ESSAY | TOWARD JES 100TH ANNIVERSARY
Once in a Lifetime~Dream, Passion, Challenge, and Respect for Peers~
2024 Volume 71 Issue 7 Pages 637-642
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2024 Volume 71 Issue 7 Pages 637-642
I would like to congratulate the Japan Endocrine Society on its upcoming 100th anniversary. Clinical and research endeavors in endocrinology at the Second Department of Internal Medicine, Tohoku University School of Medicine, were pioneered by Professor Tatsuo Torikai (Fig. 1), who was the first in Japan to discover primary aldosteronism [1]. Under Professor Torikai’s guidance, a lineage of leaders emerged, including successors like Drs. Kaoru Yoshinaga (Tohoku University), Keishi Abe (Tohoku University), Yukio Miura (Tohoku University), Tatsuo Sato (Kumamoto University), Kiyoshi Miura (Gifu University), Soetsu Fukuchi (Fukushima Medical University), and the Demuras (Tokyo Women’s Medical University). I joined the Second Department of Internal Medicine in 1981 and began my research on the renin-angiotensin-aldosterone system under the guidance of Dr. Abe. Subsequently, I spent over ten years living in the United States, and even after returning to Japan, I was involved in various national projects, gaining valuable experience. I have been fortunate to meet and receive assistance from many outstanding individuals, which has brought me to this point in my professional career. This article summarizes these experiences, and I hope it will be of use to the next generation.
Professor Tatsuo Torikai. Around 1960 (approximately at the age of 50).
I graduated from Tohoku University School of Medicine in 1979 and completed my initial clinical training at Furukawa City Hospital (currently Osaki Citizen Hospital), where I received the kind attention of many doctors on the staff. In particular, when I first met Dr. Takashi Kusaka, who was ten years my senior, he said to me, “We are colleagues as physicians, and we must respect and help each other. Therefore, I will call you ‘Dr. Ito’ instead of addressing you as a trainee doctor or using ‘Ito-kun.’ Keep that in mind.” These words deeply resonated with me.
In April 1981, I joined the Second Department of Internal Medicine (led by Professor Kaoru Yoshinaga) at Tohoku University, to study the pathophysiology of internal medicine. I apprenticed under Dr. Abe (Associate Professor). Three months after joining his team, Dr. Abe told me, “Starting next year, you will go to Oscar Carretero’s lab at Henry Ford Hospital in Detroit. At any rate, your assignment is to write an original research paper in English in one year. A mentor will be assigned to you (Dr. Masahide Seino). However, you must fulfill all your duties as a first-year fellow.” Well, I accepted the challenge with a mixture of optimism and a desire to explore the wider world. Fortunately, with the help of Dr. Seino and colleagues, I managed to complete the paper after a year [2], and in May 1982, I traveled to the United States with my newlywed wife. The memory of the huge, bright, rising red sun as we landed at Dallas Airport in Texas remains unforgettable.
My predecessor, Dr. Ken Omata, had published papers in Kidney International using microdissection methods to measure the kallikrein in connecting tubules. For the time being, I learned the microdissection methods from Dr. Omata. After a while, Oscar (as I called Dr. Carretero) said to me, “I have arranged with Keishi Abe that you would work with me for two years. You have two research projects. One is a biochemical study using microdissection methods in the tubules, which would probably result in about two papers in top-class journals over two years. The other is a project to verify whether the macula densa is involved in renin secretion. However, it’s uncertain if this is feasible. Also, you need to come up with all the methods by yourself. Which one will you choose?” I chose the latter.
The macula densa consists of specialized tubular cells and is closely in contact with the glomerular afferent arteriole containing renin-secreting juxtaglomerular cells. Over 40 years before I began my research, Norbert Goormaghtigh proposed that the macula densa senses NaCl concentration in the lumen and regulates renin secretion and glomerular hemodynamics [3]. Subsequently, Dr. Arthur J. Vander from the University of Michigan conducted detailed in vivo analyses in dogs, suggesting that decreased NaCl reaching the macula densa leads to increased renin secretion, and hypothesized the importance of Na-K-2Cl co-transporter-mediated reabsorption in the macula densa [4]. On the other hand, Thurau K et al. from the University of Munich, using micropuncture techniques, hypothesized that an increase in NaCl concentration at the macula densa activates the renin-angiotensin system, causing constriction of the afferent arteriole and decreased glomerular filtration rate [5]. Both hypotheses contradicted each other and lacked direct evidence due to the use of in vivo research approaches.
To start with, I decided to verify whether the macula densa indeed regulates renin secretion. I planned to prepare two samples, one made up of isolated afferent arterioles alone and the other afferent arterioles with attached macula densa, and to measure renin secretion from each. Since the only difference in the two preparations was the presence or absence of the macula densa, any observed differences would directly demonstrate the existence of the macula densa mechanism. Moreover, with such simplified samples, I believed I could unveil the details of the macula densa mechanism without the influence of systemic hemodynamics or neurohormones. The idea was straightforward and simple, yet achieving it was not easy. Various innovations were implemented, such as developing methods to isolate the afferent arterioles and the macula densa, consecutive incubation of tiny samples, and measuring minute amounts of secreted renin from these samples. Techniques included using titanium forceps sharpened at the tip with diamond-polishing sandpaper for isolation. As a result, after 2 years, experimental results revealed significant differences in baseline renin secretion and responsiveness to drugs when the macula densa was present (Fig. 2), and this was the first demonstration that the macula densa regulates renin secretion [6].
Effect of furosemide on renin release from afferent arteriole (Af, red circle) and afferent arteriole with macula densa (Af + MD, purple circle). * = p < 0.001 compared with the control period.
During that time, I repeated many trials and errors but also received the benefit from fortunate accidents as well as the help of many people. Especially, Mrs. Matsuko Nakano, my middle school Japanese teacher, sent me encouraging letters every day for the two and a half years until we returned to Japan. Her letters were the support my wife and I needed as we faced the challenges of our impoverished life living on a meager fellowship in dangerous Detroit with the highest murder rate in the United States, especially since I had not yet obtained the research results I sought even after the first 2 years. We were truly grateful for her encouragement.
I finally could present my research findings at the American Heart Association (AHA) Council on High Blood Pressure Research (currently Council on Hypertension) held in Cleveland. Dr. Abe attended this conference and was greatly pleased. Dr. Abe, my wife, and I came back together to Detroit by the car I drove, enjoying the beautiful autumn leaves and unforgettable scenery. On the day we came back, Oscar hosted a welcoming party for Dr. Abe. Coincidentally, it was the day of the final game of the World Series in baseball, and it was the day when the Detroit Tigers won. Everybody was excited, and so was Dr. Abe because his hobby was playing baseball.
I noticed that in order to further advance my research, I needed to microperfuse the macula densa and investigate the renin secretion response when changing the NaCl concentration in the lumen. However, I had already spent over two and a half years in the United States, so I decided to return to clinical practice in Japan. I said to Oscar, “Let my successor handle that project.” Despite his many efforts to keep me, I eventually returned to the Second Department of Internal Medicine at Tohoku University in December 1984.
Upon my return to Tohoku University, I continued my research while assisting at associated hospitals in the region. About a year later, I received repeated phone calls from Oscar, always in the middle of the night, requesting me to return to Henry Ford Hospital as Senior Staff. After much contemplation, I decided to challenge myself, aiming to successfully complete the macula densa perfusion experiment and return to Japan in a year and a half. In June 1987, I went to Henry Ford Hospital with my family once again.
Dr. Richard J. Roman from the Medical College of Wisconsin kindly lent me a set of perfusion equipment, and I learned microperfusion techniques from Dr. Phillip Darwin Bell in the Navar lab at the University of Alabama. By the end of August, preparations for the experiment were almost complete. However, in the September issue of Science, the results of the experiment I had planned to obtain were reported by Skott and Briggs [7]. I was greatly disappointed, but with the encouragement from many people and the support of excellent researchers, I gathered up my courage and redirected my focus on directly demonstrating the mechanism of regulating glomerular hemodynamics, another function of the macula densa. This required microperfusing both the macula densa and the afferent arteriole simultaneously, observing them under a microscope, and investigating whether the afferent arteriole constricts or dilates in response to changes in NaCl concentration of the macula densa perfusion fluid. Arterial perfusion was much more challenging than tubular perfusion. The difficulties included: 1) the afferent arteriole was about 200 μm in length, with a very limited portion suitable for perfusion; 2) it was necessary to measure intravascular pressure in the arteriole; 3) perfusing the afferent arteriole at a high pressure of 60 mmHg required complete airtightness throughout the system. Thus, I needed to design and develop a complex perfusion system with a glass pipette made up of four layers and apparatus to manipulate it. There were many difficulties since there were no precedents, but fortunately, about a year and a half after arriving in the United States, I completed this system in January 1989 (Fig. 3). Then, I was able to directly observe, for the first time, that the afferent arteriole contracted when the NaCl concentration in the macula densa perfusion fluid increased [8, 9] (Fig. 4).
