title: The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as a target for antihypertensive therapy.
abstract: Chronic high blood pressure (hypertension) is the most common disease in the Unites States. While several classes of drugs exist to treat it, many patients (up to 10 million Americans) respond poorly to therapy, even when multiple classes are used. Recent evidence suggests that a significant portion of patients will always remain hypertensive despite maximum therapy with the drugs currently available. Therefore, there is a pressing need to develop novel antihypertensive agents. One limitation has been the identification of new targets, a limitation that has been overcome by recent insights into the mechanisms underlying monogenic forms of hypertension. The disease familial hyperkalemic hypertension is caused by mutations in with-no-lysine (WNK) kinases 1 and 4 and in cullin-3 and kelch-like 3, components of an E3 ubiquitin ligase complex that promotes WNK kinase degradation. The study of the mechanisms by which this pathway regulates blood pressure has identified several candidates for the development of new antihypertensive agents. This pathway is particularly attractive since its inhibition may not only reduce renal sodium reabsorption along multiple segments but may also reduce vascular tone. Here, we will describe the mechanisms by which this pathway regulate blood pressure and discuss the potential of targeting it to develop new antihypertensive drugs.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon.
authors.forename: Mohammed Z
authors.initials: MZ
authors.lastname: Ferdaus
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon mccormij@ohsu.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: McCormick
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000378:metabolism*; D044842:Cullin Proteins / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000959:Antihypertensive Agents; C503645:CUL3 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C489837:KLHL3 protein, human; D008840:Microfilament Proteins; C118135:OXSR1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Na+-Cl− cotransporter; drugs; hypertension; kinases