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Dr. Jennifer Pluznick: Olfactory Receptors in the Kidney and the Gut-Microbe Signal

Olfactory receptors are known by a single address — the nose. But a microarray Dr. Jennifer Pluznick ran as a postdoctoral fellow placed them, surprisingly, at the top of a kidney gene expression list. She almost dismissed the result as an artifact. Instead, she followed it, and the decision has shaped the direction of her lab at Johns Hopkins ever since.

In this conversation, Dr. Pluznick explores what changes when olfactory receptors are treated not as smell receptors but as general-purpose chemosensors — scattered across the body and tuned to ligands circulating in the blood. She walks through the kidney ORs her group has connected to renin release, to proximal tubule glucose handling, and to blood pressure regulation. One of those receptors is activated by small-molecule metabolites produced by gut microbes, a finding she still calls mind-blowing and that she continues to unpack.

The conversation also surfaces the field's quiet bottlenecks: the trafficking problem that traps ORs in the ER, the orthology gap between 1,000 mouse receptors and 350 human ones, and the reagents — antibodies, agonists, antagonists — that the community still does not have.

About the Guest

Dr. Jennifer Pluznick is Associate Professor of Physiology at Johns Hopkins University School of Medicine. Her lab studies the role of understudied GPCRs — olfactory receptors, taste receptors, and orphan GPRs — in kidney physiology. Her group has linked specific kidney olfactory receptors to blood pressure regulation via the renin-angiotensin pathway, to glucose handling in the proximal tubule, and to circulating metabolites generated by the gut microbiota. She first encountered olfactory receptors in the kidney during her postdoctoral training, and her lab continues to deorphanize and functionally characterize them today.

Scientific Themes of the Conversation

Olfactory receptors as general-purpose chemosensors outside the nose
Deorphanization strategies for kidney-expressed GPCRs
The renin-angiotensin axis and OR-mediated blood pressure control
Gut microbiota metabolites as endogenous GPCR ligands
Receptor trafficking and the ER-retention problem for ectopically expressed ORs
Mouse-to-human orthology in a highly expanded receptor family

Key Insights from the Conversation

A surprise at the top of a microarray. When Dr. Pluznick's postdoc screen flagged olfactory receptors as top hits in a kidney disease cell line, her first instinct was to distrust the data. A single comment from her advisor — olfactory receptors in the kidney could actually be really cool — reframed a possible artifact as a research program.

Reframing olfactory receptors as chemosensors. The name "olfactory receptor" narrows the imagination. Dr. Pluznick argues they are better understood as chemical sensors that happen to dominate the nose. Once reframed that way, ectopic expression in tissues like the kidney stops seeming strange and starts making sense.

Two kidney ORs with physiology attached. One OR her lab has studied modulates renin release and therefore blood pressure; another regulates glucose handling through a transporter family that includes a validated type 2 diabetes target. Both started as receptors with no known ligand, no known localization, and no reason to expect physiological relevance.

Gut microbes at the other end of the signal. The OR linked to blood pressure is activated by small-molecule metabolites produced by gut bacteria at low millimolar circulating concentrations. That makes blood pressure regulation, in part, a readout of microbial metabolism — a connection Dr. Pluznick describes as something that still blows her mind.

Trafficking as a field-wide bottleneck. Exogenously expressed ORs tend to get stuck in the ER. Matsunami's RTP1S chaperone, the Rho tag, and the Pluznick lab's Lucy tag — a cleavable leucine-rich signal sequence developed by a rotation student — each help, but no combination fully solves the problem for every OR. The trafficking failure itself may encode something about how tightly ORs are regulated in olfactory sensory neurons.

The orthology gap. Mice have ~1,000 olfactory receptors; humans have ~350. Sequence-based orthology calls are often ambiguous, and in the Pluznick lab's hands, putative orthologs frequently fail to share ligand profiles. Finding functional orthologs — not just sequence matches — is non-trivial, and it matters for anyone hoping to translate kidney OR biology into a human drug.

Follow the data that surprises you. Dr. Pluznick's advice to early-career scientists is shaped by her own near-dismissal of an inconvenient microarray result. Established assumptions about where a receptor "belongs" are often what stop a discovery from being recognized as one.

Episode Timeline

Timestamps were generated using AI for readability.

00:00 Opening: newsletter, season close, and welcome

02:13 Becoming a scientist as a first-gen college student

04:17 The case for chasing understudied GPCRs in the kidney

06:18 "Olfactory receptors will always be my first love"

08:45 Renin, blood pressure, and a glucose-handling receptor

12:14 Localization and ligand screening when there's no antibody

17:06 What happens to OR expression in a disease kidney

19:56 The orthology problem: 1,000 mouse ORs, 350 human ones

23:08 RTP1S, the Rho tag, and the Lucy tag

29:20 One-neuron-one-receptor and the tight regulation of smell

36:57 The aha moment: gut microbes, a GPCR, and blood pressure

39:58 Diversity as everyone's responsibility

Selected Quotes

"I famously said that I wasn't sure I could really trust the data because these crazy receptors came out as the top hits. But my postdoc advisor, who's much wiser than I, said, 'olfactory receptors in the kidney, though — that could be really cool.' And somehow when he said it, it sounded like a much better idea."

"Olfactory receptors as a class will always be my first love in terms of GPCRs."

"Your blood pressure regulation is somehow tied to the activity of your gut microbes. And that is something that still kind of blows my mind."

"You need to follow your data, even when it surprises you, even when it might go against what you assumed to be true before you started the experiment."

About this episode

Dr. Pluznick discovered that olfactory receptors in mice are also expressed in their kidneys and blood vessels. Her research is focused on the role of chemosensory GPCRs in regulating renal and cardiovascular function, and identifying renal/cardiovascular olfactory receptor ligands, and relating them to whole-animal physiology. This work contributes to a better understanding of how the kidney helps maintain homeostasis in humans.

Jennifer is currently an assistant professor of physiology at the Johns Hopkins School of Medicine. She received her undergraduate degree in biology from Truman State University and earned her Ph.D. in renal physiology from the University of Nebraska Medical Center. She then spent five years training as a postdoctoral fellow in the laboratory of Michael Caplan at Yale University, where she studied both renal physiology and sensory biology systems and focused on olfaction.

Dr. Jennifer Pluznick on the web