April 30, 2015

Team tracks how kidney responds to blood pressure meds

Changes in the kidney can limit the blood pressure-lowering effects of thiazide diuretics, a new study reports.

Eric Delpire, Ph.D., and colleagues are studying the kidney mechanisms that may underlie resistance to commonly used anti-hypertensive medications. (photo by Anne Rayner)

Changes in the kidney can limit the blood pressure-lowering effects of thiazide diuretics, a new study reports.

A multi-institutional research team — including investigators at Vanderbilt University, the University of Maryland and Emory University — has discovered the kidney mechanisms that may underlie resistance to commonly used antihypertensive medications. The findings, reported in the Journal of Clinical Investigation, point to new targets for treating high blood pressure.

Thiazide diuretics are among the most cost effective and commonly used antihypertensive medications. Some patients, however, never respond to thiazide diuretics, and other patients respond initially but become resistant over time, prompting investigators to wonder why.

Thiazide diuretics block the action of a sodium chloride co-transporter (NCC) — a protein that normally reabsorbs salt from the urine into the blood in a particular region of the kidney.
Salt reabsorption by NCC is important for overall salt balance and blood pressure regulation.

“The major question of the current study was, how does the kidney compensate for the loss of salt reabsorption by NCC,” said Eric Delpire, Ph.D., professor of Anesthesiology at Vanderbilt and a co-author of the JCI report.

Delpire had developed a mouse model for non-functional NCC — he and his team knocked out the gene for another protein, SPAK, which is required to activate NCC. Mice missing SPAK do not reabsorb salt through NCC, functionally mimicking the effect of thiazide diuretics.

P. Rick Grimm, Ph.D., and Paul Welling, M.D., at the University of Maryland, analyzed gene expression in the kidneys of mice missing SPAK and identified changes in a network of more than 400 genes.

They showed that the gene expression changes altered kidney physiology by: activating salt transport in pendrin-positive cells in a different region of the kidney, expanding the number of pendrin-positive cells, and activating a kidney signaling system involving alpha-ketoglutarate to stimulate salt retention.

“It looks like extensive remodeling occurs in the kidney to try to compensate for the loss of sodium reabsorption in the distal convoluted tubule (the region where NCC normally functions),” Delpire said.

The findings point to new mechanisms for salt reabsorption, Delpire noted.

“These mechanisms are potential targets for new antihypertensive medications — pendrin and the receptor for alpha-ketoglutarate may be targets for novel diuretics,” he said.

The changes observed in mice missing NCC function also occur in normal mice that have received thiazide diuretics, Delpire said.

Studies are underway to determine whether or not patients taking thiazide diuretics also experience kidney remodeling — and if any compensatory changes explain resistance to the medications. The findings also suggest that urine alpha-ketoglutarate may serve as a potential biomarker for resistance to thiazide diuretics.

Current treatment for high blood pressure involves a “trial and error” process for arriving at the right medication, or combination of medications. A biomarker for thiazide resistance could eliminate the time spent trying thiazide drugs in patients who are not likely to respond.

The research was supported by grants from the National Institutes of Health (GM074771, DK093501, DK063049, DK054231, DK032839, NR014129, DK055881, DK046493).