Naoki Yoshimura

  • Professor, Departments of Urology and of Pharmacology & Chemical Biology

Education & Training

  • School of Medicine, Kyoto University, M.D. 03/1981 Medicine
  • School of Medicine, Kyoto University, Residency 03/1985 Urology
  • Graduate School, Kyoto University, Ph.D. 03/1989 Neuro-urology

A. Personal Statement

I have extensive training in physiology and neuropharmacology applied to visceral and somatic systems in the lower urinary tract. One of the most important discoveries involves my work on bladder and urethral dysfunction using animal models of lower urinary tract dysfunction induced by spinal cord injury, bladder outlet obstruction (BOO) and prostatic inflammation. Our findings revealed that chemical mediators such as growth factors and inflammatory changes in the lower urinary tract (bladder, urethra, prostate) significantly alter lower urinary tract function to induce bladder and urethral dysfunctions causing both storage and voiding problems, which potentially underlies lower urinary tract symptoms (LUTS). Thus, my expertise has laid the groundwork to study this new and exciting area exploring prostate-to-bladder sensitization mechanisms underlying bladder dysfunction and afferent hyperexcitability in chemically and genetically induced rodent models of prostatic inflammation. In summary, I have a demonstrated record of successful and productive research projects in this area of urologic problems, and my expertise and experience have prepared me to complete the proposed Project 2 of this U54 renewal application.

B. Positions and Honors

1989-1990                    Division of Urology, Osaka Chief Urologist Saiseikai-Noe Hospital,
                                     Osaka, Japan
1990-1996                    Department of Urology Instructor Faculty of Medicine, Kyoto
                                     University, Kyoto, Japan
1991-1993                    Department of Pharmacology Research Associate University of
                                     Pittsburgh, School of Medicine, Pittsburgh, PA
1996-1999                    Department of Pharmacology Research Assistant Professor
                                     University of Pittsburgh, School of Medicine, Pittsburgh, PA
1999-2001                    Department of Pharmacology Research Associate Professor
                                     University of Pittsburgh, School of Medicine, Pittsburgh, PA
2001-2008                    Departments of Urology and Pharmacology Associate Professor
                                     University of Pittsburgh, School of Medicine, Pittsburgh, PA
2008-present                Departments of Urology and Pharmacology Professor (with tenure)
                                     University of Pittsburgh, School of Medicine, Pittsburgh, PA
2016-present                Department of Urology UPMC Endowed Chair of Neurourology
                                     Research, University of Pittsburgh, School of Medicine, Pittsburgh, PA

Honors and Awards

1995    The Japanese Society for Neurogenic Bladder Award for Basic Research
1999     International Jack Lapides Essay Contest on Urodynamic and Neuro-urology Research,
             Grand Prize Winner
1999     Urodynamic Society’s 20 Annual Meeting Best Poster Essay Contest,
             Grand Prize Winner
1999     94th American Urological Association Annual Meeting Best Abstract Contest in Urinary
             Incontinence, Grand Prize Winner
2001     International Jack Lapides Essay Contest on Urodynamic and Neuro-urology Research,
             2nd Prize Winner; Michael E. Franks (Mentee)
2007     International Jack Lapides Essay Contest on Urodynamic and Neuro-urology Research,
             2nd Prize Winner; Ryuichi Kato (Mentee)
2009     Winter Meeting of Society for Urodynamics and Female Urology (SUFU) Prize Essay
             Winner; Minoru Miyazato (Mentee)
2009     International Jack Lapides Essay Contest on Urodynamic and Neuro-urology Research,
             Grand Prize Winner; Minoru Miyazato (Mentee)
2012     International Jack Lapides Essay Contest on Urodynamic and Neuro-urology Research,
             Grand Prize Winner; Akira Furuta (Mentee)
2016     International Diokno/Lapides Essay Contest on Urodynamic and Neuro-urology
             Research, Grand Prize Winner; Takahiro Shimizu (Mentee)

C. Contributions to Science

Selected from 335 research articles, 34 reviews

1. We conducted the electrophysiological studies to characterize the functional properties of organspecific visceral efferent and primary afferent pathways using patch-clamp techniques.

