A5016613844- Ion Transport and Channel Regulation
- Renal and related cancers
- Genetic and Kidney Cyst Diseases
- Ion channel regulation and function
- Pancreatic function and diabetes
- Electrolyte and hormonal disorders
- Renal Diseases and Glomerulopathies
- Hormonal Regulation and Hypertension
- Dialysis and Renal Disease Management
- Magnesium in Health and Disease
- Potassium and Related Disorders
- Diet, Metabolism, and Disease
- Genetic Syndromes and Imprinting
- Chronic Kidney Disease and Diabetes
- Metabolism, Diabetes, and Cancer
- Sodium Intake and Health
- Renal function and acid-base balance
- Parathyroid Disorders and Treatments
- Platelet Disorders and Treatments
- Pediatric Urology and Nephrology Studies
- Aldose Reductase and Taurine
- Cell Adhesion Molecules Research
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Adipose Tissue and Metabolism
- Cardiac, Anesthesia and Surgical Outcomes
Tokyo Medical and Dental University
2015-2024
The University of Tokyo
2017-2024
Institute of Science Tokyo
2024
Tokyo Medical and Dental University Hospital
2022-2023
Weatherford College
2022
Obayashi (Japan)
2022
Fukuoka University
2013-2019
National Defense Medical Center
2013
Tri-Service General Hospital
2013
MRC Protein Phosphorylation and Ubiquitylation Unit
2012
Mutations in WNK kinases cause the human hypertensive disease pseudohypoaldosteronism type II (PHAII), but regulatory mechanisms of are not well understood. kelch-like 3 (KLHL3) and Cullin3 were also recently identified as causing PHAII. Therefore, new insights into hypertension can be gained by determining how these components interact they involved pathogenesis Here, we found that KLHL3 interacted with WNK4, induced WNK4 ubiquitination, reduced protein level. The interaction PHAII-causing...
Mutations in the WNK4 gene cause pseudohypoaldosteronism type II (PHAII), an autosomal-dominant disorder of hyperkalemia and hypertension. The target molecules this putative kinase molecular mechanisms by which mutations phenotypes are currently unknown. Although recent reports found that expression Xenopus oocytes causes inhibition thiazide-sensitive NaCl cotransporter renal K channel ROMK, there may be additional targets WNK4. For example, increase paracellular chloride permeability has...
Aquaporin-7 (AQP7) is a water/glycerol transporting protein expressed in adipocyte plasma membranes. We report here remarkable age-dependent hypertrophy adipocytes AQP7-deficient mice. Wild type and AQP7 null mice had similar growth at 0-16 weeks as assessed by body weight; however, 16 3.7-fold increased fat mass. Adipocytes from of age were greatly enlarged (diameter 118 mum) compared with wild (39 mum). also accumulated excess glycerol (251 versus 86 nmol/mg protein) triglycerides (3.4 1.7...
Na(+)-K(+)-2Cl(-) cotransporters (NKCCs), including NKCC1 and renal-specific NKCC2, the Na(+)-Cl(-) cotransporter (NCC) play pivotal roles in regulation of blood pressure (BP) renal NaCl reabsorption. Oxidative stress-responsive kinase-1 (OSR1) is a known upstream regulator N(K)CCs. We generated analyzed global kidney tubule-specific (KSP) OSR1 KO mice to elucidate physiological role vivo, particularly on BP function. Although OSR1(-/-) were embryonically lethal, OSR1(+/-) had low associated...
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 DCT (distal convoluted tubules) kidney. However, role WNK4 regulation remains controversial. To address this, generated and analysed WNK4−/− mice. Although moderate decrease SPAK phosphorylation...
Chronic kidney disease (CKD) accelerates vascular calcification via phenotypic switching of smooth muscle cells (VSMCs). We investigated the roles circulating small extracellular vesicles (sEVs) between kidneys and VSMCs uncovered relevant sEV-propagated microRNAs (miRNAs) their biological signaling pathways.We established CKD models in rats mice by adenine-induced tubulointerstitial fibrosis. Cultures A10 embryonic rat showed increased transcription osterix (Sp7), osteocalcin (Bglap),...
Nek8 is a serine/threonine kinase that mutated in the jck (juvenile cystic kidneys) mouse, model of autosomal recessive juvenile polycystic kidney disease, but its function poorly understood. We used mouse to study functional relationship between and other proteins have been implicated diseases. In collecting tubules ducts wild-type mice, we found was localized proximal portion primary cilia weakly detected cytosol. mutant, however, along entire length cilia. Coimmunoprecipitation...
We recently generated Wnk4D561A/+ knockin mice and found that a major pathogenesis of pseudohypoaldosteronism type II was the activation OSR1/SPAK kinase-NaCl cotransporter (NCC) phosphorylation cascade by mutant WNK4. However, physiological roles wild-type WNK4 on regulation Na excretion blood pressure, whether functions positively or negatively in this cascade, remained to be determined. In present study, we hypomorphic deleting exon 7 Wnk4 gene. These did not show hypokalemia metabolic...
Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, in turn aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt sensitivity of hyperinsulinemic remain unclear. Abnormal activation the recently identified with-no-lysine kinase (WNK)-oxidative stress-responsive 1 (OSR1)/STE20/SPS1-related proline/alanine-rich (SPAK)-NaCl cotransporter (NCC) phosphorylation cascade results salt-sensitive hypertension...
The NaCl cotransporter (NCC) is essential for sodium reabsorption at the distal convoluted tubules (DCT), and its phosphorylation increases transport activity apical membrane localization. Although insulin has been reported to increase in kidney, linkage between NCC not yet investigated. This study examined whether regulates phosphorylation. In cultured mpkDCT cells, increased of STE20/SPS1-related proline-alanine-rich kinase (SPAK) a dose-dependent manner. insulin-induced was suppressed...
Pseudohypoaldosteronism type II (PHAII) is a hereditary disease characterized by salt-sensitive hypertension, hyperkalemia and metabolic acidosis, genes encoding with-no-lysine kinase 1 (WNK1) WNK4 kinases are known to be responsible. Recently, Kelch-like 3 (KLHL3) Cullin3, components of KLHL3-Cullin3 E3 ligase, were newly identified as responsible for PHAII. We have reported that the substrate ligase-mediated ubiquitination. However, WNK1 Na–Cl cotransporter (NCC) also ligase other groups....
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) Na+-K+-2Cl− type 1 (NKCC1) 2 (NKCC2); these have important roles in regulating BP through NaCl reabsorption vasoconstriction. SPAK knockout mice are viable display hypotension with decreased activity (phosphorylation) of NCC NKCC1 kidneys aorta, respectively. Therefore, agents that inhibit could be a...
Dietary potassium intake is inversely related to blood pressure and mortality. Moreover, the sodium-chloride cotransporter (NCC) plays an important role in regulation urinary excretion response intake. Previously, it was shown that NCC activated by WNK4-SPAK cascade dephosphorylated protein phosphatase. However, mechanism of with acute still unclear. To identify molecular intake, we used adult C57BL/6 mice fed a 1.7% solution oral gavage. We confirmed load rapidly NCC, which not dependent on...
Heritable nephrogenic diabetes insipidus (NDI) is characterized by defective urine concentration mechanisms in the kidney, which are mainly caused loss-of-function mutations vasopressin type 2 receptor. For treatment of heritable NDI, novel strategies that bypass receptor required to activate aquaporin-2 (AQP2) water channel. Here we show Wnt5a regulates AQP2 protein expression, phosphorylation and trafficking, suggesting an endogenous ligand can regulate without activation classic...
Abstract Tolvaptan, a vasopressin type 2 receptor antagonist initially developed to increase free-water diuresis, has been approved for the treatment of autosomal dominant polycystic kidney disease in multiple countries. Furthermore, tolvaptan shown improve renal functions rodent models chronic (CKD); however, underlying molecular mechanisms remain unknown. CKD is characterized by increased levels oxidative stress, and an antioxidant transcription factor—nuclear factor erythroid 2-related...
Aging | doi:10.18632/aging.205164. Hisazumi Matsuki, Shintaro Mandai, Hiroki Shiwaku, Takaaki Koide, Naohiro Takahashi, Tomoki Yanagi, Shunsuke Inaba, Saaya Ida, Tamami Fujiki, Yutaro Mori, Fumiaki Ando, Takayasu Koichiro Susa, Soichiro Iimori, Eisei Sohara, Hidehiko Shinichi Uchida
The aquaporin-7 (AQP7) water channel is known as a member of the aquaglyceroporins, which facilitate transport glycerol well water. Although AQP7 abundantly expressed on apical membrane proximal straight tubules in kidney, physiological role still unknown. To investigate this, we generated knockout mice. permeability tubule brush-border measured by stopped-flow method was slightly but significantly reduced mice compared with that wild-type (AQP7, 18.0 +/- 0.4 x 10(-3) cm/s vs. wild-type,...
Frame-shift mutations within the C terminus of aquaporin 2 (AQP2) cause autosomal-dominant nephrogenic diabetes insipidus (AD-NDI). To identify molecular mechanism(s) this disease in vivo and to test possible therapeutic strategies, we generated a mutant AQP2 (763–772 del) knockin mouse. Heterozygous mice showed severely impaired urine-concentrating ability. However, they were able slightly increase urine osmolality after dehydration. This milder phenotype, when compared with...
Urea transporter UT-A2, the major urea of thin descending limb loop Henle in short nephrons, has been implicated recycling medulla, thereby producing concentrated urine. To investigate physiological role UT-A2 vivo, we generated UT-A2-selective knockout mice by deleting promoter. Western analysis, immunohistochemistry, and quantitative reverse transcription-PCR were used to confirm specific deletion with preservation other UT-A transporters. Compared wild-type mice, differences urine outputs...
We recently reported increased phosphorylation of the NaCl cotransporter (NCC) in Wnk4D561A/+ knock-in mice, an ideal model human hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII). Although previous vitro studies had suggested existence a cascade involving WNK, OSR1 and SPAK kinases, whether WNK-OSR1/SPAK is fact fully responsible for NCC vivo activation this sole mediator PHAII remained to be determined. To clarify these issues, we mated mice with Spak Osr1 which...