2024/03/12 更新

写真a

ヤマダ　タケヒサ
山田　剛久
YAMADA TAKEHISA
所属
千葉北総病院 腎臓内科 准教授
職名
准教授
外部リンク

学位

  • 医学博士 （ 東京医科歯科大学 ）

研究キーワード

  • 腎臓病学

研究分野

  • ライフサイエンス / 腎臓内科学

学歴

  • 東京医科歯科大学大学院   医学研究科

    1993年4月 - 1997年3月

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  • 東京医科歯科大学

    1985年4月 - 1991年3月

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経歴

  • 日本医科大学大学院   内分泌代謝・腎臓内科学   准教授

    2023年4月 - 現在

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  • 日本医科大学千葉北総病院   腎臓内科   講師

    2013年4月 - 2023年3月

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  • 日本医科大学千葉北総病院   腎臓内科   部長

    2011年4月 - 現在

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所属学協会

委員歴

  • 日本透析医学会   評議員  

    2022年6月 - 2024年5月   

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    団体区分：学協会

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  • 日本腎臓学会   症例評価委員会委員  

    2018年1月 - 2020年3月   

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    団体区分：学協会

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  • 日本腎臓学会   評議員  

    2015年4月 - 現在   

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    団体区分：学協会

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論文

  • Additional effect of dotinurad on serum uric acid concentration in chronic kidney disease patients treated with febuxostat. 査読

    Takehisa Yamada, Yukinao Sakai, Osamu Kurihara, Tetsuya Kashiwagi, Masato Iwabu

    Journal of Nippon Medical School   in press   2024年

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    担当区分：筆頭著者  

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  • Efficacy of dotinurad in patients with severe renal dysfunction. 査読

    Osamu Kurihara, Takehisa Yamada, Katsuhito Kato, Yasushi Miyauchi

    Clinical and experimental nephrology   2023年10月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    BACKGROUND: Although hyperuricemia is associated with the progression of chronic kidney disease (CKD), a reduction in CKD progression by uric acid (UA)-lowering therapy has been controversial. Recently, dotinurad, a uricosuric drug with selective urate reabsorption inhibitory properties, has been developed. However, its efficacy in lowering serum UA levels and its effects on renal function in patients with severe renal dysfunction are unclear. Thus, this study aimed to determine the effects of dotinurad on renal function in patients with severe renal dysfunction. METHODS: Data from 53 outpatients with hyperuricemia who newly received dotinurad between December 2020 and October 2022 were retrospectively analyzed. The mean baseline estimated glomerular filtration rate (eGFR) was 38.7 ± 17.0 mL/min/1.73 m2. The patients were divided into three groups based on their baseline eGFR: eGFR < 30 (n = 17), 30 ≤ eGFR < 45 (n = 17), and eGFR ≥ 45 (n = 19). RESULTS: The mean follow-up period was 9.8 ± 4.5 (range, 3-21) months. Serum UA levels significantly decreased in all groups. Although eGFR did not significantly change in patients with 30 ≤ eGFR < 45 and eGFR ≥ 45 (P = 0.918 and P = 0.535, respectively), it improved significantly in patients with eGFR < 30 (P = 0.032). The proportion of patients with improved eGFR was significantly higher in patients with eGFR < 30 (P = 0.038) than in patients with 30 ≤ eGFR < 45 and eGFR ≥ 45. In the multivariate logistic regression analysis, baseline eGFR < 30 and achieving a serum UA level of ≤ 6.0 mg/dL were significantly associated with improved eGFR (P = 0.033 and P = 0.015, respectively). CONCLUSIONS: Dotinurad may have UA-lowering effects and the potential to improve kidney function in patients with severe renal dysfunction.

