TY - JOUR
T1 - The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as a target for antihypertensive therapy
AU - Ferdaus, Mohammed Z.
AU - McCormick, James A.
N1 - Funding Information:
J. A. McCormick is funded by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-098141.
Publisher Copyright:
© 2016 the American Physiological Society.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
KW - Drugs
KW - Hypertension
KW - Kinases
KW - Na-Cl cotransporter
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U2 - 10.1152/ajprenal.00132.2016
DO - 10.1152/ajprenal.00132.2016
M3 - Article
C2 - 27076645
AN - SCOPUS:84984601507
VL - 310
SP - F1389-F1396
JO - American journal of physiology. Renal physiology
JF - American journal of physiology. Renal physiology
SN - 0363-6127
IS - 11
ER -