Tadashi Inagami (February 20, 1931–March 13, 2023): A Legend in Renin–Angiotensin Research

On March 13, 2023, we lost a legend in our field. Tadashi Inagami, PhD who had retired to Pittsburgh, Pennsylvania, to be near family passed away at age 92. On behalf of his many friends, colleagues, and over 400 trainees including the authors of this tribute, we would like to express our deepest condolences to his wife Masako and his entire family. Dr. Tadashi Inagami was born in the port city of Kobe, Japan, on February 20, 1931. After leaving Kobe when he was 5, the Inagami family settled in Japan’s historical center of Kyoto during World War II. In April of 1945 his eighth-grade schoolwork was suspended, and he was sent to work in a munitions factory to help build aircraft engines. He found that he liked working with the sophisticated machinery. While this was only a 4-month experience until the end of the war, it fostered in Inagami a fledgling interest in mechanics and science (Stories from REPORTER, Vanderbilt University Medical Center Weekly publication, 6/30/2006). While attending high school during the post war period, Inagami started reading translations of American scientific journals. His interest took a turn toward the life sciences opening new opportunities to him. In 1953, he received his bachelor’s degree in nutritional chemistry from Kyoto University, one of Japan’s top public universities. He began graduate school there, but quickly realized that educational opportunities in post war Japan were quite limited. He took advantage of the Fulbright Program for educational exchange, was accepted to Yale University in 1958, and completed his doctoral degree in Biophysical Chemistry. He also obtained a Ph.D. degree from Kyoto University but with limited postdoctoral positions in Japan, he decided to return to Yale. There he worked on protein crystallography and obtained the molecular structure of several enzymes. In 1966, he was recruited as an assistant professor by the Biochemistry Department at Vanderbilt University School of Medicine. The Department desperately needed a protein structure specialist to collaborate with Dr. Stanley Cohen, whose seminal discovery of epidermal growth factor (EGF) was a perfect candidate for crystallography. Notably, the collaboration with Dr. Cohen for EGF purified from mouse salivary gland not only contributed to Cohen’s Nobel Prize winning research but also provided Dr. Inagami the opportunity to purify renin from the same source. This seminal discovery of renin led to Dr. Inagami’s legendary lifetime accomplishment of the identification and elucidation of the renin–angiotensin system (RAS) in blood pressure regulation. Throughout his career, Dr. Inagami published over 500 scientific articles. His major contributions to the field include purification and identification of the primary structure of mouse renin,1,2 identification and cloning of genomic DNA for rat atrial natriuretic peptide (ANP),3 identification and cloning of the angiotensin II type 1 (AT1) receptor,4 identification and cloning of the angiotensin II type 2 (AT2) receptor,5 and characterization of angiotensin II type 2 receptor gene knock out mice.6 These findings significantly impacted the field leading to the creation of the current first-line human anti-hypertensive treatments, the AT1 receptor blockers. Additionally, his work led to the discovery of the so-called protective arm of the renin–angiotensin system. In 1979, Dr. Inagami became director of the Specialized Center of Research (SCOR) in Hypertension and served in that role for 17 years, overseeing a large, interdisciplinary research center funded by the National Institutes of Health. During his career, he received a long list of prestigious accolades, including the Bristol-Myers-Squibb Award for Distinguished Achievement in Cardiovascular Research, the Research Achievement Award from the American Heart Association (AHA), and the Japan Academy Prize—Japan’s highest academic honor awarded by that nation’s equivalent of the United States National Academy of Sciences. He was particularly proud of the Ciba Award from the High Blood Pressure Research Council of the AHA, which he received in 1985. The highly selective award recognizes the most original research in the hypertension field. Before I (Mitsuhide Naruse) joined Dr. Inagami’s Lab as a postdoctoral fellow in 1980, as a physician, I wrote him a letter confessing my worry about my limited biochemical research experience. He replied, “I agree. I am hesitant about accepting a clinician since they can just leave the research if it doesn’t go well”. However, he continued, “Every clinician is different, your mentor strongly recommended you, and the potential is more important than experience”. My anxiety was swept away, and I was deeply impressed by his decision. Even though I felt his enthusiasm for my talents may have been far beyond my ability. I have treasured all the handwritten letters, including the very first one, that Dr. Inagami sent to me over the years. In the 1980s, the entire Inagami Lab was filled with tension and excitement after the pioneering accomplishment in renin and the acquisition of significant research funding from the NIH. Many researchers were working guided by his intelligence and motivated by his enthusiasm. I was working hard to meet his expectations. However, I quickly realized that I was not a super researcher and was unable to fulfill his expectations. One of the talented first-generation researchers who contributed to the purification of renin and discovery of the brain RAS,7 Dr. Hirose, told me “Don’t try to accomplish 100% of his requests since you are not Dr. Inagami. 