A Renal Olfactory Receptor Aids in Glucose Handling in the Proximal Tubule

Abstract

Olfactory receptors (ORs) are seven transmembrane‐domain G protein‐coupled chemosensors that detect odorants in the nose. We previously reported that ORs play roles in the kidney, and identified 9 renal ORs including Olfr1393. In reverse‐transcribed RNA from microdissected renal segments, Olfr1393 is exclusively expressed in the proximal tubule (PT; S1, S2 and S3). When stably expressed in polarized MDCK cells, Olfr1393 localizes to the apical plasma membrane (PM), but not to cilia. Because Olfr1393 is an “orphan receptor” with no known ligand, we screened over 1400 chemicals and found that Olfr1393 detects preconstrained cyclic molecules containing carbonyl or alcohol groups. To determine the physiological role of Olfr1393, we generated knockout (KO) mice. At baseline, KO mice are similar to wild‐type (WT) littermates with regard to plasma electrolytes, blood pressure and GFR (measured via iStat, tail cuff, and elimination kinetics of plasma sinistrin). However, despite being euglycemic, KO mice exhibit glycosuria (1.4x increase in glucose/creatinine vs WT) and can better handle a glucose challenge during a glucose tolerance test as indicated by plasma glucose values (area under curve: WT 22.4 ± 1.9 vs KO 15.7 ± 1.1; P = 0.001). These data suggest that Olfr1393 helps to regulate glucose reabsorption on the apical PM of the PT. In support of this, preliminary data suggests that heterologously expressed Olfr1393 can co‐immunoprecipitate with Sglt1 and Sglt2, the two Na+/glucose co‐transporters responsible for apical glucose reabsorption. We are currently examining the possibility that Olfr1393 influences the function of these transporters to regulate PT glucose handling.Funding: ASN, NIDDK