The Juxtaglomerular Apparatus

Homer Smith died in 1962, the year before I started my career in the Department of Physiology of the University of Goettingen. At that time, his original work was still well known and widely quoted. Several decades later, this has of course changed, and the newer generation of renal physiologists and nephrologists is often unaware of who Homer Smith was and what he did. This is not totally surprising given the time elapsed and the short half-life of scientific fame and the fact that the electronic library, which we more and more rely on exclusively, does not go back beyond 1965 or so. I would therefore like to begin my presentation by honoring the man who is commemorated by this award. Born in 1895 in Denver, he received an A.B. from the University of Denver in 1917. He joined the armed forces and was transferred to the Chemical Warfare Station in Washington D.C., where he studied the biologic effects of gases, specifically of mustard gas, under the supervision of E.K. Marshall, who later provided proof for tubular secretion of organic compounds and its saturable nature. After the end of the war, Homer Smith enrolled in graduate studies at Johns Hopkins University and received the D.Sc. degree in chemistry in 1921. His early scientific work revolved around the chemotherapeutic value of arsenic compounds and the chemistry of secondary valence. After 2 years in the laboratory of Walter Cannon at Harvard University (1923–1925), he turned to studies of marine biology and of the physiology of fish. Around 1930, he began to develop and apply quantitative methods to studying the function of the mammalian kidney. He was appointed chairman of the Department of Physiology of the University of Virginia at the age of 30 yr. In 1928, he became chairman of the Physiological Laboratories at New York University College of Medicine, a position that he held until 1961. In the late 1920s, when Homer Smith started his work on the kidney, renal physiology as a field was not particularly advanced; in fact, it was considerably underdeveloped. This is reflected, for example, in the following statements of Alfred Richards, one of the other greats of kidney physiology in that same time: The literature of investigation of the kidney, since Bowman, contains no great illuminating discoveries comparable to those which are so conspicuous in other fields. Many of the questions of kidney function which are now being actively debated by physiologists are practically identical with those which were subjects of controversy seventy-five years ago…. Is the Malpighian body with its contained glomerulus a filter or is it a “secretory” structure? Is the epithelium which composes the tubule walls capable of secreting substances from blood into lumen of tubule, or is its task that of permitting or enabling restoration to the blood of substances lost to it in passage through the glomerulus? (41). These were very basic questions indeed! Thirty years later, by the end of the “Homer Smith era,” the function of the kidney at the organ level was adequately described in quantitative terms of filtration, perfusion, absorption, and secretion, through his work and through the work of others that he had stimulated. One could argue, as Robert Berliner has done, that his summary and interpretation of the available knowledge may be his most important contribution to the field (5). He wrote three textbooks on renal physiology and pathophysiology of which the second, The Kidney, was enormously influential, because it was the first modern and correct summary of how the kidney works in quantitative terms (58,61,63). His scientific work is summarized in a little over 100 original publications — papers used to be fewer and longer then. His major scientific contribution was to co-invent, simultaneously with Richards (42), the clearance methodology for measuring GFR and RBF, and then apply it in a wide array of conditions, mostly in clinical conditions, since Homer Smith had long-standing and intense collaborations with his clinical colleagues at New York University (14,23,54,64). Among his other contributions are the development of the concept of free water clearance with urinary dilution being a consequence of NaCl absorption across a water impermeable segment, the distal nephron, the discovery that urea back-diffusion accounts for its relatively low clearance and its dependence on urine flow (10), the notion that bulk absorption of the majority of filtered water occurs in the proximal tubule by active absorption of Na followed by passive absorption of water, the concept of “obligatory” reabsorption in the proximal tubule and “facultative” reabsorption in the distal tubule, and the introduction of the concept of glomerulotubular balance. Homer Smith was a much sought-after speaker as judged from the number of talks he was invited to give, and it is from the transcripts of these talks that one can glean a more personal view of who Homer Smith was. The titles of some of these presentations indicate his interests, titles such as “Error in Physiology” (1936), “Plato and Clementine” (1947), “Objectives and Objectivity in Science” (1949), “Agnosticism versus Atheism” (1956), “De Urina” (1958), and “The Biology of Consciousness” (1959) among others. It is apparent that he was broadly interested; he was a humanist, an evolutionary biologist, a paleontologist, a philosopher, and a musician, somewhat of a renaissance man. Throughout his life, he struggled with the place of man in nature and therefore with the interface of science, philosophy, and religious beliefs. He did not believe in the supernatural or in creationism, and was skeptical about all established religions. In his words: All human history reveals that transcendental metaphysics is not only futile but dangerous. Those who have, frequently by dishonest means, foisted upon the naïve and gullible their own unsupported speculations have served to retard man’s self realization more than any other misfortune that has ever befallen him. History also reveals that man does not need any brand of transcendental metaphysics — his lasting contentments and achievements he has found wholly within the frame of reference that takes things as they are in the here and now (62). In addition to his textbooks, he wrote four other books, Kamongo, or The Lungfish and the Padre (Viking Press, 1932), The End of Illusion (Harper, 1935), Man and His Gods (Little Brown, 1952), and From Fish to Philosopher (Little Brown, 1953). Particularly pleasant to read is From Fish to Philosopher. His enthusiasm and understanding for comparative physiology has substantial resonance in this era in which we learn more and more about the extent of evolutionary conservation both at the genomic and functional level. The Juxtaglomerular Apparatus I would like to turn to the topic of this overview, the mechanisms of juxtaglomerular cell communication, with these quotes of Homer Smith that are as true and puzzling now as they were then: Examining