Dysregulation of renal transient receptor potential melastatin 6/7 but not paracellin-1 in aldosterone-induced hypertension and kidney damage in a model of hereditary hypomagnesemia

Yogi, A., Callera, G.E., OʼConnor, S.E., He, Y., Correa, J.W., Tostes, R.C., Mazur, A. and Touyz, R.M. (2011) Dysregulation of renal transient receptor potential melastatin 6/7 but not paracellin-1 in aldosterone-induced hypertension and kidney damage in a model of hereditary hypomagnesemia. Journal of Hypertension, 29(7), pp. 1400-1410. (doi: 10.1097/HJH.0b013e32834786d6)

Abstract

Rationale: Hyperaldosteronism, important in hypertension, is associated with electrolyte alterations, including hypomagnesemia, through unknown mechanisms.<p></p> Objective: To test whether aldosterone influences renal Mg2+ transporters, (transient receptor potential melastatin (TRPM) 6, TRPM7, paracellin-1) leading to hypomagnesemia, hypertension and target organ damage and whether in a background of magnesium deficiency, this is exaggerated.<p></p> Methods and results: Aldosterone effects in mice selectively bred for high-normal (MgH) or low (MgL) intracellular Mg2+ were studied. Male MgH and MgL mice received aldosterone (350 µg/kg per day, 3 weeks). SBP was elevated in MgL. Aldosterone increased blood pressure and albuminuria and increased urinary Mg2+ concentration in MgH and MgL, with greater effects in MgL. Activity of renal TRPM6 and TRPM7 was lower in vehicle-treated MgL than MgH. Aldosterone increased activity of TRPM6 in MgH and inhibited activity in MgL. TRPM7 and paracellin-1 were unaffected by aldosterone. Aldosterone-induced albuminuria in MgL was associated with increased renal fibrosis, increased oxidative stress, activation of mitogen-activated protein kinases and nuclear factor-NF-[kappa]B and podocyte injury. Mg2+ supplementation (0.75% Mg2+) in aldosterone-treated MgL normalized plasma Mg2+, increased TRPM6 activity and ameliorated hypertension and renal injury. Hence, in a model of inherited hypomagnesemia, TRPM6 and TRPM7, but not paracellin-1, are downregulated. Aldosterone further decreased TRPM6 activity in hypomagnesemic mice, a phenomenon associated with hypertension and kidney damage. Such effects were prevented by Mg2+ supplementation.<p></p> Conclusion: Amplified target organ damage in aldosterone-induced hypertension in hypomagnesemic conditions is associated with dysfunctional Mg2+-sensitive renal TRPM6 channels. Novel mechanisms for renal effects of aldosterone and insights into putative beneficial actions of Mg2+, particularly in hyperaldosteronism, are identified.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Touyz, Professor Rhian
• Authors: Yogi, A., Callera, G.E., OʼConnor, S.E., He, Y., Correa, J.W., Tostes, R.C., Mazur, A., and Touyz, R.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of Hypertension
• ISSN: 0263-6352
• ISSN (Online): 1473-5598