TRPM7 IS PROTECTIVE AGAINST CARDIOVASCULAR DAMAGE INDUCED BY ALDOSTERONE AND SALT

Abstract

Objective: TRPM7 is a channel-kinase that regulates cellular signaling and Mg2+ homeostasis. We demonstrated that TRPM7 is protective against cardiac inflammation and dysfunction. Since hyperaldosteronism causes hypertension and Mg2+ wasting, we questioned whether TRPM7 plays a role in aldosterone-induced hypertension and fibrosis. Design and method: Wild-type (WT) and TRPM7-deficient (M7+/δ) mice were treated with aldosterone (600 μg/Kg/day) and/or 1% NaCl (drinking water) (aldo, salt or aldo/salt) for 4 weeks. Blood pressure (BP) was evaluated by tail-cuff. Vascular function was investigated by wire myography. Inflammatory infiltrate was investigated by flow cytometry. Molecular mechanisms of fibrosis and inflammation were investigated in cardiac fibroblasts (CF) isolated from WT and M7+/δ mice. Protein expression was assessed by western-blot and histology. Results : Aldo/salt reduced TRPM7-phosphorylation (62%) and expression (30%) in WT, similarly to reduced levels observed in M7+/δ-veh. M7+/δ exhibited increased BP by aldo (140mmHg), salt (135mmHg) and aldo/salt (137mmHg) vs M7+/δ-veh (117mmHg) (p < 0.05), whereas in WT, BP was increased only by aldo/salt (134mmHg). All treatments induced endothelial dysfunction in M7+/δ as observed in acetylcholine-relaxation curves [Emax% M7+/δ: aldo (81±4), salt (69 ± 4) and aldo/salt (75 ± 3.0), p < 0.05], whereas in WT, Emax% was reduced after aldo (68 ± 4) and aldo/salt (80 ± 3). Phenylephrine-contraction and SNP-relaxation curves were similar among groups. In kidneys from WT, aldo/salt increased numbers of macrophages (47% vs 32% WT-veh) and CD4+T cells (33% vs 22% WT-veh) (p < 0.05), effects observed in M7+/δ-veh (macrophages: 42%, CD4+T cells: 34%). Aldosterone increased CD8+T cells in kidneys from M7+/δ (16% vs M7+/δ-veh 9%). Collagen was increased only in aortas from M7+/δ-aldo (31%) and M7+/δ-aldo/salt (45%). Aldo/salt induced higher collagen deposition in hearts (68%) and kidneys (126%) from vs WT. Hearts from M7+/δ-veh exhibited increased p-Stat1 and p-Smad3 (1.5-fold), whereas tissues from WT exhibited 3-fold increase only after treatments. CF from M7+/δ showed increased activation of Stat1 (2-fold), Smad3 (9-fold), ERK1/2 (8-fold) and reduced pStat3 (70%) vs WT. These effects were ameliorated by Mg2+ supplementation (p < 0.05). Conclusions: We define a novel protective role of TRPM7 in aldosterone-salt induced cardiovascular damage, which when downregulated, facilitates hypertension, vascular remodeling and cardiac fibrosis through Mg2+-dependent mechanisms.