Olfactory receptors (ORs) are seven transmembrane domain G protein-coupled chemosensory receptors that serve as sensors of smell in the nose. Recently, studies have found that ORs and other chemosensors are also expressed outside of their native tissues, including in sperm, muscle and the spinal column, where they have important functional roles. We have previously reported that OR signaling also plays a role in the kidney and recently found one of these receptors, Olfr1393, to be found on the apical plasma membrane of the proximal tubule. Olfr1393 knockout (KO) mice present with euglycemic glycosuria and improved glucose tolerance. Thus, it appears that Olfr1393 plays a role in renal glucose handling. Glucose is freely filtered by the renal glomerulus, and nearly 100% of it is reabsorbed from the lumen of the proximal tubule by two sodium-glucose co-transporters, Sglt1 and Sglt2. These transporters handle all glucose reabsorption, and it is typically only during periods of hyperglycemia that glucose appears in the urine. In keeping with a function for Olfr1393 in glucose handling, we found that there is a 22% decrease in the luminal staining of Sglt1 in Olfr1393 KO mice, but no change in Sglt2. Thus, we propose that Olfr1393 is a novel regulator for Sglt1 in the renal proximal tubule. In this proposal, we are aiming to understand how Olfr1393 regulates Sglt1 by examining its ability to influence Sglt1 localization, expression or activity. In addition, we will examine Olfr1393 in the context of the only other known basal regulator of Sglt1, RS1. Finally, we are also investigating how Olfr1393 signaling functions in the progression of diabetes, and whether modulation can lower plasma glucose. To do that, we will induce diabetes in Olfr1393 wild type and KO mice and investigate their rise in plasma glucose, glucose tolerance, glomerular filtration rate and progression of neuropathy and vascular disease. The candidate's goals are to understand renal physiology and renal transporter regulation, and this proposal will be completed under the guidance of an experienced mentor team that includes accomplished renal physiologists and metabolic researchers. To accomplish this, the candidate will work with her mentors and the Professional Development Office to follow a career development plan that includes manuscript preparation, attending and presenting at international conferences and departmental seminars, mentoring of graduate and undergraduate students, and preparation of application materials.
Diabetes is a worldwide epidemic, and the consequence of high blood sugar can lead to a number of debilitating conditions. Currently, there is interest in identifying new therapeutic agents that can help reduce blood sugar in patients with diabetes. We recently found that olfactory receptors that govern your sense of smell in the nose are found in the kidney, and one of these was found to contribute to renal glucose handling. In this proposal, we are aiming to understand how this receptor controls blood glucose homeostasis, and whether modifying this receptor would be an effective therapeutic target.
|Nizar, Jonathan M; Shepard, Blythe D; Vo, Vianna T et al. (2018) Renal tubule insulin receptor modestly promotes elevated blood pressure and markedly stimulates glucose reabsorption. JCI Insight 3:|
|Shepard, Blythe D; Pluznick, Jennifer L (2017) Saving the sweetness: renal glucose handling in health and disease. Am J Physiol Renal Physiol 313:F55-F61|
|Shepard, Blythe D; Cheval, Lydie; Peterlin, Zita et al. (2016) A Renal Olfactory Receptor Aids in Kidney Glucose Handling. Sci Rep 6:35215|