In Memoriam: Professor Tadashi Inagami

Dr. Tadashi Inagami

(February 20, 1931–March 13, 2023)

We have lost a great legend in the research field of hypertension and cardiovascular endocrinology with the passing of Dr. Tadashi Inagami, Ph.D., DSc, Vanderbilt University Professor of Biochemistry, Emeritus, and Honorary Member of the Japan Society of Hypertension. He passed away in Pittsburgh, Pennsylvania, on March 13 at age 92.

Dr. Inagami was born in Kobe, Japan, in 1931 and spent his formative school years in Kyoto during the difficult times of World War II. He received his bachelor’s degree in nutritional chemistry from Kyoto University, earned his Ph.D. in Biophysical Chemistry from Yale University through the Fulbright Program, and was awarded a second Doctor of Science degree in nutritional sciences from Kyoto University. He returned to Yale where he worked on X-ray crystallography and obtained the molecular structure of several enzymes.

Two pioneering bioactive substances for cancer research and cardiovascular disease and hypertension were discovered in mouse salivary glands. In 1966, the Biochemistry Department at Vanderbilt University recruited Dr. Inagami as an assistant professor, where he spent the rest of his research career as a faculty member. In 1972, by collaborating with Dr. Stanley Cohen, he contributed to Cohen’s Nobel Prize-winning research on the discovery and purification of epidermal growth factor (EGF) [1] and successfully purified Renin [2] from mouse submaxillary glands. The Journal of Biological Chemistry recognized Inagami’s contribution to Cohen’s work on EGF in 2006 as part of their centennial anniversary. In 1979, he became director of the Specialized Center of Research (SCOR) in Hypertension at Vanderbilt, funded by the National Institutes of Health, and served in that capacity for more than 15 years.

Dr. Inagami dedicated his whole life to the biochemical and biophysical research of hypertension and cardiovascular diseases and published over 500 scientific articles. His notable achievements include the purification and identification of the primary structure of Renin, the identification of Renin in extrarenal tissues, the identification and cloning of the angiotensin II type 1 (AT1) receptor [3], and the characterization of the angiotensin II type 2 receptor [4]. These achievements laid the groundwork for first-line medicines that block the renin-angiotensin system to treat hypertension and cardiovascular diseases. Another achievement was the identification of the primary structure of atrial natriuretic factor (ANF) and cloning genomic DNA for ANF [5] and its receptors, providing the biochemical basis for the ANF system. At the end of his career, he left landmark research on two critical biosystems that have counteracting effects on body homeostasis.

Dr. Inagami received many awards for these achievements, including the Bristol-Myers-Squibb Award for Distinguished Achievement in Cardiovascular Research, the Research Achievement Award from the American Heart Association (AHA), the Japan Academy Prize from the Japan Academy, the CIBA Award for Hypertension Research from the High Blood Pressure Research Council of the AHA, and the American Heart Association/American Stroke Association Distinguished Scientist Award.

Dr. Inagami was recognized for his research achievements by Vanderbilt University when he was appointed the Stanford Moore Professor of Biochemistry and awarded the Earl Sutherland Prize for Achievement in Research in 1990, the prize named after Vanderbilt’s first Nobel laureate in Medicine. In addition, the university awarded him the 2004 Award for Excellence in Teaching for his mentorship of over 100 graduate students and postdoctoral fellows and created an endowed chair in his name called the Tadashi Inagami Chair in Biochemistry. The American Association for the Advancement of Science and the Japan Academy also elected him as a member.

He was earnest about his search for truth through research, constantly looking far beyond his current projects. He was always diligent and acquired much knowledge from academic papers and conference presentations, re-organized them in his brain, and provided information and feedback to the research fellows on each project. I still vividly remember him earnestly reading every poster and taking notes in the deserted poster venue at a hypertension meeting. We were accustomed to his international call from Europe for new information daily. He was passionate about research and frequently engaged in discussions on research topics. He was always gentlemanly, courteous, and sincere and was supportive and kind to his postdoctoral fellows. We can glimpse his way of life as a researcher and humanitarian from the words of his friends, collaborators, and research fellows.

