WNK4 is the major WNK positively regulating NCC in the mouse kidney
| Autor: | Eisei Sohara, Sei Sasaki, Tatemitsu Rai, Daiei Takahashi, Muhammad Zakir Hossain Khan, Yuya Araki, Moko Zeniya, Naohiro Nomura, Takayasu Mori, Shinichi Uchida |
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| Rok vydání: | 2014 |
| Předmět: |
BP
blood pressure lcsh:Life lcsh:QR1-502 angiotensin II DCT distal convoluted tubule Biochemistry lcsh:Microbiology WNK with-no-lysine kinase Mice chemistry.chemical_compound TG transgenic Solute Carrier Family 12 Member 3 Phosphorylation Kidney Tubules Distal Mice Knockout distal convoluted tubule Kidney Aldosterone Kinase AngII angiotensin II Akt also called protein kinase B (PKB) WNK1 WNK4 with-no-lysine kinase (WNK) medicine.anatomical_structure PHAII pseudohypoaldosteronism type II embryonic structures RAA renin–angiotensin–aldosterone Signal Transduction kidney medicine.medical_specialty hypertension Biophysics Protein Serine-Threonine Kinases Biology NCC Na–Cl co-transporter OSR1 oxidative stress-responsive 1 Internal medicine parasitic diseases medicine Animals Molecular Biology Original Paper Ion Transport urogenital system ES embryonic stem Pseudohypoaldosteronism ENaC epithelial Na+ channel Cell Biology medicine.disease Angiotensin II lcsh:QH501-531 Endocrinology chemistry BAC bacterial artificial chromosome KLHL3 Kelch-like family member 3 SPAK Ste20-like proline/alanine-rich kinase Na–Cl co-transporter NKCC2 Na-K-Cl co-transporter isoform 2 ROMK renal outer medullary K+ channel |
| Zdroj: | Bioscience Reports Bioscience Reports, Vol 34, Iss 3, p e00107 (2014) |
| ISSN: | 1573-4935 0144-8463 |
| DOI: | 10.1042/bsr20140047 |
| Popis: | By analysing the pathogenesis of a hereditary hypertensive disease, PHAII (pseudohypoaldosteronism type II), we previously discovered that WNK (with-no-lysine kinase)–OSR1/SPAK (oxidative stress-responsive 1/Ste20-like proline/alanine-rich kinase) cascade regulates NCC (Na–Cl co-transporter) in the DCT (distal convoluted tubules) of the kidney. However, the role of WNK4 in the regulation of NCC remains controversial. To address this, we generated and analysed WNK4−/− mice. Although a moderate decrease in SPAK phosphorylation and a marked increase in WNK1 expression were evident in the kidneys of WNK4−/− mice, the amount of phosphorylated and total NCC decreased to almost undetectable levels, indicating that WNK4 is the major WNK positively regulating NCC, and that WNK1 cannot compensate for WNK4 deficiency in the DCT. Insulin- and low-potassium diet-induced NCC phosphorylation were abolished in WNK4−/− mice, establishing that both signals to NCC were mediated by WNK4. As shown previously, a high-salt diet decreases phosphorylated and total NCC in WNK4+/+ mice via AngII (angiotensin II) and aldosterone suppression. This was not ameliorated by WNK4 knock out, excluding the negative regulation of WNK4 on NCC postulated to be active in the absence of AngII stimulation. Thus, WNK4 is the major positive regulator of NCC in the kidneys. The analyses of WNK4 (with-no-lysine kinase 4) knockout mice help to end a long-standing controversy about the role of WNK4 on NCC (Na–Cl co-transporter) regulations in the kidney. WNK4 is a strong positive regulator of NCC. |
| Databáze: | OpenAIRE |
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