title: GPR48 increases mineralocorticoid receptor gene expression.
abstract: 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.
authors.affiliation: 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 of Medicine, Shanghai, China.
authors.forename: Jiqiu
authors.initials: J
authors.lastname: Wang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Li
authors.forename: Yingying
authors.initials: Y
authors.lastname: Ke
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Nengguang
authors.initials: N
authors.lastname: Fan
authors.forename: Haiyan
authors.initials: H
authors.lastname: Sun
authors.forename: Huijie
authors.initials: H
authors.lastname: Zhang
authors.forename: Ruixin
authors.initials: R
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Lei
authors.initials: L
authors.lastname: Ye
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007671:Kidney Concentrating Ability; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D018161:Receptors, Mineralocorticoid / Q000235:genetics*; D012964:Sodium / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C496200:LGR4 protein, mouse; D043562:Receptors, G-Protein-Coupled; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D012964:Sodium; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases