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

J Hypertens. 2011 Jul;29(7):1400-10. doi: 10.1097/HJH.0b013e32834786d6.


Rationale: Hyperaldosteronism, important in hypertension, is associated with electrolyte alterations, including hypomagnesemia, through unknown mechanisms.

Objective: To test whether aldosterone influences renal Mg(2+) 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.

Methods and results: Aldosterone effects in mice selectively bred for high-normal (MgH) or low (MgL) intracellular Mg(2+) 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 Mg(2+) 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-κB and podocyte injury. Mg(2+) supplementation (0.75% Mg(2+)) in aldosterone-treated MgL normalized plasma Mg(2+), 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 Mg(2+) supplementation.

Conclusion: Amplified target organ damage in aldosterone-induced hypertension in hypomagnesemic conditions is associated with dysfunctional Mg(2+)-sensitive renal TRPM6 channels. Novel mechanisms for renal effects of aldosterone and insights into putative beneficial actions of Mg(2+), particularly in hyperaldosteronism, are identified.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / toxicity*
  • Animals
  • Claudins
  • Disease Models, Animal*
  • Hypercalciuria / physiopathology*
  • Hypertension / chemically induced
  • Hypertension / physiopathology*
  • Membrane Proteins / physiology*
  • Mice
  • Nephrocalcinosis / physiopathology*
  • Oxidative Stress
  • Renal Tubular Transport, Inborn Errors / physiopathology*
  • TRPM Cation Channels / physiology*


  • Claudins
  • Membrane Proteins
  • TRPM Cation Channels
  • Trpm6 protein, mouse
  • claudin 16
  • Aldosterone
  • Trpm7 protein, mouse

Supplementary concepts

  • Hypomagnesemia primary