Mitsuishi, Yuko



School of Medicine, Center for Preventive Medicine (Shinanomachi)



Academic Background 【 Display / hide


    Keio University

    Graduate School, Doctoral course

Academic Degrees 【 Display / hide

  • 博士(医学), Keio University, Coursework, 2018.03

Licenses and Qualifications 【 Display / hide

  • 日本内分泌学会内分泌代謝内科専門医

  • 日本糖尿病学会糖尿病専門医

  • 日本医師会認定産業医, 2018.11

  • 総合内科専門医, 2018.12


Research Areas 【 Display / hide

  • Life Science / Metabolism and endocrinology


Papers 【 Display / hide

  • Epidermal growth factor receptor/extracellular signal-regulated kinase pathway enhances mineralocorticoid receptor transcriptional activity through protein stabilization

    Mitsuishi Y., Shibata H., Kurihara I., Kobayashi S., Yokota K., Murai-Takeda A., Hayashi T., Jo R., Nakamura T., Morisaki M., Itoh H.

    Molecular and Cellular Endocrinology (Molecular and Cellular Endocrinology)  473   89 - 99 2018.09

    ISSN  03037207

     View Summary

    © 2018 Elsevier B.V. Activation of mineralocorticoid receptor (MR) is evoked by aldosterone, and it induces hypertension and cardiovascular disease when it's concomitant with excessive salt loading. We have proposed the notion of “MR-associated hypertension” in which add-on therapy of MR blockers is effective even though serum aldosterone level is within normal range. To elucidate its underlying molecular mechanism, we focused on the effect of epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) activation on MR activity. Epidermal growth factor (EGF) administration increased MR transcriptional activity through EGFR/ERK pathway and increased protein level by counteracting MR ubiquitylation in vitro. EGF administration in vivo also increased MR protein level and target gene expression in kidney, which were decreased by EGFR inhibitor. In addition, the administration of EGFR inhibitor lowered systolic blood pressure and MR activity in DOCA/salt-treated mice. In conclusion, EGFR/ERK pathway activation is considered as one of the underlying mechanisms of aberrant MR activation and EGFR/ERK pathway blockade could be an alternative approach for the prevention of MR-related cardiovascular events.

  • Intestinal mineralocorticoid receptor contributes to epithelial sodium channel–mediated intestinal sodium absorption and blood pressure regulation

    Nakamura T., Kurihara I., Kobayashi S., Yokota K., Murai-Takeda A., Mitsuishi Y., Morisaki M., Kohata N., Oshima Y., Minami Y., Shibata H., Itoh H.

    Journal of the American Heart Association (Journal of the American Heart Association)  7 ( 13 )  2018.07

     View Summary

    © 2018 The Authors. Background-—Mineralocorticoid receptor (MR) has pathological roles in various cell types, including renal tubule cells, myocytes, and smooth muscle cells; however, the role of MR in intestinal epithelial cells (IECs) has not been sufficiently evaluated. The intestine is the sensing organ of ingested sodium; accordingly, intestinal MR is expected to have essential roles in blood pressure (BP) regulation. Methods and Results-—We generated IEC-specific MR knockout (IEC-MR-KO) mice. With a standard diet, fecal sodium excretion was 1.5-fold higher in IEC-MR-KO mice, with markedly decreased colonic expression of b- and c-epithelial sodium channel, than in control mice. Urinary sodium excretion in IEC-MR-KO mice decreased by 30%, maintaining sodium balance; however, a low-salt diet caused significant reductions in body weight and BP in IEC-MR-KO mice, and plasma aldosterone exhibited a compensatory increase. With a high-salt diet, intestinal sodium absorption markedly increased to similar levels in both genotypes, without an elevation in BP. Deoxycorticosterone/salt treatment elevated BP and increased intestinal sodium absorption in both genotypes. Notably, the increase in BP was significantly smaller in IEC-MR-KO mice than in control mice. The addition of the MR antagonist spironolactone to deoxycorticosterone/salt treatment eliminated the differences in BP and intestinal sodium absorption between genotypes. Conclusions-—Intestinal MR regulates intestinal sodium absorption in the colon and contributes to BP regulation. These regulatory effects are associated with variation in epithelial sodium channel expression. These findings suggest that intestinal MR is a new target for studying the molecular mechanism of hypertension and cardiovascular diseases.

Research Projects of Competitive Funds, etc. 【 Display / hide

  • アルドステロン産生細胞クラスターの成因と食塩感受性高血圧における意義の解明


    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Early-Career Scientists , Principal investigator