    DOI： 10.1007/s10157-023-02419-w

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  • Analysis of Cognitive aging Estimated by the Japanese Version of the Montreal Cognitive Assessment in Patients Aged 75 years or Older with and Without Type 2 diabetes Mellitus. 査読

    Taeko Saito, Takehisa Yamada, Yasushi Miyauchi, Naoya Emoto, Fumitaka Okajima

    Journal of Nippon Medical School = Nippon Ika Daigaku zasshi   89 ( 2 )   196 - 202   2022年4月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    BACKGROUND: The number of people diagnosed with dementia worldwide is set to increase significantly. While patients with dementia often have comorbidities, particularly diabetes, patients with type 2 diabetes mellitus (T2DM) have a high risk of cognitive decline. This study aimed to determine whether older people with T2DM exhibit specificity in cognitive function. METHODS: The Montreal Cognitive Assessment (MoCA) is a well-known tool for examining mild cognitive impairment. The modified Japanese version (MoCA-J) has been confirmed as effective. We conducted an investigative survey to assess the cognitive function of Japanese individuals aged ≥75 years with and without T2DM, using the MoCA-J, and analyzed the results. RESULTS: Thirty-three patients with T2DM and 23 non-DM patients completed the examination. Between both groups, a significant difference in the MoCA-J total scores was found. (T2DM mean, 21.4 ± 3.5; non-DM mean, 23.5 ± 3.6). Only 9% of patients with T2DM and 39% of those with non-DM showed scores ≥26, which is the cutoff point for mild cognitive impairment, whereas all patients had the ability of self-care. Additionally, older patients with T2DM had significantly lower delayed recall scores than the non-DM group. CONCLUSIONS: Patients aged ≥75 years with T2DM might have lower cognition than those without T2DM; the inability to perform delayed recall in T2DM patients might denote a cognitive function decline.Therefore, compared with other patients, patients aged ≥75 years with T2DM need to receive individually tailored explanations about their care, based on their cognition.

    DOI： 10.1272/jnms.JNMS.2022_89-215

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  • Effects of renal function on the urinary excretion and serum concentration of uric acid in patients with chronic kidney disease treated with febuxostat. 査読

    Takehisa Yamada, Tetsuya Kashiwagi, Yukinao Sakai

    Journal of Nippon Medical School = Nippon Ika Daigaku zasshi   89 ( 4 )   360 - 367   2021年11月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    BACKGROUND: Febuxostat is recommended for patients with chronic kidney disease (CKD) associated with hyperuricemia to lower the serum uric acid (sUA) concentration. However, it remains uncertain how this drug affects correlations between several laboratory parameters regarding glomerular filtration and renal tubular reabsorption of uric acid. METHODS: We enrolled 148 patients with CKD with hyperuricemia. Of them, 122 were treated with febuxostat, and 26 were treated without it. Clinical and laboratory parameters were recorded to calculate the estimated glomerular filtration rate (eGFR), fractional excretion of uric acid (FEUA), and the estimated 24-h urinary excretion of uric acid (eEUA). We retrospectively examined the correlations between those parameters to compare the patients treated with febuxostat to those without it. RESULTS: A significant inverse correlation between eGFR and FEUA was demonstrated in both patients treated with febuxostat and those without it. In patients treated with febuxostat, a significant inverse correlation was demonstrated between eGFR and sUA, whereas no significant correlation was demonstrated in those without it. There was a significant positive correlation between FEUA and eEUA in patients treated with febuxostat, whereas no significant correlation was revealed in those without it. CONCLUSIONS: FEUA increased as eGFR declined in our study population. Febuxostat changed the correlation patterns between the clinical laboratory parameters. An additional administration of uricosuric agents would be helpful for further sUA lowering by increasing both FEUA and eEUA in patients treated with febuxostat.

    DOI： 10.1272/jnms.JNMS.2022_89-401

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  • <p>Low-Density Lipoprotein Apheresis in Patients with Acute Kidney Injury Due to Minimal Change Disease Requiring Acute Renal Replacement Therapy</p> 査読

    Kohsuke Terada, Koji Mugishima, Sayuri Kawasaki, Fumiaki Itagaki, Takehisa Yamada, Yukinao Sakai

    International Journal of Nephrology and Renovascular Disease   Volume 13   157 - 162   2020年6月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Informa UK Limited  

    添付ファイル： ijnrd-248610-low-density-lipoprotein-apheresis-in-patients-with-acute-kid.pdf

    DOI： 10.2147/ijnrd.s248610

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  • Prognostic markers for heart failure in patients undergoing peritoneal dialysis 査読