  1. Yoshimura, N., Seki, S., Erickson, K.A., Erickson, V.L., Chancellor M.B. and de Groat, W.C.: Histological and electrical properties of rat dorsal root ganglion neurons innervating the lower urinary tract. Journal of Neuroscience, 23: 4355-4561, 2003.
  2. Yoshimura, N., Bennett, N.E., Hayashi, Y., Ogawa, T., Nishizawa, O., Chancellor, M.B., de Groat, W.C., Seki, S.: Bladder overactivity and hyperexcitability of bladder afferent neurons following intrathecal delivery of nerve growth factor in rats. Journal of Neuroscience, 26: 10847-10855, 2006.
  3. Kadekawa, K.*, Majima T.* (* Equal contribution), Shimizu, T., Wada, N., de Groat, W.C., Kanai, A.J., Goto, M., Yoshiyama, M., Sugaya, K., Yoshimura, N.: The role of capsaicin-sensitive C-fiber afferent pathways in the control of micturition in spinal intact and spinal cord injured mice. American Journal of Physiology Renal Physiology, 313: F796–F804, 2017

2. Electrophysiological and pharmacological experiments revealed the ion channel mechanisms underlying afferent hyperexciatbility in animal models of lower urinary tract dysfunction.

  1. Yoshimura, N. and de Groat W.C.: Increased excitability of afferent neurons innervating rat urinary bladder following chronic bladder inflammation. Journal of Neuroscience, 19: 4644-4653, 1999.
  2. Yoshimura, N., Seki, S., Novakovic, S.D., Tzoumaka, E., Erickson, V.L., Erickson, K.A., Chancellor, M.B. and de Groat, W.C.: The involvement of the tetrodotoxin-resistant sodium channel Nav1.8 (PN3/SNS) in a rodent of visceral pain. Journal of Neuroscience, 21: 8690-8696, 2001.
  3. Hayashi, Y., Takimoto, K., Chancellor, M.B., Erickson, K.A., Erickson, V.L., Kirimoto, T., Nakano, K., de Groat, W.C., Yoshimura, N.: Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 α-subunit in rats with cystitis. American Journal of Physiology Regulatory, Integrative and Comparative Physiology, 296: R1661-1670, 2009.

3. We also revealed the importance of nerve growth factor (NGF) for the control of bladder activity and afferent excitability in various lower urinary tract dysfunction using animal models.

  1. Yoshimura, N., Bennett, N.E., Hayashi, Y., Ogawa, T., Nishizawa, O., Chancellor, M.B., de Groat, W.C., Seki, S.: Bladder overactivity and hyperexcitability of bladder afferent neurons following intrathecal delivery of nerve growth factor in rats. J Neuroscience, 26: 10847-10855, 2006.
  2. Kadekawa, K., Yoshizawa, T., Wada, N., Shimizu, T., Majima, T., Tyagi, P., de Groat, W.C., Sugaya, K., Yoshimura, N.: Effects of liposome-based local suppression of nerve growth factor in the bladder on autonomic dysreflexia during urinary bladder distention in rats with spinal cord injury. Experimental Neurology, 291:44-50, 2017.
  3. Shimizu, T., Majima, T., Suzuki, T., Shimizu, M., Wada, N., Kadekawa, K., Takai, S., Takaoka, E., Kwon, J.B., Kanai, A.J., de Groat, W.C., Tyagi, P., Saito, M., Yoshimura, N.: Nerve growth factor-dependent hyperexcitability of capsaicin sensitive bladder afferent neurones in mice with spinal cord injury. Experimental Physiology, 103: 896-904, 2018.

4. We also developed a rat model of chemically-induced prostatic inflammation and characterized the prostate-to-bladder sensitization mechanisms inducing bladder overactivity following prostatic inflammation that is often associated with BPH/LUTS.

