School of Medicine and Health Sciences Poster Presentations

Title

GPR83 function contributes to salt resistance

Document Type

Poster

Keywords

Gpr83; Salt-sensitivity; hypertension

Publication Date

Spring 2017

Abstract

The G protein-coupled receptor (GPCR) 83 (Gpr83) is an orphan receptor belonging to the rhodopsin-like family of GPCRs. Gpr83 was originally identified as a glucocorticoid-induced transcript in a murine T cell line and referred to as glucocorticoid-induced receptor. Gpr83 is expressed in brain hypothalamic nuclei relevant to energy metabolism control and has a role in the central regulation of energy metabolism. Gpr83 is also expressed in the kidney but its function is unknown. We found that Gpr83 is expressed in mouse renal proximal and distal convoluted tubules, as well as in human renal proximal tubule cells (hRPTCs). High salt diet increased Gpr83 transcription by 2-fold (P<0.05; n=4/group) in Swiss Jim Lambert (SJL/J) and Bagg Albino (BALB/c) salt-resistant mice, relative to C57 Black (C57Bl/6J) salt-sensitive mice. In C57Bl/6J mice on normal salt diet, the lack of one (Gpr83+/-) or both Gpr83 (Gpr83-/-) alleles resulted in an increase in systolic blood pressure (SBP, ~20 mm Hg (P<0.05; n=4/group, measured under anesthesia) compared with Gpr83+/+ littermates, suggesting that Gpr83 is needed to keep a normal BP. Renal-specific Gpr83 silencing by the renal subcapsular infusion of Gpr83 siRNA (3 µg/day; 7 days) increased SBP in C57Bl/6J mice on a normal salt diet, relative to mice treated with non-silencing siRNA (120±5 vs 98±6 mmHg; P<0.05; n=4/group). In hRPTCs, forskolin (10 µM, 30 min) increased Gpr83 mRNA (3.5±0.06 vs 1.0±0.12-fold; P<0.05; n=4-5/group), the effect of which was blocked by the protein kinase A (PKA) inhibitor H-89 (20 µM, 1 h). In hRPTCs, phorbol myristate acetate (200 ng/mL, 30 min) which activates protein kinase C (PKC) decreased Gpr83 mRNA (0.43±0.2 vs 1.0±0.04-fold, P<0.05; n=4-5/group), effect that was partially blocked by the PKC inhibitor GF109203x (1µM, 1h). Stimulation of hRPTCs with ZnCl2 (100 µM, 1 h), an activator of Gpr83, increased AKT (2.5±0.5 vs 1.0±0.06-fold; P<0.05; n=4-5/group) and ERK1/2 (1.4±0.1 vs 1.0±0.08-fold; P<0.05; n=4-5/group) phosphorylation and decreased p-38 mitogen-activated protein kinase (MAPK) phosphorylation (0.1±0.05 vs 1.0±0.1-fold; P<0.05; n=4-5/group). Our results suggest that Gpr83 may protect against the development of salt sensitivity. PKA positively while PKC negatively regulates Gpr83 expression. Gpr83 function may be mediated by the phosphorylation of AKT/ERK1/2 and dephosphorylation of MAPK. Thus, several pathways are involved in the Gpr83-mediated regulation of salt-sensitive hypertension.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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Comments

Poster to be presented at GW Annual Research Days 2017.

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GPR83 function contributes to salt resistance

The G protein-coupled receptor (GPCR) 83 (Gpr83) is an orphan receptor belonging to the rhodopsin-like family of GPCRs. Gpr83 was originally identified as a glucocorticoid-induced transcript in a murine T cell line and referred to as glucocorticoid-induced receptor. Gpr83 is expressed in brain hypothalamic nuclei relevant to energy metabolism control and has a role in the central regulation of energy metabolism. Gpr83 is also expressed in the kidney but its function is unknown. We found that Gpr83 is expressed in mouse renal proximal and distal convoluted tubules, as well as in human renal proximal tubule cells (hRPTCs). High salt diet increased Gpr83 transcription by 2-fold (P<0.05; n=4/group) in Swiss Jim Lambert (SJL/J) and Bagg Albino (BALB/c) salt-resistant mice, relative to C57 Black (C57Bl/6J) salt-sensitive mice. In C57Bl/6J mice on normal salt diet, the lack of one (Gpr83+/-) or both Gpr83 (Gpr83-/-) alleles resulted in an increase in systolic blood pressure (SBP, ~20 mm Hg (P<0.05; n=4/group, measured under anesthesia) compared with Gpr83+/+ littermates, suggesting that Gpr83 is needed to keep a normal BP. Renal-specific Gpr83 silencing by the renal subcapsular infusion of Gpr83 siRNA (3 µg/day; 7 days) increased SBP in C57Bl/6J mice on a normal salt diet, relative to mice treated with non-silencing siRNA (120±5 vs 98±6 mmHg; P<0.05; n=4/group). In hRPTCs, forskolin (10 µM, 30 min) increased Gpr83 mRNA (3.5±0.06 vs 1.0±0.12-fold; P<0.05; n=4-5/group), the effect of which was blocked by the protein kinase A (PKA) inhibitor H-89 (20 µM, 1 h). In hRPTCs, phorbol myristate acetate (200 ng/mL, 30 min) which activates protein kinase C (PKC) decreased Gpr83 mRNA (0.43±0.2 vs 1.0±0.04-fold, P<0.05; n=4-5/group), effect that was partially blocked by the PKC inhibitor GF109203x (1µM, 1h). Stimulation of hRPTCs with ZnCl2 (100 µM, 1 h), an activator of Gpr83, increased AKT (2.5±0.5 vs 1.0±0.06-fold; P<0.05; n=4-5/group) and ERK1/2 (1.4±0.1 vs 1.0±0.08-fold; P<0.05; n=4-5/group) phosphorylation and decreased p-38 mitogen-activated protein kinase (MAPK) phosphorylation (0.1±0.05 vs 1.0±0.1-fold; P<0.05; n=4-5/group). Our results suggest that Gpr83 may protect against the development of salt sensitivity. PKA positively while PKC negatively regulates Gpr83 expression. Gpr83 function may be mediated by the phosphorylation of AKT/ERK1/2 and dephosphorylation of MAPK. Thus, several pathways are involved in the Gpr83-mediated regulation of salt-sensitive hypertension.