    Kohsuke Terada, Yukinao Sakai, Yuichiro Sumi, Koji Mugishima, Sayuri Kawasak, Fumiaki Itagaki, Takehisa Yamada, Shuichi Tsuruoka

    Renal Replacement Therapy   5   36   2019年9月

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  • A case of membranous nephropathy diagnosed with lupus nephritis 11 years after onset. 査読

    Yamada T, Itagaki F, Aratani S, Kawasaki S, Terada K, Mugishima K, Kashiwagi T, Shimizu A, Tsuruoka S

    CEN case reports   8 ( 4 )   301 - 307   2019年8月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    DOI： 10.1007/s13730-019-00412-5

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  • A case of anti-glomerular basement membrane antibody-positive systemic lupus erythematosus with pulmonary hemorrhage successfully treated at an early stage of the disease 査読

    Takehisa Yamada, Koji Mugishima, Seiichiro Higo, Yukie Yoshida, Fumiaki Itagaki, Shizuka Yui, Tetsuya Kashiwagi, Yoko Endo, Akira Shimizu, Shuichi Tsuruoka

    Journal of Nippon Medical School   85 ( 2 )   138 - 144   2018年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Medical Association of Nippon Medical School  

    We report here a case of systemic lupus erythematosus (SLE) with pulmonary hemorrhage and antiglomerular basement membrane (anti-GBM) antibodies. A 42-year-old woman was admitted to our hospital with complaints of exanthema, arthralgia, shortness of breath, and hemoptysis. Plain chest computed tomography (CT) scan revealed pericardial effusion, bilateral pleural effusions, and pulmonary hemorrhage. Laboratory findings on admission revealed proteinuria, microscopic hematuria, anemia, leukopenia, hypoalbuminemia, hypocomplementemia, and slightly elevated levels of serum creatinine. Serological tests revealed elevated titers of serum anti-GBM antibodies, proteinase 3-antineutrophil cytoplasmic antibodies (PR3-ANCA), and anti-double stranded deoxyribonucleic acid (dsDNA)-immunoglobulin G (IgG) antibodies. Early treatment with steroid pulse therapy combined with plasma exchange resolved the patient’s pulmonary hemorrhage and renal dysfunction. Renal biopsy carried out after the treatment revealed a recovery phase of acute tubular injury with minor glomerular abnormalities without linear IgG deposition along the GBMs. For a good prognosis, it is necessary to start treatment immediately in patients with anti-GBM antibody-positive SLE associated with pulmonary hemorrhage.

    DOI： 10.1272/jnms.2018_85-21

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  • Correlation between Pathological Findings and the Usefulness of Clinical Guidelines for the Treatment of ANCA-Positive RPGN: A Retrospective Analysis. 査読

    Yamada T, Kashiwagi T, Shimizu A, Tsuruoka S

    Journal of Nippon Medical School = Nippon Ika Daigaku zasshi   85 ( 5 )   259 - 264   2018年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    DOI： 10.1272/jnms.JNMS.2018_85-41

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  • A Case of Sjögren's Syndrome Complicated with Interstitial Nephritis and Delayed Onset Autoimmune Hepatitis. 査読

    Yamada T, Fukui M, Kashiwagi T, Arai T, Itokawa N, Atsukawa M, Shimizu A, Tsuruoka S

    Journal of Nippon Medical School = Nippon Ika Daigaku zasshi   85 ( 2 )   117 - 123   2018年

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    DOI： 10.1272/jnms.2018_85-18

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  • A case of monoclonal immunoglobulin G1-lambda deposition associated with membranous feature in a patient with hepatitis C viral infection 査読

    Takehisa Yamada, Yusuke Arakawa, Akiko Mii, Tetsuya Kashiwagi, Tomohiro Kaneko, Koichi Utsumi, Yukinari Masuda, Akira Shimizu, Yasuhiko Iino, Yasuo Katayama

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   16 ( 3 )   468 - 472   2012年6月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

    A 63-year-old man with hepatitis C virus infection was admitted to our hospital for nephrotic syndrome. Light microscopic analysis of a percutaneous renal biopsy showed thickening of the glomerular capillary walls and spike formation. Immunofluorescence revealed granular deposition of monoclonal immunoglobulin G1-lambda and C3 complement along the glomerular basement membrane. Urinary protein excretion decreased slightly after combined treatment with steroid and an immunosuppressive agent. Monoclonal immunoglobulin deposition disease with membranous feature is rare. Additional reports of such cases are needed to elucidate the mechanisms and optimal therapy for this rare entity.

