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GPR83 function contributes to salt resistance
Author(s) -
Patel Milan,
Zheng Xiaoxu,
Asico Laureano,
Konkalmatt Prasad,
Jose Pedro A,
Armando Ines
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1027.4
Subject(s) - medicine , endocrinology , chemistry , protein kinase c , forskolin , receptor , messenger rna , gene silencing , distal convoluted tubule , kidney , kinase , biology , gene , biochemistry , reabsorption
The G protein‐coupled receptor 83 (Gpr83) is an orphan G protein‐coupled receptor that is 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 SJL/J and BALB/c salt‐resistant mice, relative to 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 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 GF109203× (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 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.