Aldosterone and the mineralocorticoid receptor (MR) are critical to the maintenance of electrolyte and BP homeostasis.
Mutations in the MR cause aldosterone resistance known as pseudohypoaldosteronism type 1 (PHA1); however, some cases consistent with PHA1 do not exhibit known gene mutations, suggesting the possibility of alternative genetic variants.
We observed that G protein-coupled receptor 48 (Gpr48/Lgr4) hypomorphic mutant (Gpr48(m/m)) mice had hyperkalemia and increased water loss and salt excretion despite elevated plasma aldosterone levels, suggesting aldosterone resistance.
When we challenged the mice with a low-sodium diet, these features became more obvious; the mice also developed hyponatremia and increased renin expression and activity, resembling a mild state of PHA1. There was marked renal downregulation of MR and its downstream targets (e.g., the α-subunit of the amiloride-sensitive epithelial sodium channel), which could provide a mechanism for the aldosterone resistance.
We identified a noncanonical cAMP-responsive element located in the MR promoter and demonstrated that GPR48 upregulates MR expression via the cAMP/protein kinase A pathway in vitro.
Taken together, our data demonstrate that GPR48 enhances aldosterone responsiveness by activating MR expression, suggesting that GPR48 contributes to homeostasis of electrolytes and BP and may be a candidate gene for PHA1.
2012-02-09
Eng.
Journal of the American Society of Nephrology : JASN
Shanghai 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
J Am Soc Nephrol. 2012 Feb;23(2):281-93
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