A Renal Olfactory Receptor Aids in Kidney Glucose Handling

Olfactory receptors (ORs) are G protein-coupled receptors which serve important sensory functions beyond their role as odorant detectors in the olfactory epithelium. Here we describe a novel role for one of these ORs, Olfr1393, as a regulator of renal glucose handling. Olfr1393 is specifically expressed in the kidney proximal tubule, which is the site of renal glucose reabsorption. Olfr1393 knockout mice exhibit urinary glucose wasting and improved glucose tolerance, despite euglycemia and normal insulin levels. Consistent with this phenotype, Olfr1393 knockout mice have a significant decrease in luminal expression of Sglt1, a key renal glucose transporter, uncovering a novel regulatory pathway involving Olfr1393 and Sglt1. In addition, by utilizing a large scale screen of over 1400 chemicals we reveal the ligand profile of Olfr1393 for the first time, offering new insight into potential pathways of physiological regulation for this novel signaling pathway. Olfactory receptors (ORs) are seven transmembrane domain G protein-coupled receptors (GPCRs) that serve as the chemical sensors of smell in the olfactory epithelium (OE). While these receptors were originally thought to be restricted to the nose 1 , it is now appreciated that ORs and other sensory receptors are found in a variety of other tissues where they play important physiological functions 2–9. We previously reported that at least 10 different ORs as well as their downstream signaling components (adenylate cyclase 3 and the olfactory G protein) are expressed in the kidney, and that one of these renal ORs contributes to blood pressure regulation 6,10. However, the functions of the remaining renal ORs have remained a mystery. In this study, we report for the first time the localization, ligand profile and physiological relevance of renal Olfactory Receptor 1393 (Olfr1393). We find that Olfr1393 localizes to all three segments of the renal proximal tubule, which is the site of renal glucose reabsorption. Typically, an individual's entire blood volume is filtered ~50 times/day, and because glucose is neither protein-bound nor complexed with macromolecules, it is freely filtered by the glomerulus 11,12. Under normal conditions, the proximal tubule reabsorbs the entirety of the ~180 grams of glucose filtered per day from the ultra-filtrate, such that no glucose is detected in the final urine. Glucose reabsorption in the proximal tubule is mediated by two apical sodium-glucose co-transporters: Sglt2 (SCL5A2) and Sglt1 (SLC5A1) 11–14. The low affinity , high-flux transporter, Sglt2, is localized to the apical membrane of the early proximal tubule (S1 and S2) and handles > 90% of all glucose reabsorption. The remaining glucose is cleared from the lumen by the high affinity, low-flux transporter, Sglt1, in the straight proximal tubule (S3). While these transporters have been extensively characterized and explored as potential drug targets for type II diabetes 11,15,16 , the understanding of their regulation within the proximal tubule is limited 17. Here, we report that Olfr1393 knockout (KO) mice present with euglycemic glycosuria and improved glucose tolerance. Consistent with this, we observe an altered distribution of Sglt1 in the proximal tubule of KO animals, implicating Olfr1393 as a novel contributor to renal glucose handling. Additionally, when we began these studies, Olfr1393 was an 'orphan' receptor with no known ligands; therefore, we undertook a ligand screen and identified 8 ligands for Olfr1393. In sum, these studies have uncovered a novel role for a renal OR in kidney glucose handling , and have identified a novel mechanism for potential physiologic regulation of Sglt1.