Fasting results in significant changes in the distribution of body fluids, leading to a decrease in blood pressure and circulatory volume. Lately, several primary gastrointestinal hormones and orphan receptors in taste and olfaction have been implicated in the regulation of renal function1-5, and hence, one can speculate that appetite-regulating signalling might be responsible for the circulatory volume contraction observed in response to anorectic states. Activation of the orphan receptor GPR39 of the ghrelin receptor family in the gastrointestinal tract results in local GLP-1 release and a following decrease in food intake and weight reduction in mice6. In the current study, oral gavage of a selective GPR39 agonist (Cpd1324) increases the water intake in C57BL/6J mice. The effect is dose-dependent fashion, and results in over two-fold increase in 24-hour water intake relative to vehicle controls, an effect that was completely absent in global GPR39 deficient mice. Cpd1324 markedly reduced the urinary concentrate capacity in C57BL/6J mice after eight hours of water restriction (1927.0±129.3 mosmol/kg, n=5) compared to vehicle controls (3196.0±139.9 mosmol/kg, n=5, p<0.001). In ex vivo perfused cortical collecting ducts, GPR39 (10µM) directly counteracted the AVP-induced water permeability, corresponding to a Cpd1324-induced around 50% reduction in phosphorylated AQP2 (S256) abundance assessed by immunoblotting of renal tubule suspension. GPR39 activation also reduced the amount of phosphorylated NCC in distal convoluted tubules, with a parallel increase in urinary K+ excretion. These data suggest that the Cpd1324-induced drinking behaviour is secondary to a urinary concentration deficiency caused by opposing AVP-induced water reabsorption in the collecting duct. Moreover, we propose that a GPR39-dependent urine concentration defect and reduced NaCl reabsorption in the distal convoluted tubule might explain the circulatory volume contraction observed during fasting.
Physiology in Focus 2024 (Northumbria University, UK) (2024) Proc Physiol Soc 59, SA38
Research Symposium: Direct activation of renal, Ghrelin-family GPR39 receptors reduces urinary concentration capacity
Lingzhi Lui1, Mackenzie Kui1, Lena L Rosenbaek1, Samuel L Svendsen1, Annemette Overgaard Brethvad1, Alexander Jakobsen1, Mattias Skov1, Jacob R Therkildsen1, Jesper Kingo Andresen1, Anna Laitakari1, Thomas Michael Frimurer1, Boye Lagerbon Jensen1, Jennifer Pluznick1, Robert A Fenton1, Birgitte Holst1, Helle Praetorius1,
1Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, University of Copenhagen Copenhagen Denmark, 2Department of Physiology, Johns Hopkins University School of Medicine Baltimore United States, 3Department of Biomedicine, Aarhus University Aarhus Denmark, 4Section of Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen Copenhagen Denmark, 5The Faculty of Health Sciences, Department of Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark Odense Denmark,
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Where applicable, experiments conform with Society ethical requirements.