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GPR48 increases mineralocorticoid receptor gene expression

Jiqiu Wang1, Xiaoying Li, Yingying Ke

  • 1Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrinology and Metabolism, Shanghai Key Laboratory for Endocrine Tumors and E-Institute of Shanghai Universities, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Journal of the American Society of Nephrology : JASN
|December 3, 2011
PubMed

Insights

G protein-coupled receptor 48 (GPR48) enhances mineralocorticoid receptor (MR) expression, improving aldosterone response and electrolyte balance. This suggests GPR48 may be a potential cause of pseudohypoaldosteronism type 1.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Physiology

Background:

  • Aldosterone and the mineralocorticoid receptor (MR) are vital for blood pressure (BP) and electrolyte homeostasis.
  • Mutations in MR cause pseudohypoaldosteronism type 1 (PHA1), a condition of aldosterone resistance.
  • Some PHA1 cases lack identifiable MR gene mutations, indicating potential alternative genetic factors.

Purpose of the Study:

  • To investigate the role of G protein-coupled receptor 48 (Gpr48/Lgr4) in aldosterone responsiveness and electrolyte balance.
  • To determine if GPR48 dysfunction contributes to PHA1-like phenotypes.

Main Methods:

  • Analysis of Gpr48 hypomorphic mutant (Gpr48(m/m)) mice under normal and low-sodium diet conditions.
  • Assessment of electrolyte levels, plasma aldosterone, renin activity, and renal MR and downstream target expression.
  • In vitro studies to elucidate the mechanism of GPR48 regulation of MR expression via the cAMP/protein kinase A pathway.

Main Results:

  • Gpr48(m/m) mice exhibited hyperkalemia, increased salt and water excretion, and hyponatremia, indicative of aldosterone resistance.
  • Renal MR expression and that of its downstream targets were significantly downregulated in mutant mice.
  • GPR48 was found to upregulate MR expression through the cAMP/protein kinase A pathway.

Conclusions:

  • GPR48 plays a crucial role in maintaining aldosterone responsiveness by regulating MR expression.
  • GPR48 dysfunction can lead to aldosterone resistance and electrolyte imbalance, mimicking PHA1.
  • GPR48 is identified as a potential contributing gene for PHA1 and a key factor in BP and electrolyte homeostasis.

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