This is a related project designed to determine the mechanism by which kidney distal tubules ‘sense’ the blood potassium concentration.  Working with Wen-Hui Wang at Medical College of New York, we have determined that potassium is sensed by the action of potassium channels (Kir4.1) in the basolateral membrane of the distal tubule. Naturally occurring mutations of these channels cause the human disease, EAST syndrome.  We have postulated that these channels determine the membrane voltage, which in turn, affects the cell chloride concentration.  It is known that chloride affects the activity of a unique class of serine/threonine kinases, called WNK kinases.  When cell chloride concentration is low, the kinases are activated, thereby switching NaCl transporters from the off state to the on state.  We are currently focusing efforts on measuring the chloride concentration inside of living distal tubule cells. 

Supported by a Multiple PI grant (Wang and Ellison) from NIDDK, R01DK054983. 

The cause of most hypertension (also known as high blood pressure) is unknown.  Yet there are some cases caused by mutations in single genes.  One of the most interesting is called familial hyperkalemic hypertension or Gordon syndrome.  Mutations in four genes have been shown to cause this disease, and they all do so by activating salt transporters in the kidney tubules.  The identification of these genes has unraveled a kinase network that was previously unknown, and in addition to affecting blood pressure, has effects on nerve transmission and on cell stability.  These genes are called WNK kinases, and they act by phosphorylating and activating other kinases.  Interestingly, other genes that cause the same disease phenotype are members of the cullin ring ligase family, which is involved in degrading WNK kinases.  We are studying how mutations in these genes lead to hypertension, by developing novel mouse knock-in and knock-out models, and by studying cell culture model systems.  The hope is that unraveling this new pathway will lead to new and more effective drugs to treat hypertension in people.   

Supported by a Multiple PI grant (Ellison & Yang, with Gamba and Hadchouel) from NIDDK, R01DK051496. 

Aldosterone is a potent salt retaining hormone, which plays key roles in the pathogenesis of hypertension, as well as heart failure and liver cirrhosis.  Blocking the actions of aldosterone with drugs prolongs life in patients with heart failure.  We recently discovered that the effects of aldosterone to promote salt retention in the kidney are different from what was long believed.  Many groups, including our own, had believed that aldosterone activated both sodium channels and sodium chloride transporters in the kidney.  We developed a novel mouse model and showed, instead, that aldosterone’s direct effects were only on sodium channels.  Surprisingly, the effects on sodium chloride transport resulted from changes in blood potassium; they were not direct.  We are now investigating how aldosterone stimulates sodium channels.  While this has been a ‘holy grail’ for many years, the advent of new technology, such as RNAseq, is permitting us to explore the transcripts induced by aldosterone in more detail.  Additionally, it seems that the effects of depleting aldosterone, which acts by binding to mineralocorticoid receptors, are not the same as those of depleting mineralocorticoid receptors.  We postulated that this is because another steroid hormone, cortisol, stimulates mineralocorticoid receptors in vivo.  We are using other unique mouse models to test this hypothesis.   

Supported by a grant (Ellison) from Department of Veterans Affairs, I0BX002228.