    DOI： 10.1007/s10157-011-0579-x

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  • Lovastatin inhibits mesangial cell proliferation via p27(Kip1) 査読

    Y Terada, S Inoshita, O Nakashima, T Yamada, M Kuwahara, S Sasaki, F Marumo

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY   9 ( 12 )   2235 - 2243   1998年12月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

    Mesangial cell proliferation is a key feature of glomerulonephritis. The hydroxymethylglutaryl-coenzyme A reductase inhibitor lovastatin is known to inhibit cell cycle progression. To determine the inhibitory mechanisms of mesangial cell proliferation by lovastatin, the cyclin-dependent kinase (CDK) activity, and expression of CDK inhibitor (p27(Kip1), p21(Cip1), and p16(INK4)) mRNA and protein were measured. Lovastatin inhibited phosphorylation of retinoblastoma protein and mesangial cell proliferation dose dependently. Lovastatin increased the p27(Kip1) protein level but produced no changes in the abundance of the p27(Kip1) mRNA level both in the presence and absence of mitogens. Treatment with lovastatin revealed the increment of both CDK2- and CDK4-bound-p27(Kip1). The experiment using antisense oligonucleotide against p27(Kip1) showed significant amelioration of lovastatin-induced cell cycle arrest. Lovastatin reduced both platelet-derived growth factor-stimulated CDK2 and CDK4 kinase activities. In conclusion, lovastatin inhibited mesangial proliferation via translational upregulation or impairment of p27(Kip1) protein degradation. Lovastatin serves as a potential therapeutic approach to mesangial proliferative disease.

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  • Cyclin D1, p16, and retinoblastoma gene regulate mitogenic signaling of endothelin in rat mesangial cells 査読

    Y Terada, S Inoshita, O Nakashima, T Yamada, M Tamamori, H Ito, S Sasaki, F Marumo

    KIDNEY INTERNATIONAL   53 ( 1 )   76 - 83   1998年1月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL SCIENCE INC  

    To elucidate the mechanisms by which endothelin (ET)-1 induces proliferation of mesangial cells, we investigated the involvement of the first gap phase of the cell cycle (G1) cyclin, cyclin-dependent kinase 4 (CDK4) activity, and the retinoblastoma gene product (pRb) in ET-l-stimulated cell cycle progression. In the present study, ET-1 stimulated CDK4 activity and cell cycle progression via ET A-type receptors and induced cyclin D1 mRNA and protein expression in rat mesangial cells. We also found that ET-1 stimulation of mesangial cell proliferation was inhibited by antisense oligonucleotides directed against cyclin D1 and by overexpression of a nonphosphorylatable form of pRb. To investigate the functional roles of p16(INK4) and p21(cip1) in ET-l-stimulated mesangial cell proliferation, we used adenovirus-mediated gene transfer. Endothelin-l-stimulated [H-3]-thymidine incorporation, CDK4 kinase activity, and the percent of cells in S phase were found to be significantly inhibited by overexpression of p16(INK4) and slightly inhibited by overexpression of p21(cip1). Thus, ET-1 induced cyclin D1 expression and stimulated CDK4 activity and cell cycle progression via the A-type receptor in rat mesangial cells. These effects were regulated by the expression of cyclin D1, p16(INK4), p21(cip1), and phosphorylatable form of pRb. The results of the present study provide the basis for further investigation of basic and therapeutic approaches towards mesangial proliferative diseases.

