TRPM7 is protective against hypertension, cardiovascular inflammation and fibrosis induced by aldosterone and salt.

R2706 --> Introduction: : TRPM7 is a channel permeable to Mg2+, Ca2+ and Zn2+ bound to an alpha‐kinase domain with essential role in cation homeostasis and cell cycle and activation. Hyperaldosteronism, which induces hypertension and cardiovascular fibrosis, is associated with Mg2+ wasting. Here we investigate the importance of TRPM7 in hypertension and fibrosis induced by aldosterone and salt. Methods: Wild‐type (WT) and TRPM7‐deficient (M7+/Δ) mice were treated with aldosterone (600µg/Kg/day) and/or 1% NaCl (drinking water) (aldo, salt or aldo‐salt) for 4 weeks. Blood pressure (BP) was evaluated by tail‐cuff. Vessel structure was assessed by pressure myography. Inflammatory cell infiltrate was investigated by flow cytometry. Molecular mechanisms were investigated in cardiac fibroblasts (CF) from WT and M7+/Δ mice. Protein expression was assessed by western‐blot and histology. Results: M7+/Δ mice exhibited reduced TRPM7 expression (30%) and phosphorylation (62%), levels that were recapitulated in WT mice treated with aldo‐salt. M7+/Δ exhibited increased BP by aldo, salt and aldo‐salt (135‐140mmHg) vs M7+/Δ veh (117mmHg) (p<0.05), whereas in WT, BP was increased only in the aldo‐salt group (134mmHg). Mesenteric arteries from M7+/Δ aldo‐salt exhibited thinner walls by reducing cross‐sectional area (35%) vs WT aldo‐salt (p<0.05). Aldo‐salt induced greater collagen deposition in hearts (68%), kidneys (126%) and aortas (45%) from M7+/Δ vs WT. In kidneys from WT mice, aldo‐salt increased frequency of macrophages (47% vs 32% WT veh) and CD4+T cells (33% vs 22% WT veh) (p<0.05), effects observed already 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%). Hearts from M7+/Δ veh exhibited increased TGFβ, p‐Smad3 and p‐Stat1 (1.5‐fold) whereas in WT these effects were only found after aldo‐salt. Cardiac expression of PPM1A, a Mg2+‐dependent phosphatase, was reduced (3‐fold) only in M7+/Δ mice. CF from M7+/Δ mice showed reduced of proliferation (30%) and PPM1A (4‐fold) and increased expression of TGFβ, IL‐11, IL‐6 (2‐6‐fold), p‐Stat1 (2‐fold), p‐Smad3 (9‐fold) and p‐ERK1/2 (8‐fold) compared with WT. Mg2+ supplementation normalized cell proliferation and reduced protein phosphorylation in M7+/Δ CF (p<0.05. Conclusions: Our findings identify a protective role of TRPM7 in aldosterone‐salt induced cardiovascular injury, which when downregulated, facilitates hypertension, vascular remodeling and cardiac fibrosis through Mg2+ ‐dependent mechanisms. [ABSTRACT FROM AUTHOR]