期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 26, 期 7, 页码 1525-1536出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2014060560
关键词
cell physiology; transport physiology; cell signaling; hypertension
资金
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Ministry of Health, Labor and Welfare of Japan
- Salt Science Research Foundation [1422]
- Takeda Science Foundation
- Banyu Foundation
- Vehicle Racing Commemorative Foundation
- Grants-in-Aid for Scientific Research [24659412, 25460146, 15K15327, 25670406] Funding Source: KAKEN
Upon activation by with-no-lysine kinases, STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) phosphorylates and activates SLC12A transporters such as the Na+-Cl- cotransporter (NCC) and Na+-K+-2Cl(-) cotransporter type 1 (NKCC1) and type 2 (NKCC2); these transporters have important roles in regulating BP through NaCl reabsorption and vasoconstriction. SPAK knockout mice are viable and display hypotension with decreased activity (phosphorylation) of NCC and NKCC1 in the kidneys and aorta, respectively. Therefore, agents that inhibit SPAK activity could be a new class of antihypertensive drugs with dual actions (i.e., NaCl diuresis and vasodilation). In this study, we developed a new ELISA-based screening system to find novel SPAK inhibitors and screened >20,000 small-molecule compounds. Furthermore, we used a drug repositioning strategy to identify existing drugs that inhibit SPAK activity. As a result, we discovered one small-molecule compound (Stock 1S-14279) and an antiparasitic agent (Closantel) that inhibited SPAK-regulated phosphorylation and activation of NCC and NKCC1 in vitro and in mice. Notably, these compounds had structural similarity and inhibited SPAK in an ATP-insensitive manner. We propose that the two compounds found in this study may have great potential as novel antihypertensive drugs.
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