An Interview with Professor Sadayoshi Itoh on the Reception of the American Heart Association Arthur C. Corcoran Memorial Lecturer Award
"Measuring the Health of the Brain Based On the Functioning of the Kidney"
October 20, 2014
We've heard that you received a very prestigious award. Congratulations. Could you give us the background about how you earned this award?
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.
Establishing a perfusion technique and accumulating results
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.
The kidney in our body has a feedback-based elaborate regulation mechanism.
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.
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.
*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).