ESSAY | TOWARD JES 100TH ANNIVERSARY: REMARKS FROM HONORARY MEMBERS
Essay: Endocrinology and my research life
2023 Volume 70 Issue 11 Pages 1029-1034
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2023 Volume 70 Issue 11 Pages 1029-1034
First, let me congratulate the Japan Endocrine Society on its 100th anniversary. It is a great honor and privilege to share some messages about my research life and special remarks on endocrinology.
I graduated from Osaka University in 1968 and completed my residency at the endocrine wards, Osaka University Hospital, and Osaka Prefectural Center for Lifestyle Diseases. During this time, I began research in endocrinology, the renin-angiotensin (RA) system, hypertension, and geriatrics under the guidance of Dr. Yuichi Kumahara in the thyroid research group, First Department of Medicine, Osaka University Hospital. Since then, I have dealt with endocrinology in my research and clinical practice for over 50 years.
My first encounter with thyroid diseases led me to endocrine research, and in 1971 I participated in a medical survey in Sarawak, Borneo Island, Malaysia, as a member of the South East Asia Medical Mission of Osaka University. During the survey of iodine-deficient endemic goiter in this area, I could report the relationship between iodine content in water, goiter size, and serum TSH level (Endocrinol Jpn 1971, JCEM 1972). In addition, I have published my observation of the clinical course and the fluctuations in serum TSH levels of three subacute thyroiditis cases, which I experienced during my residency in JCEM (1973). These marked the beginning of my endocrinology research directly related to clinical practice.
In 1973, I joined the Central Laboratory Medicine, Osaka University Hospital, where Prof. Yuichi Kumahara was director, to work on the development of assay methods for the renin-angiotensin system. In 1974, I studied abroad in the laboratory of Prof. Charles A. Nugent, University of Arizona, Tucson, Arizona. Prof. Nugent was an expert in steroid hormone research and a clinical endocrinologist. I learned a lot about research on steroid hormones and clinical endocrinology during my stay in Tucson (Fig. 1). After returning to Japan, the Kumahara Laboratory at that time was very active in the clinical application of peptide hormones such as TRH and LHRH, and I also worked on the clinical application of an angiotensin II antagonistic analogue (1Sar-8Ile-AII, Sarileusin) provided by Dr. Shumpei Sakakibara of the Peptide Institute, Osaka.
Prof. Charles A Nugent (left), Endocrinology, University of Arizona and Prof. Yuichi Kumahara (right), Laboratory Medicine, Osaka University, Osaka, who visited Dr. Nugent’s office in Arizona Medical Center, Tucson in 1974
Renin-angiotensin system blockers such as ACE inhibitors and ARBs are now widely used as antihypertensive drugs. But at that time, peptides, such as teprotide and saralasin, were research targets that competed with Dr. John H. Laragh’s group. Dr. F. Merlin Bumpus’s group at Cleveland Clinic synthesized many angiotensin analogues. Cleveland was the mecca of hypertension research, and the Hypertension Council Meeting was held there every year, and I continued my visits to Cleveland. I was able to meet Dr. Irvine H. Page, Dr. Bumpus, and many other outstanding hypertension researchers at this meeting.
Clinical applications of angiotensin II (AII) analogues have been tested in a variety of diseases, including hypertension and secondary aldosteronism, and have been proven to be useful in screening for renin-dependent hypertension, including renovascular hypertension and malignant hypertension, and have demonstrated diagnostic potential. Although the role of AII analogues in clinical applications ended with the advent of oral inhibitors, they played a pivotal role in clarifying the pathophysiology of secondary aldosteronism. Bartter’s syndrome is a normotensive salt-losing nephropathy, in which the response to AII analogues turned from a depressor response to a pressor response (agonist effect) after fluid compensation by high salt treatment. A similar response was seen in Addison’s disease after cortisol supplementation. Liver cirrhosis with ascites is also a typical secondary aldosteronism with high plasma renin activity, but an increased RA system also maintains blood pressure in this syndrome. These studies on the conditioning of the AII analog test and the pathophysiological significance of the RA system in various diseases became my doctoral dissertation.