    DOI： 10.1046/j.1523-1755.1998.00730.x

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  • Expression of PDGF and PDGF receptor mRNA in glomeruli in IgA nephropathy 査読

    Y Terada, T Yamada, O Nakashima, S Sasaki, H Nonoguchi, K Tomita, F Marumo

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY   8 ( 5 )   817 - 819   1997年5月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILLIAMS & WILKINS  

    This study investigated the mRNA expression of the platelet-derived growth factor (PDGF) A-chain and B-chain and PDGF-beta receptor in glomeruli of 15 immunoglobulin A (IgA) nephropathy kidneys and those with minimal-change lesion (N = 7), membranous nephropathy (N = 3), and focal segmental glomerulonephritis (N = 5), by using competitive RT-PCR methods. The level of PDGF B-chain and beta receptor mRNA expression in IgA nephropathy was significantly higher than in the other forms of glomerulonephritis, but mRNA expressions of PDGF A-chain were not significantly different. Significant correlations were observed between the urinary protein level and the mRNA level of PDGF-beta receptor expression and PDGF B-chain expression, and between the serum creatinine level and the mRNA level of PDGF-beta receptor expression. The PDGF B-chain and beta-receptor may be upregulated and accelerate cell proliferation in a paracrine or autocrine manner and may play a role in the pathogenesis of IgA nephropathy.

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  • Overexpression of cell cycle inhibitors (p16(INK4) and p21(Cip1)) and cyclin D1 using adenovirus vectors regulates proliferation of rat mesangial cells 査読

    Y Terada, T Yamada, O Nakashima, M Tamamori, H Ito, S Sasaki, F Marumo

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY   8 ( 1 )   51 - 60   1997年1月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILLIAMS & WILKINS  

    To elucidate the mechanisms of the cell cycle of mesangial cells, adenovirus vectors containing coding sequences of cyclin D1 (AxCAD1), p16(INK4) (AxCAp16) and p21(Cip1) (AxCAp21) were produced and investigated to determine whether transfer of these genes changes serum- and PDGF-induced proliferation of rat mesangial cells. Efficiency of the transfer of the genes was examined by Northern and Western blot analyses. The cell cycle of mesangial cells was evaluated by measurement of [H-3]-thymidine incorporation, flow cytometry, and cyclin-dependent kinase 4 kinase assay. Expression of cyclin D1, p16(INK4) and p21(Cip1) was observed from 24 h after the infection, and the expression increased up to 48 h. AxCAp16 and AxCAp21 caused a significant inhibition in the [H-3]-thymidine incorporation to 47% and 76%, respectively. AxCAp16 and AxCAp21 also inhibited the mitogen-induced increase in cyclin-dependent kinase 4 kinase activity and reduced the percentage of cells in S phase, Coinfection of AxCAp16 with AxCAp21 showed no additive inhibition. Overexpression of cyclin D1 reduced cell size and increased the percentage of the cells in S and G2 phase. These findings suggest that p16(INK4) and p21(Cip1) function as inhibitors of the proliferation of mesangial cells induced by growth-promoting factors and that deregulated expression of cyclin D1 causes cell cycle disturbances. Adenovirus-mediated gene transfer of p16(INK4) and p21(Cip1) serves as a potential therapeutic approach to mesangial proliferative diseases.

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  • Role of urinary arginine vasopressin in the sodium excretion in patients with chronic renal failure 査読

    H Nonoguchi, M Takayama, A Owada, K Ujiie, Y Sakuma, F Marumo, T Yamada, J Koike, K Tomita

    AMERICAN JOURNAL OF THE MEDICAL SCIENCES   312 ( 5 )   195 - 201   1996年11月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT-RAVEN PUBL  

    Patients with chronic renal failure show almost equal levels of sodium excreted in the urine as healthy subjects through an increase of the fractional excretion sodium (FE(Na)). The mechanisms of this adaptation, however, are unknown. Recently, urinary arginine vasopressin (AVP) has been shown to inhibit the antidiuretic action of plasma AVP in the collecting ducts of rabbits and rats. In this article, the roles of plasma and urinary AVP are examined with other hormones in the sodium excretion of 57 patients with chronic renal disease. The fractional excretion of AVP, plasma atrial natriuretic peptide (ANP) and endothelin-1 (ET-1), urinary ET-1, and FE(ET-1) correlated with the decrease of creatinine clearance (Ccr). Multiple and stepwise regression analyses showed that FE(AVP) is the major dependent determinant for FE(Na) (adjusted r(2) = 0.78). These results suggest that the increase of AVP excretion per remaining nephron could be a cause of the increase of FE(Na) in patients with renal failure. Although plasma AVP works as an antidiuretic hormone, urinary AVP serves as an intrinsic diuretic, especially in patients with chronic renal failure.

