Jen Pluznick


Dept. Physiology, Johns Hopkins Univ. School of Medicine
Novel Sensory Receptors in ‘Non-Sensory’ tissues
• Taste receptors and olfactory
receptors play important roles in:
◦ Airway smooth muscle
◦ Bladder
◦ Spinal column
◦ Skeletal muscle
◦ GI tract
◦ Sperm
(Nature Medicine 2010; J Urology 2011, Nature Letters 2006,
Developmental Cell 2009; J Cell Science 2004, Science 2003;
Gastroenterology 2007)
• What about the kidney?
Novel Sensory Receptors in ‘Non-Sensory’ tissues
• Olfactory Receptor 78
(Olfr78) in the kidney and
blood pressure regulation
Spoiler Alert: Olfr78, Blood Pressure…and the Microbiome
• Olfactory Receptor 78
(Olfr78) in the kidney and
blood pressure regulation
The Economist, Microbes Maketh Man, Aug. 2012
Viruses, Fungi, and Bacteria…oh, my!
Marsland and Gollwitzer, Nature Reviews 2014
Microbiota and Host Physiology: an emerging field
'microbiota' articles per year
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Microbiota and Host Physiology:
what we do know vs. what we don’t know
Microbial cells outnumber human cells by 10:1.
Microbial genes outnumber human genes by 100:1.
Gut microbiota have been implicated in pathophysiological processes as varied as:
immune disorders, atherosclerosis, irritable bowel syndrome, coilitis,
obesity, type II diabetes, susceptibility to type I diabetes, metabolic
syndrome, susceptibility to HIV infection, chronic kidney disease…
(references: too many to cite!)
We are just beginning to understand
the implications of the microbiota,
let alone the mechanisms
underlying these interactions.
Olfr78 in the Kidney
One olfactory receptor expressed in the kidney is Olfr78 (PNAS 2009).
What is the physiological role of Olfr78?
Where is Olfactory Receptor 78 localized?
What is Olfactory Receptor 78 “smelling”?
Olfr78: localization
Olfr78 localizes to cell types important in blood pressure regulation.
renal afferent arteriole (100X)
vSMCs in resistance beds (diaphragm, 4X)
Olfr78 in the Kidney
What is the physiological role of Olfr78?
Where is Olfactory Receptor 78 localized?
Cells which play important roles in blood pressure regulation.
What is Olfactory Receptor 78 “smelling”?
Olfr78 is an “orphan receptor” – no known ligand!
Olfr78: a receptor for short chain fatty acids (SCFAs)
Identified acetate and propionate as ligands for Olfr78 and its human ortholog (hOR51E2)
Are SCFAs in plasma? What is their source?
Short Chain Fatty Acids (SCFAs) come from the gut microbiota!
SCFAs
Activates Olfactory Receptor 78
SCFAs modulate blood pressure via Olfr78
….and via another receptor called Gpr41
SCFAs
Gut Microbiota
Gpr41
Peripheral
Vasculature
↓Blood Pressure
Together, Olfr78 and Gpr41 modulate blood pressure control
JGA
Olfr78
Angiotensinogen
SCFAs
Gut Microbiota
↑Renin
Angiotensin I
ACE
Angiotensin II
Gpr41
Olfr78
Peripheral
Vasculature
~Blood Pressure
Blood Pressure and Hypertension
- Incidence: 29% of American Adults have high
blood pressure or ‘hypertension’ (CDC)
- Hypertension costs the US $46 billion/year in
health services, medication, and missed work.
(CDC)
- Another 1/3 of American adults are
“prehypertensive’ (CDC)
- ~95% of hypertension patients have “essential
hypertension” – hypertension with no known
cause
- Genes? Salt intake? Vitamin D? Stress? Obesity?
Alcohol? Combination of different factors?
- There is a need to better understand causes and
contributing factors: perhaps there is a role for
gut microbiota?
Is there evidence that microbial SCFAs affect BP regulation?
- Dysbiosis (changes in the gut microbiota) has been noted in two rat models
of hypertension, and in a small cohort of human patients (Hot off the press!
published March 31, 2015 and April 13, 2015)
- In humans:
- An increase in dietary fiber intake (which leads to elevated SCFA
production) decreases BP
- A meta-analysis of randomized controlled trials found that probiotic use
(which elevates SCFA production) was associated with lowered blood
pressure
- In a population of >4,000 humans from Asia and Europe, lower urinary
levels of formate (an SCFA produced by gut microbiota) are correlated
with higher BP
- Future studies needed!
AC Guyton 1972
Blood Pressure Control is Complex!!
Conclusion
SCFA activation of Olfr78 and Gpr41 represents a novel crosstalk pathway
through which colonic bacteria can modulate blood pressure control.
The Economist, Microbes Maketh Man, Aug. 2012
Acknowledgements
Yale
Michael Caplan
Tong Wang
Anne Eichmann
Jinah Han
Johns Hopkins
Niranjana Natarajan
Blythe Shepard
Victoria Halperin
Prem Rajkumar
Will Aisenberg
Omar Acres
Ryan Protzko
Dan Berkowitz
Nick Flavahan
Cindy Sears
Dan Peterson
USC (78 mice)
Janos Peti-Peterdi
Arnold Sipos
Haykanush Gevorgyan
Columbia (OR Signaling)
Stuart Firestein
Zita Peterlin
Thank you!
UT-Southwestern (41 mice)
Masashi Yanagisawa
Wash U. (41 mice, microbiota)
Jeffrey Gordon
Federico Rey
Funding: NIH-NIDDK, ASN Gottschalk, AHA (to NN), JHU GI Core Center