When I was at the Central Laboratory, Osaka University Hospital, I started to develop a radioimmunoassay for aldosterone following the method of Prof. Nugent and coworkers. It was a complicated process using H3 aldosterone and paper chromatography, which led me to study under Prof. Nugent. In addition to working on measuring dopamine-β-hydroxylase, I learned a lot about steroid hormones while studying abroad. After returning to Japan, I developed the aldosterone direct RIA method with Dr. Kazushige Iinuma of Dainabot, aiming at simple and multiple sample measurements in the RA system (JCEM 1977). Next, I tried to develop a renin antibody with Prof. Kazuo Murakami, Tsukuba University, and Dr. Jitsuo Higaki (Prof. Emeritus, Ehime University) and succeeded in human renin direct radioimmunoassay.
Prof. Victor J. Dzau (Duke University, President of the US National Academy of Medicine) reported the importance of the tissue RA system and atherosclerosis, and he proposed the RA system’s role in the cardiovascular continuum process. Dr. Hiromi Rakugi (Prof. Emeritus, Osaka University), Dr. Ryuichi Morishita (Endowed chair Prof., Osaka University), and my many fellows studied in Prof. Dzau’s Laboratory at Harvard and Stanford University (Fig. 2). They have been very active after returning to Japan and continued collaboration with Prof. Dzau. Other research on the RA system has developed in various ways. Collaborative studies on the RA system, atherosclerosis, insulin resistance, etc., have been conducted with Prof. Michael L. Tuck (UCLA), Prof. Teodore Kurtz (UCSF), Prof. Morton Prinz (UCSD), Prof. Makiko Ueda (Osaka City University/Morinomiya University of Medical Sciences) and many other researchers around the world (Fig. 3).
With Prof. Victor J. Dzau (center), Duke University (Currently also President of National Academy of Medicine) and Dr. Hiromi Rakugi (right), Osaka University, at the 21st Scientific Meeting of International Society of Hypertension, Fukuoka in 2006
Pathogenesis of atherosclerosis and the possible role of the renin-angiotensin system
Against the background of expectations for new molecular therapies based on molecular biology, which have been accelerated since the end of the 20th century, my laboratory explored the possibility of treating hypertension by regulating gene expression. Prof. Morishita, Prof. Motokuni Aoki (Morinomiya University of Medical of Sciences), and their colleagues investigated this in animal experiments using renin antisense or decoy oligodeoxynucleotides against AGE2, a transcription factor that acts on the angiotensinogen gene. The results showed that renin antisense or decoy oligodeoxynucleotides used against AGE2 exerted antihypertensive effects by regulating RA gene expression in vivo and revealed the role of the RA system in the maintenance of hypertension of SHR (spontaneously hypertensive rats), suggesting the possibility of a new therapeutic approach for hypertension. In particular, decoy oligodeoxynucleotides, a unique method to suppress transcription factors, was a highly novel approach developed by our research group (Morishita, Nature Med 1997).
We have been involved in hypertension gene-hunting research since the 1990s, with Dr. Tomohiro Katsuya playing a central role. We have focused on the relationship between renin-angiotensin-related genes and hypertension. Prevention of lifestyle diseases from adulthood is important for healthy longevity, and the search for such genes was an important issue for the hypertension laboratory in the geriatric department.
We found that the M235T polymorphism of the angiotensinogen gene (AGT) affects the family history of hypertension and diurnal blood pressure variation patterns. Furthermore, in the Suita study, Dr. Higaki reported in Circulation (2001) that the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene increased the risk of hypertension only in men, as in the Framingham study.
There are two types of hypertension: salt-sensitive and non-salt-sensitive. Black individuals and older people are known to have a higher percentage of salt-sensitive hypertension. Angiotensinogen, alpha-adducin, aldosterone synthase, and G-protein beta 3 are all genes involved in salt retention in the body, and polymorphisms of these genes indicate that Japanese people are more salt-sensitive than Caucasians (Katsuya, Hypertens Res 2003).
We have also confirmed that the Na-Cl cotransporter gene is the cause of Gitelman’s syndrome, which we have experienced in the past, and that this gene polymorphism is associated with hypertension in young women (Matsuo, J Hypertens 2004).
Next, I turned to elderly hypertension, a significant part of my research history. Elderly hypertension is characterized by systolic hypertension, wide pulse pressure, increased blood pressure variability, orthostatic hypotension, and postprandial hypotension. These are caused by a decrease in vascular elasticity due to arteriosclerosis by aging and an age-related suppression or decline in humoral and neural blood pressure regulation mechanisms.
