A Renal Olfactory Receptor Aids in Kidney Glucose Handling

Olfactory receptors (ORs) are G protein‐coupled receptors which serve to detect odorants in the nose. Recently, ORs have been shown to play novel roles beyond odorant detection in a number of tissues, and we previously determined that a subset of ORs are expressed in the kidney. One of these ORs is Olfr1393, which we now report plays a novel role in renal glucose handling. In the absence of a reliable Olfr1393 antibody, we localized this receptor using reverse‐transcribed RNA from microdissected renal segments. These studies showed that Olfr1393 is exclusively expressed in the proximal tubule (PT; S1, S2 and S3), the site of renal glucose reabsorption (n=3 mice, PCR products sequenced to confirm). When stably expressed in polarized MDCK cells, Olfr1393 localizes to the apical plasma membrane, but not to cilia, indicating that Olfr1393 likely localizes apically in vivo . We generated whole‐animal Olfr1393 knockout (KO) mice and found that they 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, respectively). However, Olfr1393 KOs exhibit urinary glucose wasting (1.4× increase in glucose/creatinine vs WT; P = 0.01) despite being euglycemic under both fed and fasted conditions, with normal insulin levels. Olfr1393 KOs also have improved glucose tolerance as measured by a glucose tolerance test (area under curve: WT 20.4 ± 1.6 vs KO 16.3 ± 1.1; P = 0.008). Consistent with a role in renal glucose reabsorption, Olfr1393 co‐immunoprecipitates with Sglt1 and Sglt2, the two Na + /glucose co‐transporters responsible for apical glucose reabsorption. When Sglt1 and Sglt2 were localized within the kidney, we detected a 22% decrease in the luminal expression of Sglt1 in Olfr1393 KO mice, but no change in Sglt2. These data suggest that Olfr1393 is a novel regulator of Sglt1. In addition, as Olfr1393 is an orphan receptor with no known ligands, we utilized a large scale screen of over 1400 chemicals to determine the ligand profile of Olfr1393 (see abstract 987). Together, this data offers new insight into potential pathways of physiological regulation for this novel signaling pathway. Support or Funding Information NIDDK, ASN