    DOI： 10.1097/00000441-199611000-00001

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  • Presence and regulation of Raf-1-K (kinase), MAPK-K, MAP-K, and S6-K in rat nephron segments 査読

    Y Terada, T Yamada, M Takayama, H Nonoguchi, S Sasaki, K Tomita, F Marumo

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY   6 ( 6 )   1565 - 1577   1995年12月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC NEPHROLOGY  

    Renal nephron segments are heterogeneous, and receptors for endothelin (ET)-1, ET-3, Angiotensin II (All), epidermal growth factor (EGF), and insulin-like growth factor I distribute differently along the nephron segments. Recently, growth factors and vasoactive substances are reported to stimulate mitogen-activated protein kinase (MAP-K). In this study, we showed that mRNA and proteins of MEK-K, Raf-1-K, MAPK-K, MAP-K (p42 and p44), and S6-K are expressed ubiquitously in intact nephron segment. We demonstrated that four tiers of a cascade composed of the Raf-1-K, MAPK-K, MAP-K, and S6-K are stimulated by ET-1 and ET-3 in rat intact glomeruli (Glm) via primarily B-type ET receptors and PKC. The stimulatory effect of EGF and IGF-I to MAP-K activity is inhibited by a tyrosine kinase inhibitor in Glm. IGF-I significantly stimulates MAP-K activity and EGF and All moderately stimulate MAP-K activity in the proximal convoluted tubule (PCT). EGF significantly increased MAP-K cascades and ET-1 and ET-3 slightly increased MAP-K cascades in the medullary thick ascending limb (MTAL), EGF significantly stimulated MAP-K cascades, and ET-1 and ET-3 moderately stimulate MAP-K cascades in the outer medullary collecting duct (OMCD) and the inner medullary collecting duct (IMCD). MAPK-K and S6-K are similarly stimulated by these agonists in each segment. This study shows that MAP-K cascades are expressed in every nephron segment, ET-1, ET-3, All, EGF, and IGF-I stimulate MAP-K cascades heterogeneously along the nephron segment. It was concluded that MAP-K cascades play an important role in the regulation of renal function.

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  • SEQUENTIAL ACTIVATION OF MAP KINASE CASCADE BY ANGIOTENSIN-II IN OPOSSUM KIDNEY-CELLS 査読

    Y TERADA, K TOMITA, MK HOMMA, H NONOGUCHI, TX YANG, T YAMADA, Y YUASA, EG KREBS, F MARUMO

    KIDNEY INTERNATIONAL   48 ( 6 )   1801 - 1809   1995年12月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL SCIENCE PUBL INC CAMBRIDGE  

    Angiotensin II (Ang II) is a potent regulator of proximal tubule functions, including transport, metabolism, and cell proliferation. The opossum kidney (OK) cell line is a useful model of renal proximal tubule. Mitogen-activated protein (MAP) kinases are rapidly phosphorylated and activated in response to various agonists. We investigated Ang II effects on serine/threonine kinase cascades in OK cells. The major findings of the present study are that Ang II stimulated MAP kinase kinase (MAPKK), MAP kinase (MAPK), and S6 kinase activities, and that it increased phosphorylation of Raf-1 kinase and p42 MAP kinase in OK cells. These stimulations of kinases were dose-dependent (from 10(-6) to 10(-11) M). The time course of activation was sequential; the peak stimulation was reached at 5 to 10 minutes for Raf-1 kinase, MAPKK and MAPK, and at 20 minutes for S6 kinase. The activation of MAPK was inhibited by approximately 70% with prolonged 24-hour PMA pretreatment or in the presence of calphostin C or H-7. Tyrosine kinase inhibitors (genistein and herbimycin) did not inhibit Ang II-induced MAPK activity. This activation of MAPK was also inhibited via AT(I) receptor antagonist, Dup753 and pertussis toxin. This evidence suggests that the activation of serine/threonine cascades by Ang II is largely dependent, on PMA-sensitive PKC, and is not dependent on tyrosine kinase and pertusis toxin.