My research on age-related changes in blood pressure-regulating hormones began in 1975 as a fellow at the University of Arizona. I found that serum DβH (dopamine-β-hydroxylase), which is thought to reflect the sympatho-adrenomedullary system, decreases with age. After returning to Japan, as a member of the Department of Geriatric Medicine, I conducted a comprehensive study comparing age-related changes in various blood pressure-related hormones in hypertensive and normotensive patients as follows. 1) Active plasma renin decreases with age in both normotensive and hypertensive patients, but inactive renin does not decrease in normal subjects (Nakamaru, Am J Ger Soc 1981). 2) Urinary kallikrein excretion, an antihypertensive factor, decreases with age in normal subjects but not in hypertensive patients (Naka, JCEM 1981). 3) Blood levels of 6-keto-PGF1α, a stable metabolite of prostaglandin I2, a vasodilator, decrease with age and are unaffected by hypertension. 4) Plasma norepinephrine levels increase with age due to decreased reuptake. However, levels are higher in younger hypertensive subjects than in normotensive subjects, and no age-related variation exists (Masuo, Hypertens 1984). On the other hand, when changes in neural regulatory mechanisms with aging were examined by frequency analysis using wavelet transform during orthostasis, we have confirmed the impairment of both sympathetic and parasympathetic nerve activity in elderly hypertensive patients, explaining the delayed autonomic nervous response and orthostatic hypotension (Moriguchi, Hypertens Res 2006). Among the many theories of aging, there is the theory of age-related homeostasis impairment. The age-related changes in the blood pressure regulation mechanism are typical examples of this theory.
ACE2 (angiotensin-converting enzyme 2), a component of the RA system, has recently attracted attention as a receptor for the COVID-19 virus. Prof. Rakugi’s laboratory started the functional analysis of ACE2 in the 2000s and found that ACE2 suppresses cardiac hypertrophy through the RA system (Yamamoto, Hypertension 2006). Focusing on its involvement in insulin resistance, they also found that deficiency of systemic ACE2 causes aging traits such as sarcopenia (Fig. 4). Subsequently, a series of studies showed that the senescence-accelerating characteristics in ACE2-deficient mice were due to mechanisms of the RA independent system (Takeshita, Hypertens Res 2020). Since ACE2 is most highly expressed in the intestine and is also associated with amino acid absorption, such as tryptophan, they initiated research on the regulation of the intestinal microbiota and validation focusing on the role of intestinal ACE2.
Regulatory mechanism of biological aging by ACE2 through intestinal tryptophan absorption metabolism
In 2015, Dr. Koichi Yamamoto and coworkers reported that oxidized LDL activates AT1 and causes vascular endothelial damage via a complex of oxidized LDL receptor (LOX-1) and AT1 (Yamamoto, FASEB J 2015). Subsequently, they investigated the detailed mechanism of AT1 activation by oxidized LDL. They demonstrated that AT1 activation by AII differs from the mode of G protein activation and promotes intracellular translocation of oxidized LDL via the β-arrestin pathway (Fig. 5). They have also shown that similar mechanisms exist in the receptor for advanced glycation endproducts (RAGE) and AT1. They are currently elucidating the synergistic effects of oxidized LDL and AII on AT1 activation and the mechanism by which AT1 activation by RAGE and amyloid-β (RAGE ligand) may be involved in the pathogenesis of Alzheimer’s disease.
Intracellular transport mechanism for circulating waste via angiotensin II Type 1 receptor (AT1) activation
These research topics, which investigate novel mechanisms associated with aging and the RA system, have emerged from integrating our department’s longstanding research on the RA system with the growing demand for aging research in geriatric medicine.
My research, which began with the development of methods to measure components of the RA system, has progressed to the importance of the RA system in the homeostatic mechanism of blood pressure regulation, the diagnosis of renin-dependent hypertension, and many clinical trials with the advent of ARBs, as well as basic research on tissue RA system and atherosclerosis, molecular biological research on the RA system as a cause of hypertension, and genetic analysis of the RA system. My successors have continued the research on aging and the RA system. Thus, endocrinology has always been a means and an aim in my research life.
In closing, I would like to thank all those who have supported me in my research life and wish the Japan Endocrine Society a fruitful and prosperous next 100 years.
Toshio Ogihara
Honorary Member
President Emeritus, Morinomiya University of Medical Sciences
Professor Emeritus, Osaka University
E-mail: ogihara@morinomiya-u.ac.jp
Careers in JES
2013– Honorary Member
2009– Senior Councilor
1993–1997 Director (Finance)
1980– Councilor
1970– Member
JES Awards
1986 6th JES Research Award