  1. Funahashi, Y, O’Malley, K.J., Kawamorita, N., Tyagi, P., DeFranco, D.B., Takahashi, R., Gotoh, M., Wang, Z., Yoshimura, N.: Upregulation of androgen-responsive genes and transforming growth factor-α1 cascade genes in a rat model of non-bacterial prostatic inflammation. The Prostate, 74: 337-345, 2014.
  2. Mizoguchi, S., Mori, K., Wang, Z., Funahashi, Y., Sato, F., DeFranco, D.B., Yoshimura, N. (Corresponding author), Mimata, H.: Effects of estrogen receptor β stimulation in a rat model of nonbacterial prostatic inflammation. The Prostate, 77: 803-811, 2017.
  3. Funahashi, Y., Takahashi, R., Mizoguchi, S., Suzuki T., Takaoka, E., Ni, J., Wang, Z., DeFranco, D.B., de Groat, W.C., Tyagi, P., Yoshimura, N.: Bladder overactivity and afferent hyperexcitability induced by prostate-to-bladder cross-sensitization in rats with prostatic inflammation. Journal of Physiology (London), 597: 2063-2078, 2019.
  4. Ni, J., Mizoguchi, S., Bernardi, K., Suzuki, T., Kurobe, M., Takaoka, E. Wang, Z., DeFranco, D.B. Tyagi, P., Gu, B., Yoshimura, N.: Long-lasting bladder overactivity and bladder afferent hyperexcitability in rats with chemically-induced prostatic inflammation. The Prostate, 79: 872-879, 2019.
  5. Li, F., Pascal, L.E., Stolz,.D.B., Wang, K., Zhou, Y., Chen, W., Xu, Y., Chen, Y., Dhir, R., Parwani, A.V., Nelson, J.B., DeFranco, D.B., Yoshimura, N., Balasubramani, G.K., Gingrich, J.R., Maranchie, J.K., Jacobs, B.L., Davies, B.J., Hrebinko, R.L., Bigley, J.D., McBride, D., Guo, P., He, D., Wang, Z.: Ecadherin is downregulated in benign prostatic hyperplasia and required for tight junction formation and permeability barrier in the prostatic epithelial cell monolayer. The Prostate, 79:1226-1237, 2019.
  6. Mizoguchi, S., Wolf-Johnson, A.S., Ni, J., Mori, K., Suzuki, T., Takaoka, E., Mimata, H., DeFranco, D.B., Wang, Z., Birder, L.A., Yoshimura, N.: The role of prostaglandin and EP4 receptors in development of bladder overactivity in a rat model of chemically induced prostatic inflammation. BJU International, 124: 883–891, 2019.
  7. Alexandre, E.C., Cao, N., Mizoguchi, S., Saito, T., Kurobe, M., Gotoh, D., Okorie, M., Igarashi, T., Antunes, E., Yoshimura, N.: Urethral dysfunction in a rat model of chemically-induced prostatic inflammation: potential involvement of the MRP5 pump. American Journal of Physiology Renal Physiology, 318: F754-F762, 2020.
  8. Mizoguchi, S,, Mori, M., Toshitaka, S., Wang, Z., DeFranco, D.B., Yoshimura, N. (Corresponding author), Mimata, H.: Effects of dutasteride in a rat model of chemically induced prostatic inflammation – potential role of estrogen receptor β. The Prostate, 2020. Dec;80(16):1413-1420. doi: 10.1002/pros.24071. Epub 2020 Sep 17. PubMed PMID: 32941694; PubMed Central PMCID: PMC7685523.

5. After appreciating the mechanisms inducing DO and DSD in SCI, we tested the feasibility of herpes simplex virus (HSV) vector-based gene delivery of therapeutic genes to the urogenital organs and their neural pathways as new, effective treatments of lower urinary tract dysfunction or new HSV vectors encoding ligand-regulated endogenous ion channels under the control of cell-type-specific promoters.

  1. Miyazato, M., Sugaya, K., Goins, W.F., Wolfe, D., Goss, J.R., Chancellor, M.B., de Groat, W.C., Glorioso, J.C., Yoshimura, N.: Herpes simplex virus vector-mediated gene delivery of glutamic acid decarboxylase reduces detrusor overactivity in spinal cord injured rats. Gene Therapy, 16: 660-668, 2009.
  2. Shimizu, N., Doyal, M.F., Goins, W.F., Kadekawa, J., Wada, N., Kanai, A.J., de Groat, W.C., Hirayama, A., Uemura, H., Glorioso, J.C., Yoshimura, N.: Morphological changes in different populations of bladder afferent neurons detected by herpes simplex virus (HSV) vectors with cell type-specific promoters in mice with spinal cord injury. Neuroscience, 364:190-201, 2017.
  3. Takai, S., Majima, T., Reinhart, B., Goins, W.F., Funahashi, Y., Gotoh, M., Tyagi, P., Glorioso, J.C., Yoshimura, N.: Effects of herpes simplex virus vectors encoding poreless TRPV1 or protein phosphatase 1α in a rat cystitis model induced by hydrogen peroxide. Gene Therapy 25: 20–26, 2018.

To summarize – by using animal models of lower urinary tract disorders that enable us to evaluate the detailed physiological mechanisms, we have identified alterations in ion channel and growth factor mechanisms that contribute to lower urinary tract dysfunction using a variety of animal models of human diseases. Thus, the above work motivates the present focus of our lab team in this project– the study of bladder overactivity and afferent sensitization in chemically and genetically induced rodent models of prostatic inflammation, which investigates the pathophysiological mechanisms inducing male LUTS following prostatic inflammation that is often detected in BPH.

View a complete listing of publications