Interview

PR Office:
We’ve heard that you received a very prestigious award. Congratulations. Could you give us the background about how you earned this award?

Professor Itoh:
The Arthur C. Corcoran Memorial Lecturer Award has a history of more than 40 years, and I am the third Japanese researcher who has received the award. Looking at the past winners, we can see that the award is given to people who have made research achievements of global significance. They presented the award to me in recognition of my work in developing the technique that allows the regulation mechanism of the filtration function of the kidney to be studied directly and laying the foundation for the understanding of renal hemodynamics. The research achievements that I have made over the years are a product of the research life that I have spent on two separate occasions in the U.S. (at the Henry Ford Hospital in Detroit where I worked with Professor Oscar Carretero) and the intellectual interaction that I have had with many researchers including the current members of the department.

Professor Itoh:
Before giving you the background about how I earned the award, there are several things that I want you to know. First, the kidney detects changes in the salt level in the body and regulates the blood pressure. By adjusting the secretion amounts of the hormones that control the blood pressure as well as the renal filtration function, the kidney regulates not only the blood pressure but also the body fluid volume, that is, the blood volume of the entire body (Figure 1). The kidney produces one hormone, called renin*1, that regulates the blood pressure and body fluid volume. This substance was discovered in 1898 by a researcher named Tigerstedt. It has also been shown in subsequent studies that the kidney secretes or does not secrete rennin depending on the amount of salt it detects. It remained unknown for a long time, however, which part of the kidney detects the salt level. Renin is produced and secreted by cells in the distal portion of the afferent arterioles that supply blood to the glomerulus*3 (a mass of capillaries that filters blood). There is a structure known as macula densa*2, which is a collection of tubular cells having a special shape that is closely adjacent to these renin productive cells (Figure 2, right). Given its anatomic positional relationship and special shape, the macula densa had long been considered to detect changes in the salt level the tubular fluid flowing through it (which reflects the overall salt level) and adjust the secretion of rennin. But, some researchers claimed that more salt flowing through the macula densa would lead to increased secretion of rennin, while others presented research results that indicated the exact opposite showing that a lower salt level would increase the secretion of rennin. Which group of researchers was right was unknown. The reason for this was that there was no method to directly monitor the secretion of rennin while changing the salt level in the macula densa area.

When I studied in the U.S. for the first time, I created two types of specimen – one consisting of only afferent arterioles having rennin productive cells and the other consisting of afferent arterioles with the macula densa attached to them – and compared the renin secretion of these two specimens. The only difference between these two was that one had the macula densa attached to it while the other didn’t. So any difference in the secretion of renin would directly prove that the macula densa was involved in the regulation of renin secretion. As a result, substantial differences in renin secretion were observed between the specimen with the macula densa and the one without it, and this was the first research in the world that proved the macula dens mechanism. But, in order to change only the salt level of the lumen of the tubule of the macula densa, it was necessary to perfuse this part through a thin glass pipette. To be able to do so, I needed to develop a new technique and, because my study period in the U.S. was approaching its end, I had to go back to Japan. This is what I did during my first stay in the U.S.

After I returned to Japan, however, Oscar asked me repeatedly to come back to Detroit and do perfusion experiments with the macula densa. So, after two years and a half, I went to the U.S. again. I succeeded in establishing a perfusion technique for the macula densa two or three months later, and my preparatory work was progressing smoothly. But, soon after that, another researcher went ahead of me and his research was reported in Science magazine. So I decided to study another mechanism of the macula densa. In addition to regulating renin secretion, the macula densa was considered to have a function to regulate the vascular resistance of afferent arterioles. This function keeps the glomerular filtration rate*4 (GFR) of the kidney constant. The glomerular filtrate filtered through the glomerulus passes through the macula densa adjacent to afferent arterioles from the proximal tubule via Henle’s loop. It was considered that the macula densa monitored the salt level and controlled the degree of contraction of afferent arterioles to keep the filtration pressure in the glomerulus constant (direction of the arrows in Figure 2, left). This phenomenon is called tubuloglomerular feedback. As a matter of fact, it had been observed that, when a thin glass pipette was inserted into the proximal tubule from the surface of the kidney and the pressure inside the tubule (which is thought to reflect the filtration pressure in the glomerulus) was measured, the pressure kept fluctuating minutely about twice a minute. But the average pressure is kept stably constant. Such stability was considered possible because the macula densa regulated the degree of contraction of afferent arterioles very elaborately.

PR Office:
The kidney in our body has a feedback-based elaborate regulation mechanism.