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  • AVP INHIBITS EGF-STIMULATED MAP KINASE CASCADE IN MADIN-DARBY CANINE KIDNEY-CELLS 査読

    T YAMADA, Y TERADA, MK HOMMA, H NONOGUCHI, S SASAKI, Y YUASA, K TOMITA, F MARUMO

    KIDNEY INTERNATIONAL   48 ( 3 )   745 - 752   1995年9月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL SCIENCE PUBL INC CAMBRIDGE  

    We investigated the effects of epidermal growth factor (EGF) and arginine vasopressin (AVP) on Raf-1-MAP kinase cascade, including Raf-1-kinase (Raf-1-K), MAP kinase kinase (MAPKK), MAP kinase (MAPK) and S6 kinase (S6K) in Madin-Darby canine kidney (MDCK) cells. In a dose-dependent manner (10(-10) M to 10(-6) M), EGF increased autophosphorylation of Raf-1-K and activated MAPKK, MAPK and S6K. Sequential activation of these kinases was indicated by their peak times of activation (Raf-1-K 5 min; MAPKK 10 min; MAPK 15 min; and S6K 30 min). AVP (10(-9) M to 10(-6) M) inhibited EGF-stimulated MAP kinase cascade. 8-Bromo-cyclic AVP (cAMP) could mimic the inhibitory effect of AVP on EGF-stimulated MAP kinase cascade, These results were confirmed using H-89, an inhibitor of protein kinase A (PKA) that blocked the effect of AVP on EGF-stimulated MAPK activity. We conclude that AVP inhibits EGF-stimulated Raf-1-K, MAPKK, MAPK, and S6K activity via cAMP in MDCK cells. Our results indicate that MAP kinase cascade may play an important role in integrating the effects of AVP and EGF on distal tubule function.

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  • SEQUENTIAL ACTIVATION OF RAF-1 KINASE, MITOGEN-ACTIVATED PROTEIN (MAP) KINASE KINASE, MAP KINASE, AND S6 KINASE BY HYPEROSMOLALITY IN RENAL-CELLS 査読

    Y TERADA, K TOMITA, MK HOMMA, H NONOGUCHI, TX YANG, T YAMADA, Y YUASA, EG KREBS, S SASAKI, F MARUMO

    JOURNAL OF BIOLOGICAL CHEMISTRY   269 ( 49 )   31296 - 31301   1994年12月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    In the renal medulla during antidiuresis, the extracellular fluid becomes hyperosmotic. Madin-Darby canine kidney (MDCK) epithelial cells adapt in hyperosmotic conditions and serve as a useful tissue culture model for cellular responses to hyperosmolality, We demonstrate that hyperosmolality stimulates phospholipase C, Raf-1 kinase mitogen-activated protein (MAP) kinase kinase, MAP kinase, and S6 kinase activities and that it increases phosphorylation of Raf-1 kinase, and p42 MAP kinase in MDCK cells. Stimulation of these kinases is osmolality-dependent (from 300 to 600 mosm/kg H2O). The time course of activation is sequential; the peak stimulation for Raf-1 kinase is at 5 min, at 10 min for MAP kinase kinase and MAP kinase, and at 20 min for S6 kinase. The activation of Raf-1 kinase and MAP kinase is inhibited by phorbol 12-myristate 13-acetate pretreatment in the presence of calphostin C or H-7. Tyrosine kinase inhibitors (genistein, herbimycin) do not significantly suppress hyperosmolality-induced MAP kinase activity. The increase of Ins-1,4,5-P-s levels by hyperosmolality suggests that activation of these kinases is mediated at least partially via activation of phospholipase C.
    Thus, hyperosmolality stimulates the serine/threonine kinases, Raf-1 kinase, MAP kinase kinase, MAP kinase, and S6 kinase, via predominantly protein kinase C-dependent, tyrosine kinase-independent pathways in MDCK cells.

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