Human blood pressure is maintained within a narrow range, despite wide variation in dietary behavior. Hypertension, the most lethal disease in the world, results when the homeostatic systems maintaining control fail, in the setting of environmental challenge. Kidneys play a surprisingly central role in these processes by adjusting salt and water excretion to meet demand. The Human Hypertension Laboratories at OHSU work to unravel mechanisms underlying normal blood pressure homeostasis, and the causes of homeostatic failure. We also work to develop novel approaches to address existing hypertension, both with lifestyle changes and novel drugs. The program comprises the Ellison Laboratory, the McCormick Laboratory, and the Rozansky Laboratory. We investigate mechanisms by which the kidneys regulate blood pressure using molecular and transgenic techniques aimed at identifying novel hemodynamic pathways. We focus on major salt transport proteins in the kidney, including the thiazide-sensitive Na-Cl cotransporter (SLC12A3) and the bumetanide-sensitive Na-K-Cl cotransporter (SLC12A1). Mutations of these genes cause salt wasting disorders in people. We also investigate how mutations in genes that regulate these transport proteins cause inherited hypertension. One such disease is familial hyperkalemic hypertension (also called pseudohypoaldosteronism type 2 or Gordon’s syndrome), which can result from mutations in a novel group of kinases known as WNKs. It can also result from mutations in members of the cullin Ring E3 ubiquitin ligase pathway. Our laboratories are elucidating mechanisms involved, using techniques that range from biochemical, to knockout model development, to human investigation.
We are also interested in translating insights gained from careful assessment of human disease back to the laboratory, to develop novel approaches to improve patient care. We noted many years ago that the combination antibiotic, trimethoprim-sulfamethoxazole (Bactrim, Septra) caused hyperkalemia in patients; we used animal models to prove that this phenomenon was the result of trimethoprim blacking sodium channels in the kidney. This insight changed clinical practice. More recently, we showed that the immunosuppressive drug tacrolimus causes hyperkalemia and hypertension, in part, by stimulating the thiazide-sensitive Na-Cl cotransporter; clinical trials are now underway testing whether blocking this pathway will ameliorate these complications in organ transplant patients. Finally, our groups have had longstanding interests in how patients become resistant to commonly used diuretic drugs. We are developing models to test how diuretic drugs elicit compensation via regulatory pathways, leading to resistance that might be susceptible to treatment.
Recent Publications (Pub Med)