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The in vivo role of the pH‐sensing receptor GPR4 in acid‐base and electrolyte homeostasis
Author(s) -
Velic Ana,
Benabbas Chahira,
Suply Thomas,
Seuwen Klaus
Publication year - 2007
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.21.6.a1415
Subject(s) - net acid excretion , metabolic acidosis , medicine , acidosis , endocrinology , homeostasis , chemistry , excretion , receptor , renal tubular acidosis , extracellular , extracellular fluid , nephron , intracellular ph , kidney , biochemistry , biology
The proton‐sensing G protein‐coupled receptor GPR4 is expressed in different organs including the kidney and increases intracellular cAMP levels upon a decrease in extracellular pH in transfected cells. We found GPR4 expressed in several nephron segments. We examined the phenotype of male GPR4 KO mice, under control conditions and under different dietary protocols. GPR4 KO mice are smaller than their litter mates and exhibit a mild metabolic acidosis with a higher anion gap, hypernatriemia and hyperkaliemia. After a 24 hrs acidosis challenge acid‐base status was similar in both genotypes and both groups showed appropriate respiratory compensation. After 7 days of acidosis challenge KO mice showed a more pronounced acidosis with a lower pCO2. Urine analysis demonstrated in the KO mice lower urine volumes, higher osmolality, normal pH, and lower Na+, K+, Mg2+ and Ca2+ excretion. During short acid loading, urine pH decreased appropriately but net acid excretion remained lower in the KO animals, while after prolonged acid loading Ca2+, phosphate, ammonia and Cl− excretion were increased. However, RT‐PCR showed similar mRNA levels of Mg2+ and Ca2 transporter proteins calbindin, TRPV5 and TRPM6. Immunoblotting showed increased expression of the Na+ transporting protein NCC. This resulted in higher urine volume output in KO after treatment with the NCC inhibitor hydrochlorothiazide. Thus GPR4 is required for normal acid‐base and electrolyte balance and may regulate expression and/or function of renal transport proteins. The mouse model identifies the pH‐sensing receptor GPR4 as critical for normal systemic acid‐base status and electrolyte handling by the kidney.