80% is fairly enough”. Following that sage advice, I bounced back and continued my research, although I had to adjust my target to even lower than 80%! While Dr. Inagmai was a biochemist, he was very curious about various aspects of cardiovascular disease. Still fresh in my memory is how he earnestly read every poster and took notes in the deserted poster venue at the AHA Hypertension meeting. My main project was to investigate the role of renin in extrarenal tissues. The advantage of having purified renin and its antibodies enabled us to be the first to demonstrate a very high concentration of adrenal renin in hypertensive rats.8 I was delighted I could hang on and did not just leave the research. While I did not pursue basic research in most of my later career in Japan, Dr. Inagami’s spirit of research has significantly impacted me throughout my career. I (Kailash N. Pandey) joined Dr. Inagami’s Research group in 1981 when Dr. John Oats, the previous Director of the Specialized Center of Research (SCOR) in Hypertension, offered me a National Research Service Award (NRSA) postdoctoral fellowship to work with Dr. Inagami, who had inherited the Directorship of SCOR-Hypertension. I got a late-night phone call from Dr. Inagami asking me to provide phone numbers of two referees, one should be PhD mentor at the University of Kentucky (Lexington). When I spoke with my mentor, he indicated that he was concerned because he was unprepared for the call but assured me, he had strongly recommended me; however, I feared my chances were slim. Dr. Inagami called me again asking to meet in person. I realized then how hard-working and determined Dr. Inagami was, and that if I did have the honor of working in his lab it would be an intense but invaluable experience. He offered me a fellowship to work on testicular renin. Under his guidance, I partially purified renin from the testis and detected mRNA of renin in testis extracts. I also used the testicular Leydig tumor cells established by Drs. David Puett and Mario Ascoli at Vanderbilt. Our 1986 Journal of Biological Chemistry paper was the first to show that it is not intracellular renin but angiotensin II that is excreted from the Leydig tumor cells.9 This is one of the pioneer papers demonstrating extra renal RAS. Since the 1981 discovery that heart contains natriuretic peptide, laboratories across the globe worked in secrecy on atrial natriuretic peptide (ANP). In 1983, Dr. Robert Grammar in Dr. Inagami’s lab discovered that heart extract contained natriuretic activity and vasorelaxant activity. In 1984, another Inagami lab member, Dr. Kuno Misono, purified ANP as a 28-amino acid peptide molecule. Dr. Inagami immediately set out to clone ANP cDNA, assigning that work to Dr. M. Maki, Dr. C. Tibett, Dr. R. Takayanagi, and myself. This resulted in cloned ANP cDNA,3 and three papers from different groups were published back-to-back in Nature in 1984. Soon after, I turned my focus to cyclic GMP, the second messenger of ANP. With help from Dr. David Garber’s lab and equipment, I showed that ANP potently stimulates cyclic GMP. Our studies showed the existence of three distinct receptors before cloning and that work was published in Journal of Biological Chemistry in 1988.10 Dr. Inagami brought a unique passion and intensity to the lab, inspiring me and my colleagues to persevere and succeed in making pioneering discoveries. We learned to work with great devotion based on his guidance, work ethics, and commitment to groundbreaking research. He was fond of reminding us that not only is science very competitive, but the competition maximizes our collaboration as a team and collaboration is the driving force behind seminal discoveries. In 1994, I (Satoru Eguchi) traveled from Japan to become a postdoctoral fellow with Dr. Inagami. I discovered that he not only scientifically mentored his trainees but helped us adjust to life in Nashville. He went above and beyond in facilitating my family’s transition to Vanderbilt University by helping to secure housing for us and welcoming us to the United States. We quickly figured out he would pass by my apartment on his way home from work and he was able to frequently stop by to enthusiastically discuss our research. He would also bring articles for me to read, not limited to angiotensin research but including the broad range of subjects he was interested in. During my postdoctoral period, Dr. Cohen was still actively studying EGF receptor signaling mechanisms and he acted as my unofficial second mentor explaining to me how EGF receptors signal and function, leading to my second major paper from Dr. Inagami’s laboratory.11 It seems some kind of miracle that we were able to merge the renin–angiotensin system and the EGF system ~40 years after Dr. Inagami and Dr. Cohen started their scientific journeys at Vanderbilt University. While I returned to Japan in 1996 to start my clinical fellowship in endocrinology, this paper changed my career trajectory. I am happy to have stayed in academia and worked on the angiotensin system, which I feel is a priceless gift from Dr. Inagami. Gerald Frank, Ph.D., one of Dr. Inagami’s final trainees remembers his mentor, especially the last few years before his retirement, as maintaining his spark for scientific discovery and always reading the latest publications of interest to discuss with his research team. Dr. Luis Gabriel Navar, one of the pioneers in the intrarenal angiotensin II system and a good friend of Dr. Inagami described that Tadashi was an icon in the field, a true scientist of incredible integrity and a wonderful and noble gentleman. We all will miss Dr. Tadashi Inagami and his extraordinary dedication to renin–angiotensin and hypertension research. Picture was taken in 1985. Dr. Tadashi Inagami at Vanderbilt University.