Renal Ghrelin-Family GPR39 Receptor and Urinary Concentrating Ability

Low-calorie intake is associated with substantial changes in volume distribution and volume status in the body, resulting in reduced circulatory volume and a reduction in blood pressure. Activation of the orphan receptor GPR39 dampens food intake and causes weight loss in a GLP-1-dependent fashion. We speculated that appetite-regulating signaling might also be responsible for the circulatory volume contraction observed in response to anorectic states. To assess the effect of GPR39 fluid homeostasis, we combined in vivo, ex vivo, and in vitro studies to assess the effect of a selective GPR39 agonist (Cpd1324). Oral gavage of Cpd1324 dose-dependently increased the water intake of wild-type (WT) C57BL/6J mice only and was completely absent in global GPR39 knockout (KO) mice. GPR39 is expressed in the distal convoluted tubule and collecting duct of the kidney, and WT mice exclusively showed Cpd1324-induced increase in urine production, increased K+ excretion, and reduced urine concentrating capacity both at baseline and after an 8-hour water restriction compared to vehicle controls. Correspondingly, Cpd1324 reduced AVP-induced cAMP production and directly counteracted the AVP-induced water permeability in perfused cortical collecting ducts. Moreover, specific GPR39 activation reduced the baseline and AVP-stimulated abundance of phosphorylated pS256-AQP2 and pT58-NCC and diminished the AVP-stimulated pS269-AQP2 abundance in renal tubular suspensions. These effects were seen exclusively in GPR39 wild-type mice and not in KO mice. These data suggest that Cpd1324 directly targets renal GPR39 to induce increased diuresis and consequently stimulate drinking behavior. We conclude that activation of GPR39 causes diuresis by opposing AVP-induced Na+ and Cl- reabsorption in the distal convoluted tubule and water reabsorption in the collecting duct.