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. Here we examined the phenotype of male GPR4 KO mice. GPR4 KO mice are smaller than their litter mates and exhibit a mild metabolic acidosis, hypernatremia and hyperkalemia. 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 in the control KO mice showed lower urine volume, 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, and Cl- excretion were increased. However, mRNA levels of Mg2+ and Ca2+ transporter proteins calbindin, TRPV5 and TRPM6 was unchanged. Thus GPR4 is required for normal acid-base and electrolyte balance and may regulate expression and/or function of renal transport proteins. This mouse model identifies the pH-sensing receptor GPR4 as critical for normal systemic acid-base status and electrolyte handling by the kidney.