Pannexin 1 Channels Control the Hemodynamic Response to Hypoxia by Regulating O<sub>2</sub>-Sensitive Extracellular ATP in Blood.
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2021-01-15
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Abstract
Pannexin1 (Panx1) channels export ATP and may contribute to increased concentration of the vasodilator ATP in plasma during hypoxia in vivo. We hypothesized that Panx1 channels and associated ATP export contributes to hypoxic vasodilation, a mechanism that facilitates the matching of oxygen delivery to tissue metabolic demand. Male and female mice devoid of Panx1 (Panx1-/-) and wild-type controls (WT) were anesthetized, mechanically ventilated, and instrumented with a carotid artery catheter or femoral artery flow transducer for hemodynamic and plasma ATP monitoring during inhalation of 21% (normoxia) or 10% oxygen (hypoxia). ATP export from WT vs. Panx1-/- erythrocytes (RBC) was determined ex vivo via tonometer experimentation across progressive deoxygenation. Mean arterial pressure (MAP) was similar in Panx1-/- (N=6) and WT (N=6) mice in normoxia, but the decrease in MAP in hypoxia seen in WT was attenuated in Panx1-/- mice (-16±9% vs -2±8%; P<0.05). Hindlimb blood flow (HBF) was significantly lower in Panx1-/- (N=6) vs. WT (N=6) basally, and increased in WT but not Panx1-/- mice during hypoxia (8±6% vs -10±13%; P<0.05). Estimation of hindlimb vascular conductance using data from the MAP and HBF experiments showed an average response of 28% for WT vs -9% for Panx1-/- mice. Mean venous plasma ATP during hypoxia was 57% lower in Panx1-/- (N=6) vs WT mice (N=6) (P<0.05). Mean hypoxia-induced ATP export from RBCs from Panx1-/- mice (N=8) was 82% lower than from WT (N=8) ( P<0.05). Panx1 channels participate in hemodynamic responses consistent with hypoxic vasodilation by regulating hypoxia-sensitive extracellular ATP levels in blood.
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Kirby, Brett S, Matthew A Sparks, Eduardo R Lazarowski, Denise A Lopez Domowicz, Hongmei Zhu and Timothy J McMahon (2021). Pannexin 1 Channels Control the Hemodynamic Response to Hypoxia by Regulating O2-Sensitive Extracellular ATP in Blood. American journal of physiology. Heart and circulatory physiology. 10.1152/ajpheart.00651.2020 Retrieved from https://hdl.handle.net/10161/22272.
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Scholars@Duke
Matthew A. Sparks
Nephrology Fellowship Program & Medical Education Leadership
I serve as the Program Director for the Nephrology Fellowship Program, where my primary goal is to support each fellow in building a successful and fulfilling career—whether in clinical practice, research, education, or advocacy. I am also the lead for the Society for Early Education Scholars (SEEDS) within the Department of Medicine. SEEDS is a year-long, mentored education program designed for fellows pursuing careers as clinician educators or education scholars.
My passion lies in advancing medical education, particularly in nephrology. I am the co-founder and advisory board member of the AJKD Blog, the first nephrology blog affiliated with a major journal—the American Journal of Kidney Diseases. I co-created NephMadness, a widely recognized and innovative educational initiative. I previously served as deputy editor of the Renal Fellow Network, where I remain actively involved as faculty lead.
I am also a member of the Board of Directors of NephJC, a nonprofit organization that champions free, open-access medical education in nephrology. Nationally, I serve on the Nephrology Board of the American Board of Internal Medicine, past chair of the Scientific and Clinical Education Lifelong Learning Committee of the American Heart Association’s Kidney in Cardiovascular Disease Council, and am a Fellow of the American Society of Nephrology (ASN), American Heart Association (AHA), and National Kidney Foundation (NKF). I serve as advisory board member and associate director of NephSIM Nephrons virtual mentorship program for trainees interested in nephrology.
Additionally, I serve as the Director of Communication for the ASN Portfolio of Journals, including JASN, CJASN, and Kidney360.
Past Research
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Hypertension and Kidney Hemodynamics: My past research delved into the mechanisms of blood pressure regulation, focusing on the renin-angiotensin system and prostanoid pathways. Utilizing genetically modified mouse models, you investigate how alterations in renal microcirculation influence sodium excretion and blood pressure, aiming to identify novel therapeutic targets for hypertension.
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SGLT2 Inhibitors and Kidney Disease: I have contributed to understanding the pathophysiology of kidney diseases and the mechanisms of action of SGLT2 inhibitors, highlighting their role in managing chronic kidney disease and associated cardiovascular risk.
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My clinical interests are glomerular diseases- particularly IgA nephropathy, membranous nephropathy, C3 glomerulopathy, and lupus nephritis.
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I also have expertise in genetic kidney diseases, ADPKD, quality improvement in outpatient nephrology, and CKRT in the ICU.
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I serve as the director of the Duke Nephrology Fellow Clinic
Awards and Honors
- Excellence in Education Award, Duke Department of Medicine, 2016
- Young Physician-Scientist Award, American Society for Clinical Investigation (ASCI), 2017
- Midcareer Distinguished Educator Award, American Society of Nephrology (ASN), 2022
Listen to my podcasts:
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The Nephron Segment
Connect with me on BlueSky: @NephroSparks
Timothy Joseph McMahon
The McMahon Lab at Duke University and Durham VA Medical Center is investigating novel roles of the red blood cell (RBC) in the circulation. The regulated release of the vasodilator SNO (a form of NO, nitric oxide) by RBCs within the respiratory cycle in mammals optimizes nutrient delivery at multiple levels, especially in the lung (gas exchange) and the peripheral microcirculation (O2 transport to tissues). Deficiency of RBC SNO bioactivity (as in human RBCs banked for transfusion), for example, appears to contribute to the serious lung and circulatory problems associated with RBC transfusion in some settings. We have also demonstrated benefit in the use of treatments that exploit RBCs as a vehicle for delivery of SNOs, in both human patients and in model animals.
RBCs also release ATP in response to stimuli including deformation and hypoxia, and the exported ATP also participates in the maintenance of a healthy circulation, according to mechanisms that we are now unraveling.
We use basic and translational approaches to understand the molecular mechanisms by which these RBC-derived signals effect circulatory changes in human health and disease, particularly in the lung. Disease states driving this research include acute and chronic lung diseases such as sepsis (severe infection, such as COVID-19), transfusion-related respiratory problems, sickle cell disease, and pulmonary hypertension of adults and newborns.
Funding: VA and NIH.
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