Matthew Sparks, MD, wants to know how blood pressure medications work and how we can make them work better. His research focuses on the maintenance of normal blood pressure and the pathogenesis of high blood pressure. Currently, Dr. Sparks is trying to understand how altering blood flow to the kidney affects sodium excretion and how that, in turn, affects blood pressure.
To do this, Sparks is working with a genetic knockout mouse model where the angiotensin receptor has been removed from vascular smooth muscle cells but is persevered throughout the rest of the body.
“One of the largest classes of drugs used to treat hypertension blocks either the formation of angiotensin II or the angiotensin II receptor itself,” Sparks said. “Even though these drugs are widely used to treat patients with hypertension, we don’t know precisely how they work.”
Sparks, a medical instructor in the Division of Nephrology, will present “Role of Vascular Angiotensin Receptors in Blood Pressure Control” and kick off the 2014-15 Medicine Research Conference series at noon on Fri., Sept. 26, in Duke North Room 2002.
Hypertension is one of the most common medical conditions seen in the world, but the control of high blood pressure remains suboptimal – even though there are drugs and treatments, Sparks said. Additionally, blood pressure medications that are widely used have a number of negative side effects, such as high potassium, low blood pressure or acute kidney injury.
“We want to find a way to minimize the untoward effects and maximize the positive effects of the medications that are currently being used,” Sparks said. “We are also interested in understanding basic mechanisms that govern blood pressure control and hypertension pathogenesis.”
Not only does the hormone angiotensin II lead to constriction of blood vessels throughout the body, it also impairs blood flow to the kidney, which in turn could regulate sodium excretion.
“Prior studies have shown that the long-term determination of your blood pressure is heavily influenced by how much sodium is excreted by the kidney,” Sparks said.
When angiotensin II is present (in both normal physiology and in pathophysiology), it constricts blood vessels, causing blood pressure to rise. With the mouse model, Sparks is focusing on how removing the angiotensin receptor only from vascular smooth muscle, but not in other tissues, affects blood pressure. His lab has found that in this mouse model blood continues to flow freely to the kidney when angiotensin II is given to the mouse. “The vascular smooth muscle angiotensin receptor appears to be important in determining the mouse’s normal resting blood pressure,” Sparks said. “Furthermore, when we implanted an angiotensin II pump into the mouse, which is the model of high blood pressure that is commonly used in laboratories throughout the world, the mice had about a 50 percent reduction in the hypertensive response. Our findings suggest that this protection from experimentally induced hypertension is secondary to the persevered renal blood flow in states on angiotensin II excess, which in turn leads to more sodium excretion by the kidney.”
Tracing the connections
Sparks said his research has had some surprising findings. For example, he has found a link between vascular smooth muscle angiotensin receptors and the sympathetic nervous system. “It seems to be a way that angiotensin II can stimulate the sympathetic nervous system to cause systemic blood vessels to constrict independently of the vascular angiotensin receptor, he said. “We think that a lot of the ways in which the body reacts to stimuli to cause high blood pressure are redundant -- that maintaining blood flow to the kidney could be an important mechanism to lower blood pressure in other scenarios besides just angiotensin II -- if we can understand how this system works, we might be able to design new drugs to treat hypertension.” Sparks said his future work will focus on trying to understand the mechanism by which changes in blood flow to the kidney affects sodium excretion. He is in the process of examining how sodium transporters in the kidney are altered in this mouse model both at baseline and after experimentally induced hypertension. Sparks also is interested in studying how cardiac hypertrophy develops in patients with high blood pressure. He wants to understand if cardiac hypertrophy is the result of directly stimulating angiotensin receptors in the heart or a consequence of high blood pressure. There is also a connection to patients with diabetes. “These drugs are commonly used in diabetes, so we are applying the same model of removing angiotensin receptors from vascular smooth muscle to a diabetes mouse model and examining how over time those mice develop kidney damage,” Sparks said. “Will this be protective? Will the mice get less kidney damage? We don’t really know how these drugs work in protecting the kidneys in diabetes so these will be important questions as well.” Sparks’ research is funded by a five-year VA Career Development Award, and he received seed funding through the Chair’s Research Award in 2011. He works closely with mentor Tom Coffman, MD, professor of medicine and chief of the Division of Nephrology. “Matt has terrific potential as a physician-scientist,” Dr. Coffman said. “He is curious, motivated, and absolutely dedicated to pursuing an academic career. He has been a great contributor to our lab and now is developing his own independent lines of investigation.”
Growing as an investigator
Sparks credits his early success to the mentoring he has received as well as the many resources available to junior investigators in the Department and School of Medicine. He participated in programs such as the Faculty Development Academy, K Club, the LEADER program, and Gopen grant writing courses. “Taking advantage of these programs has really helped me gain collaborations, diversifying my research, and most importantly allowed other eyes on my work,” he said. Sparks’ advice for trainees is to be persistent in applying for and attending these programs. Give your grant proposals to researchers outside of your lab to read and critique to make sure they are easy to understand. Take advantage of programs like the K Club when writing your first career development award. Lastly, learn as many skills as you can and make good use of the core facilities available at Duke. Social media and academics
Besides the research he is doing on hypertension, Sparks also is interested in the use of social media in medical education. He is co-founder of eAJKD, a blog associated with the American Journal of Kidney Diseases. “We’re using the blog to talk about the content from the journal as well as discuss recent advances in the field,” Sparks said. “We’ve also used games to teach important concepts and emerging research in nephrology in a fun way, such as NephMadness, a tournament of nephrology concepts modeled after the NCAA basketball tournament. This has been a great experience that has also deepened my knowledge of nephrology.” Sparks is currently working on a study surveying chairs of medicine and pediatrics throughout the U.S. to see what their opinion and awareness is of blog use among their faculty and how those endeavors affect promotion and tenure. “I think Duke is right on the cutting edge in terms of integrating blogs and social media into the culture of academia,” Sparks said. “I’m interested in setting the stage for this because it will be important to legitimize social media as a bonafide part of a faculty member’s scholarly activity.” Sparks came to Duke as a nephrology fellow in 2007. He attended the University of Arkansas for Medical Sciences College of Medicine and remained there for residency and a chief resident year.