Dr. Shigehisa Hirose, Professor Emeritus, Tokyo Institute of Technology, is one of the first-generation researchers who contributed to the biochemistry of Renin. He was recruited at a biochemistry meeting in Tokyo when Dr. Inagami was seeking talented and hard-working postdoctoral fellows to further develop the research on the molecular biology of renin-angiotensin at his Lab at Vanderbilt University which was at the forefront of the field. Dr. Hirose would go on to develop a radioimmunoassay of angiotensin II and antibodies against Renin for the first time worldwide. Carefully heeding Dr. Inagami’s advice, he secured a quiet and stress-free environment where they could carry out immunization on a particular type of rabbit using an empty animal room every Sunday morning. Their efforts culminated in a paper in Nature on their discovery of brain RAS [6]. Dr. Hirose said, “I was very impressed by Dr. Inagami’s well-organized mind and learned the importance of experimental design. I have fond memories of conversing with Dr. Inagami over lunch in the university cafeteria where he would share anecdotes on historic discoveries, critiques, and even scandals in the scientific community,” an episode showing how Dr. Inagami’s personality was always brimming with curiosity and humanity.

Dr. Tomio Okamura, Professor Emeritus, Shiga University of Medical Science and former President of the Japanese Association of Cardiovascular Pharmacology, joined Dr. Inagami’s Lab soon after establishing the SCOR. Dr. Inagami was interested in advancing research beyond the biochemical and molecular aspects to include the physiological and pathological characteristics with renin antibody as a powerful and useful tool. Dr. Okamura further developed his work on the mechanism of renin secretion at the cellular level and started to use cultured cells for renin research, leading to the discovery of Renin in cultured neuronal cells as evidence of brain renin, and the introduction of extrarenal Renin [7]. “Dr. Inagami was a researcher who studied hypertension not only from the standpoint of biochemistry and molecular biology but also from multiple perspectives such as physiology and pathophysiology,” said Dr. Okamura.

Before I joined his Lab in 1980, not only myself but also Dr. Inagami was deeply concerned whether a clinician like me would make an immediate impact in the biochemistry department. He accepted me, however, saying, “Every clinician is different. Besides, Professor Kazuo Shizume (my boss at Tokyo Women’s Medical University) highly recommended you, and to me the potential you have is more important than the experience.” His words were very encouraging to me. Before leaving for the US, when no email was available, I received so many letters detailing upcoming projects reflecting his enthusiasm and expectations of me, that I ended up prioritizing research preparations over moving. All his handwritten letters are still in my possession as my treasure from those days over 40 years ago. In Nashville, I worked hard on the fascinating new topics of extrarenal Renin [8], but he worked even harder than us. The lights on the 5th floor of the Light Hall, where the laboratory was located, never went out at night. He usually went home around 5:00 p.m. every day, and so we would all relax and also go home. But when I returned to the Lab after dinner, he would already be there. Even after 2:00 a.m., he would often stop by to ask, “Did you get that result?” And he would already be there when I arrived at the Lab the following day!”

Dr. Inagami made outstanding research contributions to ANP (ANF) in addition to the RAS. Dr. Ryoichi Takayanagi, Professor Emeritus and former Vice President of Kyushu University, former Vice President of the Japan Endocrine Society, and Fukuoka Sanno Hospital, joined Dr. Inagami’s laboratory as a postdoctoral research associate in 1983. During that time, atrial natriuretic peptide (ANP) was discovered, and researchers worldwide were in fierce competition to be the first to determine its structure. In collaboration with visiting research fellow Dr. Masatoshi Maki of Kyoto University (Professor Emeritus, Nagoya University), Dr. Takayanagi maintained an intensive work schedule with a 24-hour/2-shift basis for one month without rest, and was able to successfully determine the structure of ANP [5] and purify its receptor subtypes. “Dr. Inagami took up the challenge to conduct his target research with passion, collecting information from around the world daily to win the competition. His attitude greatly impressed me. I learned from Dr. Inagami the technologies, the research philosophy, and the spirit I needed to survive as a researcher in this field,” Dr. Takayanagi said. “My days as a researcher in Nashville are still vivid in my memory.”

Dr. Issei Tanaka, Chairman of the Board of Directors, Shizuoka Prefectural Hospital Organization and Vice Chairperson of Japan Municipal Hospital Association) joined Dr. Inagami’s Lab in 1984. He first developed the radioimmunoassay of ANF worldwide [9] and demonstrated its secretary and regulatory mechanism in the central nervous system, heart, and circulating blood, collaborating with Inagami. In 2014, Dr. Inagami visited Shizuoka Prefecture, where Dr. Tanaka was the hospital’s chairman. Dr. Tanaka said, ‘We discussed a wide range of topics besides his research every day. He even advised me on developing clinical research, where I planned to establish a Clinical Research Center in the hospital. He also discussed plant enzymology with an alumnus of Kyoto University living in Shizuoka.’ He continued, ‘It was an impressive experience of Inagami’s erudition since we only discussed experiments in Nashville.’ As his grandfather, who traveled more than 20 km by cart to the port, purchased fish, and sold them, Dr. Inagami was unbelievably diligent and devoted his life to advancing medicine. ‘His way of life was supported by typical Japanese traditional morality,’ said Dr. Tanaka.

