March 27, 2012 | March 27, 2012 | The cover photo on a recent issue of the Kidney International journal came from a study by a UAMS graduate student that suggests the compound resveratrol may better protect the kidney from sepsis.

Joseph H. Holthoff, an M.D.-Ph.D. student in pharmacology in the UAMS Graduate School and College of Medicine, was the lead author of “Resveratrol improves renal microcirculation, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis-induced acute kidney injury.” The article appeared in a February issue of the journal and culminated work started three years ago when he was an undergraduate student working at UAMS through a pharmacology and toxicology summer research program.

An image from the study showing cell-damaging oxidation in the kidney was used on the cover of the journal.

“The study results showed some very exciting possibilities for protecting the kidney from damage caused by sepsis, which often become fatal,” Holthoff said.

Sepsis is a dangerous infection in the blood that can lead to multiple organ failure and death. The mortality rate of patients who develop acute kidney injury during sepsis nearly doubles. Sepsis is the 10th leading cause of death in patients aged 65 and older and the second leading cause of death in children up to age 14.

Holthoff said the effectiveness of treatment is often hampered because it’s not started until after a patient shows symptoms of sepsis, at which point it might be too late.

In this study, Holthoff and researchers in the lab of Philip Mayeux, Ph.D., a professor in the Department of Pharmacology and Toxicology in the College of Medicine, looked at a couple of conditions that injure the kidney during sepsis. In the kidney, sepsis can kickstart damaging oxidative stress – a chemical process that damages cells – and a reduction of blood flow to the organ causing further injury.

Injections of the substance resveratrol improved blood flow and decreased oxidative stress. Additional doses improved overall survival.

“If you can protect the kidney, you can better protect the patient,” Mayeux said. “The next step is to design drugs based on the resveratrol structure that are more protective of the kidney based on what we found in this study.”

Joining Holthoff and Mayeux as authors of the article were UAMS colleagues Zhen Wang; Kathryn A. Seely, Ph.D.; and Neriman Gokden, M.D.

The work drew a comment in the journal from researchers Manjeri A. Venkatachalam of the Department of Pathology at the University of Texas Health Science Center in San Antonio and Joel M. Weinberg, M.D., a professor in the Department of Internal Medicine of the University of Michigan Medical Center. The researchers said the study’s findings “open new avenues for research into long-unresolved issues in the pathophysiology of septic acute kidney injury.”

For Holthoff, the study culminates a chapter in his academic experience that stretches back to when he worked in Mayeux’s lab as part of that undergraduate summer research program. It was that first exposure to lab work that interested him in research.

The Gould native was on track toward medical school at the time. “I had not thought about research as a career option but I loved working that summer and it made me switch gears a little,” he said.

The tantalizing possibilities of discovery attracted him. “Every day I was like a kid on Christmas morning, hoping for new research data.”

Holthoff was lead author on a 2010 article in the journal Biochemical Pharmacology that laid the ground work for the latest study. “Resveratrol, a dietary polyphenolic phytoalexin, is a functional scavenger of peroxynitrite” documented the possibility of resveratol as an agent for protecting the kidney against oxidative stress-induced cell damage.

His work is being funded by an F30 award from the National Institutes of Health. An F30 award supports promising predoctoral applicants who have the potential to become productive, highly trained physician-scientists.

As an M.D.-Ph.D. student, he completed the first two years of medical school before focusing on doctoral studies. This June, he will return to medical school to finish his medical degree.