Professor Itoh:
Yes. But, there were some researchers back then who claimed that not only the macula densa but also the connecting tubule behind it were involved in this feedback. But all these research results were based on conjectures that were formed using indirect research techniques, and there was no conclusive evidence anywhere that the macula densa and connecting tubule really regulated the vascular resistance of afferent arterioles. So, I took out afferent arterioles and the macula densa together and perfused them at the same time. I built an experimental system for observing directly under a microscope whether afferent arterioles would contract or relax when the salt level of the perfusion liquid of the macula densa was changed. As a result, I proved that an increase in the salt level of the macula densa causes afferent arterioles to contract. Later, Professor Ren, my research collaborator, applied this research technique to the connecting tubule and proved that the connecting tubule also regulates the vascular resistance of afferent arterioles. This mechanism has attracted a great deal of attention as a new mechanism for renal function regulation, and various researches are now under way.

By developing new research techniques like this one, we have been able to prove many things about the mechanism of hemodynamics of the glomerulus. All these accomplishments as a whole can be said to be a big reason that I won the award.

PR Office:
I see. You have been praised for establishing a new technique and proving many things using it.

Figure 1. Relationship between blood pressure and the kidney
While controlling the absorption and excretion of salt and water, the kidney regulates the body fluid volume and blood pressure of the entire body so as to keep them constant.

Figure 2. Filtration function of the kidney and structure of the glomerulus
After being filtered through the glomerulus, the liquid component of blood (blood plasma) enters the tubule and, as it passes through the proximal tubule, Henle’s loop and distal tubule, salt and water are reabsorbed. The salt and waste material that are not reabsorbed are sent to the bladder as urine.

Notes:
*1 Renin: An enzyme secreted from the kidney into the blood stream. It activates the vasopressor hormone (angiotensin).
*2 Macula densa: The area of the distal tubule through which the thin blood vessels (afferent arterioles) of the kidney pass immediately entering the glomerulus.
*3 Glomerulus: A mass of capillaries in the kidney. Waste material and other unwanted matters are filtered out here.
*4 Glomerular filtration rate: The amount of blood plasma that is filtered in the kidney per unit time (amount of the liquid component other than red blood cells, white blood cells and blood platelets).

Professor Itoh:
Also, in 2002, a concept of chronic kidney disease was introduced. Chronic kidney disease is a term that collectively refers to abnormal conditions of the kidney such as a glomerular filtration rate of less than 60% of the normal level (100 ml/minute) and a very slight amount of protein excreted into the urine. Epidemiological studies have shown that patients with chronic kidney disease are more likely to develop stroke or myocardial infarction than to come to receive dialysis treatments. The biggest mystery of chronic kidney disease is that, even when glomerulus filtering is normal, a person is prone to develop stroke or myocardial infarction if a very tiny amount of urine protein is present (10 mg in the form of albumin). Come to think of it, the normal glomerular filtration rate (GFR) is 150 liters a day, and the amount of protein contained in the form of albumin is as large as 6 kilograms. Of all this protein, how is a mere 10 mg of it leaking into the urine related to diseases of blood vessels in the brain and heart?

One day, one of my coworkers asked me, “Professor Itoh, when albumin leaks, is there any difference in terms of where it leaks?” In that instant, the vascular structure of the brain overlapped that of the kidney in my mind (Figure 3). When the thick blood vessels entering the kidney are exposed to high blood pressure, the thin blood vessels located near those thick blood vessels are also exposed directly to high blood pressure and damaged (A in Figure 3). Albumin leaks from such damaged vessels. The thin blood vessels far from the thick blood vessels, on the other hand, are not damaged because the blood pressure drops before blood reaches there (B in Figure 3). Since a small amount of albumin leaking from the few damaged glomeruli near the thick blood vessels is diluted by the normal urine filtered by the many other glomeruli, substantially decreasing the concentration of albumin in the urine and hence a slight amount of albumin. This means that the presence of albumin in the urine, albeit in small amounts, provides evidence that afferent arterioles near a thick artery in the kidney is damaged. The fact that a vascular anomaly is occurring in the kidney suggests that the blood vessels in the brain that has exactly the same structure as the kidney are prone to be damaged as well (Figure 3, bottom).

Then, why does our body have such a fragile vascular structure? I think that it probably concerns the evolution of organisms. When the body has this mechanism, it can send blood to its vital organs, such as the brain and kidney, even if the blood pressure lowers due to trauma or other cause. In other words, the reason why thick blood vessels are connected to thin blood vessels is to protect the body against low blood pressure. Today, the function to withstand low blood pressure acquired through the long process of evolution causes blood vessels to be damaged by high blood pressure. How strange!

