Impaired KLHL3-Mediated Ubiquitination of WNK4 Causes Human Hypertension
Mai Wakabayashi,
Takayasu Mori,
Kiyoshi Isobe,
Eisei Sohara,
Koichiro Susa,
Yuya Araki,
Motoko Chiga,
Eriko Kikuchi,
Naohiro Nomura,
Yutaro Mori,
Hiroshi Matsuo,
Tomohiro Murata,
Shinsuke Nomura,
Takako Asano,
Hiroyuki Kawaguchi,
Shigeaki Nonoyama,
Tatemitsu Rai,
Sei Sasaki,
Shinichi Uchida
Affiliations
Mai Wakabayashi
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Takayasu Mori
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Kiyoshi Isobe
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Eisei Sohara
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Koichiro Susa
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Yuya Araki
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Motoko Chiga
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Eriko Kikuchi
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Naohiro Nomura
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Yutaro Mori
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Hiroshi Matsuo
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
Tomohiro Murata
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
Shinsuke Nomura
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
Takako Asano
Department of Pediatrics, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
Hiroyuki Kawaguchi
Department of Pediatrics, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
Shigeaki Nonoyama
Department of Pediatrics, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
Tatemitsu Rai
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Sei Sasaki
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Shinichi Uchida
Department of Nephrology, Graduate Schools of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan
Mutations in WNK kinases cause the human hypertensive disease pseudohypoaldosteronism type II (PHAII), but the regulatory mechanisms of the WNK kinases are not well understood. Mutations in kelch-like 3 (KLHL3) and Cullin3 were also recently identified as causing PHAII. Therefore, new insights into the mechanisms of human hypertension can be gained by determining how these components interact and how they are involved in the pathogenesis of PHAII. Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein. Transgenic mice overexpressing WNK4 showed PHAII phenotypes, and WNK4 protein was indeed increased in Wnk4D561A/+ PHAII model mice. Thus, WNK4 is a target for KLHL3-mediated ubiquitination, and the impaired ubiquitination of WNK4 is a common mechanism of human hereditary hypertension.
