Revising molecular maps to hypertension and organ damage

Tuesday, December 12, 2017

In 2016, the Duke School of Medicine selected 38 of its faculty for the new Duke Health Scholars and Duke Health Fellows Program. With funds from the Duke University Health System, the program supports the research efforts of early to mid-career clinician-scientists at Duke. Among the faculty honored are 14 individuals from the Department of Medicine, including Steven Crowley, MD, associate professor of medicine (Nephrology).

It was the chance to try to help people, even at their sickest, that drew Dr. Steven Crowley to medicine 25 years ago.

Today the nephrologist still sees patients at the Durham VA Medical Center, but he spends much more time decoding how immune system cells contribute to hypertension and organ damage in his laboratory.

Still, the mission endures.

“The most important aspect of our work is to show solidarity with our patients. That is something we can always do, regardless of the stage of their illness,” says Crowley, whose research may lay groundwork for needed improved treatments.

In animal studies, Crowley is clarifying the molecular roles immune cells play in hypertension, a growing global public health threat. He has discovered that such cells can both contribute to and regulate high blood pressure. He also has unmasked ways that inflammation created by immune cells harms organs, including kidneys.

When asked about what drew him to medicine, Crowley indicated that shadowing a primary care doctor, a family friend, at St. Francis Hospital in his hometown of Columbus, GA, was influential.

“What sealed the deal for me were the patients, two with cancer, who had not responded to therapy. I was really struck by this doctor’s commitment to his patients even though he had no other pharmaceutical option available to help them,” Crowley says.

Crowley was introduced to research during his third year of medical school at Duke, after he and classmates fanned into laboratories to participate in the sort of biomedical studies that push clinical care forward. In the lab of David Pisetsky, PhD, MD, Crowley learned a good bit about contemporary scientific questions in immunology.

“He kindled a spark within me to study immunity and inflammation,” Crowley says. “But he also appealed to the side of me interested in what it all means. He’d ask ‘What are patients going through?’”

Crowley found himself drawn to nephrology as a clinical specialty due to caliber of the division’s faculty, he says. The field’s clinical tools appealed to him, too. Having majored in Applied Mathematics as an undergraduate, he particularly appreciated the reliability of the numbers produced by lab studies that help doctors diagnose what was ailing their patients.

After his first year of nephrology fellowship and a year as chief medical resident, he joined the lab of then division chief Thomas Coffman, MD, who was part of a drive to better understand precisely how kidneys influence serious disorders such as hypertension, chronic kidney disease and cardiovascular disease.

In studies with mice, Crowley has since discovered ways that innate and adaptive immune responses, including the activation of myeloid cells, contribute to hypertension, kidney injury and heart damage. He has shown, for instance, that activation of T cells promotes sodium retention in the kidney leading to blood pressure elevation.

Crowley also has documented that immune-regulation pathways can protect the kidneys, complicating our view of the biological risks and benefits in play. For example, he has shown that one immune system suppressing agent, mycophenolate moftil, decreases the infiltration of inflammation-producing T lymphocytes into kidneys and limits kidney injury during hypertension through blood pressure-independent mechanisms.

“This finding challenged the dogma that hypertensive renal damage resulted solely from blood pressure,” says Kenneth Lyles, MD, professor of medicine (Geriatrics) and a member of the Department of Medicine research leadership team.

Crowley intends to dive deeper to better pinpoint which immune cell subpopulations contribute to these processes. He’s also exploring whether some of his laboratory’s insights might be of use in the clinic sooner rather than later.

He is working his way to possibly testing whether disrupting an immune response, specifically by disrupting IL-1 receptor activation, reduces blood pressure in people with treatment-resistant hypertension and chronic kidney disease.

“Steve is the major pioneer in a rapidly evolving, high impact field,” says Myles Wolf, MD, MMSc, chief of the Division of Nephrology.

Over the long term, Crowley hopes his lab’s mapping of immunological mechanisms relevant to hypertension and organ damage could produce targets for the cell-specific therapies that medical scientists are working on developing at Duke and elsewhere.

“I do think cell-specific therapy is going to be the next level of pharmacological intervention. When the opportunity for cell-specific treatments arises, we will need to know, for instance, where mediators called cytokines produced by immune cells are operating,” Crowley says. “I can get excited about that.”

The series of profiles of our Duke Health Scholars were written by Catherine Clabby, freelance science journalist. Photos are by Ted Richardson.