Schematic representation of the pipette arrangement used for simultaneous perfusion of an afferent arteriole and attached macula densa (left) and V-track for the manipulation of pipettes (right). Abbreviations: Af-Art, afferent arteriole; Ef-Art, efferent arteriole; MD, macula densa; Gl, glomerulus; TAL, thick ascending limb of Henle’s loop; DCT, distal convoluted tubule; Hold-P, holding pipette; Perf-P, perfusion pipette; Exch-P, exchange pipette; Pre-P, pressure pipette.
Photographs of the microperfused afferent arteriole and attached macula densa (above) and constriction of the afferent arteriole induced by changing macula densa perfusate from low NaCl to high NaCl (below). Abbreviations: Af-Art, afferent arteriole; Ef-Art, efferent arteriole; MD, macula densa; Gl, glomerulus; TAL, thick ascending limb of Henle’s loop; DCT, distal convoluted tubule.
Subsequently, I obtained substantial research funding from the NIH and other sources and expanded my research laboratory significantly. Our group was affectionately called “the Ito Mafia” by colleagues in the AHA Hypertension Council. I received U.S. permanent residency, obtained a tenured position with a guaranteed salary of 100%, purchased a home in a beautiful suburb, and enjoyed a fulfilling life with no complaints. At such a time, my mentor, Dr. Abe (at that time, Professor of the Second Department of Internal Medicine at Tohoku University), who was supposed to retire in two years, asked me to come back to his department. Expressing my gratitude for all that Dr. Abe had done for me, I decided to go back to return the favor. Oscar understood the situation and said, “When Dr. Abe retires two years later, then come back again. We’ll keep a position open for you.” Finally, I went back to Japan with my family on March 20, 1995. Coincidentally, it was the day of the subway sarin gas attack in Tokyo. In the end, my stay in the United States lasted more than 10 years in total, during which time I worked in a very competitive environment and established by myself a research laboratory with international recognition. During this time, I learned a lot and made friends all over the world with whom I could have heartfelt conversations. This network of researchers who trusted and respected each other was essential for the subsequent success of international large-scale clinical trials such as ROADMAP and ORIENT [10, 11].
On June 25, 1997, I received a sudden call from the Dean of the Medical School, Dr. Shigeru Hisamichi, asking me to come to his office. He informed me that I was selected as a candidate for the position of Professor in the Second Department of Internal Medicine. At that time, the professor selection process was not open to public applications; it was based on the committee’s investigation and the judgment of the Board of professors. After discussing this with Oscar, I decided not to return to Henry Ford Hospital but to remain at my alma mater, Tohoku University, for the rest of my career. Ultimately, in August 1997, I was appointed as Professor and Chairman of the Second Department of Internal Medicine.
Soon after becoming a professor, I asked Dr. Abe, why he had sent me abroad right after joining the department. He replied, “I believe it’s important to expose my fellows to the world’s atmosphere when they are young and have flexible thinking, and before ‘I get their hands dirty.’ And, I know that Ito-kun won’t refuse, no matter what I ask.” His answer deeply impressed me. This spirit of fostering young people was exactly what I had been experiencing both in Japan and overseas since my graduation. I affirmed to succeed this spirit too, and for the sake of nurturing the next generation, I actively engaged in exchanges with top-class researchers from around the world. This was to show young researchers the impact of interacting with the best and motivate the next generation. Moreover, I reaffirmed that I should not refuse the tasks given to me.