“Dr. Inagami was so brilliant, gentle, and generous as a scientist that I often went to his Lab to ask for his advice whenever I encountered problems during my fellowship (1976–1979) at Vanderbilt. He was my second mentor,” said Dr. Yukio Hirata, Professor Emeritus of Tokyo Medical and Dental University, Honorary Member of the Japan Endocrine Society. Dr. Hirata spent his fellowship at the Endocrine Division led by Dr. David Orth as director. He was mentored by Dr. Grant W. Liddle as the Chairman of Medicine, and worked on the characterization of a novel human EGF discovered initially from the mouse submandibular gland by the Nobel laureate Dr. Cohen [1], with whom Dr. Inagami collaborated to purify Renin from the same source [2]. Dr. Hirata first met Dr. Inagami at his Lab, which was cramped and dilapidated at the time, but full of energetic, hard-working Japanese research fellows striving to achieve the isolation of Renin from the kidney, then a major historical achievement. “We Japanese research fellows at Vanderbilt used to have lunch together at the university cafeteria every day and enjoyed free talk in Japanese, surrounding Dr. Inagami as our very erudite leader with whom we’d share views on daily affairs and academic topics,” Dr. Hirata said. He also appreciates Dr. Inagami and his family’s long-lasting friendship and close interaction with his own Hirata family for almost half a century.

Since Dr. Inagami grew up in the Kansai area in Japan, he would occasionally use the amusing phrase in Kansai dialect, “Eraikoccha,” meaning, “Oh no, what are we gonna do now?” Now, with his passing we are having an “Eraikoccha” moment of our own. However, his achievements in biochemistry, molecular biology, and pathophysiology shall remain major contributions to the research field of cardiovascular endocrinology. The serious attitude he manifested toward research has significantly impacted an entire generation of his many trainees throughout their research careers.

We shall all surely miss Dr. Inagami, with his eyes burning with curiosity and his serious yet calm and gentle demeanor full of humanity. On behalf of his many trainees, colleagues, and friends, we would like to express our deepest condolences on the passing of Dr. Inagami to his wife, Masako, and his entire family.

The photograph is from 1985 at the time of the CIBA Award from the High Blood Pressure Research Council of the AHA.

Mitsuhide Naruse, M.D., Ph.D., Honorary Member of the Japan Endocrine Society, Director of the Endocrine Center/ Clinical Research Center, Ijinkai Takeda General Hospital, Kyoto, Japan

References

• 1   Savage Jr  CR,  Inagami  T,  Cohen  S (1972) The primary structure of epidermal growth factor. J Biol Chem 247: 7612–7621.
• 2   Cohen  S,  Taylor  JM,  Murakami  K,  Michelakis  AM,  Inagami  T (1972) Isolation and characterization of renin-like enzymes from mouse submaxillary glands. Biochemistry 11: 4286–4293.
• 3   Sasaki  K,  Yamano  Y,  Bardhan  S,  Iwai  N,  Murray  JJ, et al. (1991) Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin II type-1 receptor. Nature 351: 230–233.
• 4   Senbonmatsu  T,  Ichihara  S,  Price  E Jr,  Gaffney  FA,  Inagami  T (2000) Evidence for angiotensin II type 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload. J Clin Invest 106: R25–R29.
• 5   Maki  M,  Takayanagi  R,  Misono  KS,  Pandey  KN,  Tibbetts  C, et al. (1984) Structure of rat atrial natriuretic factor precursor deduced from cDNA sequence. Nature 309: 722–724.
• 6   Hirose  S,  Yokosawa  H,  Inagami  T (1978) Immunochemical identification of Renin in rat brain and distinction from acid proteases. Nature 274: 392–393.
• 7   Okamura  T,  Clemens  DL,  Inagami  T (1981) Renin, angiotensins, and angiotensin-converting enzyme in neuroblastoma cells: evidence for intracellular formation of angiotensins. Proc Natl Acad Sci U S A 78: 6940–6943.
• 8   Naruse  M,  Inagami  T (1982) Markedly elevated specific renin levels in the adrenal in genetically hypertensive rats. Proc Natl Acad Sci U S A 79: 3295–3299.
• 9   Tanaka  I,  Misono  KS,  Inagami  T (1984) Atrial natriuretic factor in rat hypothalamus, atria and plasma: determination by specific radioimmunoassay. Biochem Biophys Res Commun 124: 663–668.