David Ellison, M.D., professor of medicine at Oregon Health & Science University and staff physician at the Portland VA Medical Center, leads a group that has been studying causes of human hypertension. In a paper published September 24th in the Journal of Clinical Investigation, “Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3”, the group identified a novel and unexpected mechanism for this hypertensive disease. This research was done in collaboration with groups in Mexico City and Berlin, and here in Portland with Portland State University, a partnership formed through the new Collaborative Life Sciences Building. This work was led jointly by Dr. Jeffrey Singer from Portland State University.
Jeffrey Singer, James McCormick and David Ellison in the lab
According to the Centers for Disease Control and Prevention, about one in three adults in the U.S.—or 67 million people—have high blood pressure. This common condition increases the risk for heart disease and stroke, two of the leading causes of death for Americans. While physicians have a number of medications that are used to treat hypertension, often successfully, overall control rates remain poor, medication costs are high, and side effects are common.
Only five percent of patients develop hypertension from known causes with a staggering 95% from unknown causes, and nearly all treatment is empirical. Therefore the researchers focused in on the known causes, rare familial (single-gene) causes of hypertension, in order to possibly illuminate therapies that can impact the broader causes of the disease.
The researchers focused on the mechanisms behind salt transport in the kidneys because a proven cause of hypertension is excess salt. This led the researchers to study single gene mutations that provoke salt transport in the kidneys in a form of hypertension with known causes, in this case the genetic condition familial hyperkalemic hypertension (FHHt).
Dr. Ellison and his colleagues ultimately found that eliminating this gene in the kidneys not only did not mimic FHHt, but also caused kidney damage. Instead that found that the gene mutations actively degrade proteins in the kidney that help to eliminate kidney salt transport. This conclusion leads to two new pathways for research. First, it identifies a new target for blood pressure drug development, and second, it illuminates an unknown mechanism for kidney inflammation, one that likely contributes to chronic kidney disease, and likely to cancer.
Read the full paper here