Novel diuretic targets

Abstract

As the molecular revolution continues to inform a deeper understanding of disease mechanisms and pathways, there exist unprecedented opportunities for translating discoveries at the bench into novel therapies for improving human health. Despite the availability of several different classes of antihypertensive medications, only about half of the 67 million Americans with hypertension manage their blood pressure appropriately. A broader selection of structurally diverse antihypertensive drugs acting through different mechanisms would provide clinicians with greater flexibility in developing effective treatment regimens for an increasingly diverse and aging patient population. An emerging body of physiological, genetic, and pharmacological evidence has implicated several renal ion-transport proteins, or regulators thereof, as novel, yet clinically unexploited, diuretic targets. These include the renal outer medullary potassium channel, ROMK (Kir1.1), Kir4.1/5.1 potassium channels, ClC-Ka/b chloride channels, UTA/B urea transporters, the chloride/bicarbonate exchanger pendrin, and the STE20/SPS1-related proline/alanine-rich kinase (SPAK). The molecular pharmacology of these putative targets is poorly developed or lacking altogether; however, recent efforts by a few academic and pharmaceutical laboratories have begun to lessen this critical barrier. Here, we review the evidence in support of the aforementioned proteins as novel diuretic targets and highlight examples where progress toward developing small-molecule pharmacology has been made.

Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics

“…Recent advances in the small-molecule pharmacology by our group [39,40] and Merck [41] are providing critically needed tools for exploring Kir1.1 as a therapeutic target for hypertension. This work has been reviewed recently by our group [42] as well as by Garcia and Kaczorowski (2013) in this issue of Current Opinion in Pharmacology and will not be discussed further.…”

Co-Regulated Pendrin and Aquaporin 5 Expression and Trafficking in Type-B Intercalated Cells under Potassium Depletion

“…Type-B intercalated cells represent the only site where chloride can be actively reabsorbed (entry through apical Cl - /HCO 3 - exchange via pendrin, and exit from basolateral chloride channels) [5]. Due to these features, pendrin has been proposed as a novel diuretic target [16,17,18]. In support of this possibility, a recent study showed that double deletion of the Na + /Cl - cotransporter (NCC) and pendrin leads to sodium wasting, hypovolemia, and hypotension [19].…”

ROMK inhibitor actions in the nephron probed with diuretics

“…Increased fluid delivery specifically stimulates K ϩ secretion through flow-sensitive largeconductance Ca 2ϩ -activated K ϩ (BK) channels. Thus loop or thiazide diuretic use leads to urinary K ϩ excretion and hypokalemia (2).…”