Q000276:immunology / Q000473:pathology*; D009929:Organ Size; D012964:Sodium / Q000097:blood / Q000652:urine; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D050053:TRPM Cation Channels; D000450:Aldosterone; D012964:Sodium; C421903:Trpm7 protein, mouse; D008274:Magnesium