PR Office:
The story about the relationship between the evolution of humanity and low and high blood pressures is very interesting.

Professor Itoh:
Thanks to the discovery of this mechanism, if albumin is contained in the urine, no matter how small its amount is, we can check for other diseases and start treatment early. A tiny amount of albumin is present in a patient’s urine. The patient may try to play it down as no big deal, but a slight amount does not necessarily mean a minor disorder. The fact that the blood vessels in the kidney are damaged suggests a high possibility that the blood vessels in the brain are also damaged. Leaving this situation as it is could potentially lead to brain disease.

PR Office:
By checking the urine, you can find out the conditions of the brain.

Professor Itoh:
This finding is increasingly recognized in society these days. I call this entity a strain vessel*5, because these blood vessels (A in Figure 3) are under extremely high strain. They are thin arteries (whose thickness is a tenth of that of a hair) that are exposed to and endure a high pressure. On top of that, the pressure is of pulsating nature (this is because the heart pulsates). When the blood pressure becomes low, the blood stream can be maintained by dilating moderately strained blood vessels. When the blood pressure becomes high, on the other hand, it is necessary to put blood vessels under higher strain. If this excessively strained condition continues, blood vessels are gradually damaged, resulting in protein leaking and the brain suffering stroke.

PR Office:
As you continue with your research, you discover new mechanisms one after another.

igure 3. Vascular structure of the kidney and that of the brain The branches of thin blood vessels near the thick blood vessels are exposed to high pressure. The further thin blood vessels get from the thick blood vessels, the lower the pressure on these thin blood vessels becomes. Even if the glomeruli of A in the kidney are damaged by high blood pressure and albumin leaks into the urine, it is diluted by the large volume of urinary water from the majority of normal glomeruli of B, resulting in only a small amount of albumin being found in the urine. However, a slight amount of albumin in the urine indicates that the blood vessels in the brain having the same structure as the kidney are at a high risk of being damaged.

Notes:
*5: Strain vessel: A blood vessel under strain

Professor Itoh:
I always tell younger people to aim to become world-class researchers. When I was young, I thought I would become a private-practice doctor immediately after graduating from university and completing the initial training. But, when I joined the Second Internal Medicine Department of Tohoku University Hospital after finishing my internship at Furukawa City Hospital, my mentor, the late Professor Keishi Abe, said to me, “We are planning to send you to the U.S. next year to study. So, write a paper in English in this one-year period.” He then added, “You need to do all the work that will be assigned to you during your first year here.”

Since I was thinking about going into practice as soon as possible, studying in the U.S. was totally beyond the scope of assumption. But I saw the offer as a challenge worth a try and went to Detroit. There, I did research on renin secretion, as I explained earlier. And, after accomplishing some positive results, I came back to Japan.

After returning to Japan, I rejoined the Second Internal Medicine Department. But, then, I started to get calls from Professor Carretero of the Henry Ford Hospital, who repeatedly asked me to come back to the U.S. Finally, I was persuaded into going to the U.S. again. Later, as my research on perfusion of arterioles produced some good results, the National Institutes of Health (NIH) and other organizations gave me a huge sum of research funds, which allowed me to have a laboratory of my own. The next thing I knew, I had spent eight years in the U.S. My life went very differently from my original intention of becoming a private-practice doctor, but I think that the experience of doing research abroad has greatly helped me become what I am now.

PR Office:
Today, there is widespread unwillingness among young Japanese to go abroad. Is it because of the comfortable environment they have here?

Professor Itoh:
It is certainly one of the reasons. So, if you are a highly motivated person, I think you should take advantage of Japan’s comfortable environment conversely. From my own experience, I can say that working or studying abroad will benefit you much more than just staying in Japan even if it costs you your current position. If you have enough vitality and ability to work or study abroad, you will be able to get a decent job or position after you come back to Japan. That is why I always tell younger people to aim to succeed at a world-class level without being preoccupied with short-term stability of life in the home country.

PR Office:
So the abilities that you acquire studying abroad are special.

Professor Itoh:
What you can acquire is more than just abilities and research results. Through a research life abroad, you will be able to get to know leading researchers in the world and build a network of personal connections by increasing your peers. Granted, the research community is a competitive world, where everyone around you is your rival. But, in such a competitive world, you can still find friends you can mutually respect. By becoming friends with researchers from around the world, I myself have been able to absorb diverse views of life and cultural differences, which I feel has helped enrich my life.

In your research life, you may get a chance to study abroad several times. From my experience, you should do it in an early stage of life when you can think flexibly and absorb new knowledge easily. I hope that more Tohoku University students will study abroad with brave ambitions to work on the world stage.