In 2011, the Great East Japan Earthquake occurred (Fig. 5). In the Tohoku region, particularly in Miyagi and Fukushima, there were profound problems with dialysis facilities collapsing, the Fukushima nuclear power plant accident, and issues with water and electricity supply. The lives of many dialysis patients were in danger. Consequently, we decided to move about 80 dialysis patients from the Kesennuma area to Hokkaido, distributing them among various facilities. However, due to political and economic turmoil and transportation difficulties, coordinating this endeavor was extremely challenging. Nonetheless, we managed to transport them via Japanese Government Self-Defense Force aircraft. Approximately three months later, all patients were able to return safely. The success of this wide-area relocation was thanks to the hard work of my department members led by Associate Professors Mariko Miyazaki, Takefumi Mori, and Hideyasu Kiyomoto and the support from many organizations and individuals throughout Japan, particularly Japanese Society of Nephrology, the Japanese Society for Dialysis Therapy, and Japanese Association of Dialysis Physicians.
The Great East Japan Earthquake. Locations of the epicenter, Sendai, and Fukushima nuclear power plant (upper right). The massive tsunami hitting the Sanriku Coast (upper left). The Shizugawa Hospital (Minamisanriku Town) destroyed by the tsunami (bottom right). The dialysis patients from Kesennuma boarding a Self-Defense Force aircraft for transport to Hokkaido (bottom left).
After addressing dialysis-related issues, I worked alongside Professor Masayuki Yamamoto to establish the Medical MegaBank Organization (https://www.megabank.tohoku.ac.jp). However, the following year, I was appointed as the Executive Vice President (Research Affairs) of Tohoku University. I worked on various projects to revitalize the university in this role. I successfully led all these projects with the support of many people, despite numerous challenges. In particular, the Tohoku Synchrotron Radiation Project is extremely important for scientific and industrial development in our country. This project involved collaboration between the Japanese government, local government, academia, and industry and experienced a chaotic and uncertain process after the earthquake. There were many difficulties. However, at last during my tenure, it was officially decided by the Japanese Government that this facility (named NanoTerasu) would be built at Aoba-yama Campus of Tohoku University, the most ideal location (https://www.sris.tohoku.ac.jp/en/). It was an absolute joy to me when this was decided.
Looking back, I faced numerous challenges and trials, but miraculously, people who were always ready to help appeared one after another, both in Japan and worldwide. When I returned to the United States for the second time and learned that it would take over a year to create experimental equipment, and I felt disappointed, Dr. Roman called me and said, “You are my rival, but not my enemy. I have an extra set of equipment here, so I’ll lend it to you.” I was able to recruit Mr. Daisuke Toki, who had been the President of Goldman Sachs Asset Management Co., Ltd. as a full-time staff member at Tohoku University, and he greatly assisted me to establish Tohoku Venture Partners Co. Ltd (https://thvp.co.jp/). Mr. Tetsuji Yanami, a former executive at Daicel Corporation, came to work with me, saying, “Deciding not to do something out of a sense of duty is cowardice.” Mr. Yanami assumed the position of the first President of this company. Dr. Masaki Takada also joined us and supported me to establish the Tohoku Synchrotron Radiation Facility, saying, “Let’s absolutely make this project a reality.” NanoTerasu is now scheduled to open for use in 2024. There are many more examples. They were truly exceptional individuals with high aspirations and admirable personal qualities. I’m deeply grateful to them. Along with realizing the value of people and recognizing the importance of “once in a lifetime” encounters, I have engraved this sentiment in my heart.
Sadayoshi Ito
Honorary Member
Professor Emeritus, Tohoku University
Special Manager, Katta General Hospital
E-mail: db554@med.tohoku.ac.jp
Careers in JES
2023– Honorary Member
2019– Senior Councilor
2015–2017 Director (General Affairs)
2013–2015 Director (Education and Career Development)
2011–2013 Advisor
2010–2018 President for Tohoku Regional Branch
2007–2011 Director (Academic Affairs and Publication)
2003– Councilor
1997– Member
Activities in JES
2013 Chair, 86th Annual Congress of JES
2013 Chair, 26th Annual Meeting of JES Tohoku Regional Branch