the pattern of the human kidney, we must not be surprised to find that it is far from a perfect organ. In fact, it is in many respects grossly inefficient. It begins its task by pouring some 125 cc of water into the tubules each minute, demanding for this extravagant filtration one quarter of all the blood put out by the heart. Out of this stream of water, 99 per cent must be reabsorbed again. This circuitous method of operation is peculiar, to say the least…. In consequence of the circuitous pattern of the filtration and reabsorption of water, nearly half a pound of glucose and over three pounds of sodium chloride per day, not to mention quantities of phosphate, amino acids and other substances, must be saved from being lost in the urine by being reabsorbed from the tubular stream. There is enough waste motion here to bankrupt any economic system — other than a natural one… (59). The astounding conclusion that over three pounds of NaCl must be filtered and absorbed per day was a derivative of the recognition of the nature of glomerular filtrate formation as an ultrafiltration process and the determination of the GFR magnitude by the inulin clearance. Avid absorption takes place along the proximal part of the nephron by an array of transporters, and their activity reduces the amount of Na to an apparently trivial number by the time the collecting duct is reached. There is good evidence that most or all of the regulation of Na absorption that is necessary to match salt intake and excretion over the physiologic range occurs along the collecting duct through variations in Na absorption across the highly regulated epithelial Na channel ENaC. The critical role of ENaC-dependent Na absorption is highlighted by observations in patients and mice, in which ENaC deficiency is associated with severe Na loss and volume depletion, that in the case of the ENaC knockout mice, regardless of ENaC subunit, lead to rapid postnatal death, at least to a substantial extent by volume loss and circulatory collapse (1,20,33). The same outcome is seen in mice that are deficient in the mineralocorticoid receptor, and therefore do not respond to aldosterone, the most important regulator of ENaC (4). Conversely, ENaC overactivity as in Liddle syndrome causes severe volume-dependent arterial hypertension with all its dire consequences (17,55). Because the capacity of the collecting duct is limited, one could envisage unwanted Na loss by collecting duct overloading with excess Na when there is an increase in GFR or when there is a decrease in Na absorption in the proximal nephron. It is now clear that such changes in NaCl delivery are sensed in the juxtaglomerular region of the nephron and are used as a signal that feeds back to the glomerulus and tends to return distal Na delivery to its original state. This feedback system is anatomically represented in the juxtaglomerular apparatus (JGA), the complex of epithelial, mesangial, and as the of the return of the to its a fact well and in Homer In epithelial with a cell and through with the and of the glomerular It is now clear that this both to Na One is the feedback feedback or for the other is of secretion and both of these respond to the same they in their of a nephron the return of the to the of its own view of the juxtaglomerular apparatus is in the The is from Smith The of has a time with or within to it for and variations of the signal in the of its it as a of salt delivery to the distal nephron, and of the signal of the of secretion has a time and a 2 to or and it to of the those associated with changes in volume for example, it as a of body salt through changes in and it is because the signal can also of studies of feedback began with the that and After the proximal that to the same nephron, its distal tubule was and was this was an of NaCl or the proximal tubule would and this was as a severe in In it would that the of the was because of GFR is not the to distal with an of the in a more quantitative After the of a proximal tubule by of were from the proximal in an was by an and were in a for of and in the distal tubule for of Na or The of such that as there was an increase in Na and a decrease in nephron GFR decrease of was not seen when the was an of Na of of at flow and this a and flow with by about and the flow a being in the range of In a first in with flow a of glomerular was of this is somewhat and has as a method flow the same to with the that are in the and the is therefore to the and a in which the tubule is not and in which flow is by the addition or of at low flow is from the by a permitting an of the of the feedback of one would be because it would indicate that an addition of had a in flow of of and was in to around the of of and nephron GFR as the of early proximal tubular flow and the tubular to inulin are from the of of and the associated of flow are from important of is its to by its range into a or flow range and by its by or the of the This occurs when the signal is out of range for are of of volume for example, and are of and volume for In the system an and and its is at the function its is around the it can its range and its to flow it has a for at to it is a nephron can by and its is of of and The the tubular lumen with the the cell of the It begins with a in the tubular lumen that end and secretion, through an epithelial cell most of followed by an that the the nature of the tubular signal that is to the a was used in which were into the distal tubule, a that is much to the region so that one can that the the NaCl the at a flow and were seen in the range with at about was about which we to be to the NaCl in the in an that and may be in that the same of perfusion, were seen when Na was with but not when was with a number of the being a from this that variations in are for the variations in Na or are not a for the the signal for is on changes of and the is about of Na by other has no on the and is of and the NaCl in into the distal tubule at a of and the associated in the NaCl the decrease of are from secretion has and studied in by but secretion is under the of important in addition to that of the it was therefore to and to what extent these other were secretion in and a in which the and its glomerulus were from and with the through the The was into an that as a After of this in the the would that could be in time for of activity and The in in to the is because this does not of much more than the and because it has no or regulated in an increase in NaCl a and a decrease in NaCl a of with being about of the of secretion that the like the range with a of about to 30 the signal for the is on changes of the the is about to 30 of Na by or has no on the of by or the and the is by NaCl not NaCl of a glomerulus with from kidney. The the is on the In the the a that into the tubular lumen The to the has into an that as a After a the is in The the that are in time for NaCl from to causes a decrease in secretion it from to causes a increase in are from and by a NaCl such as and others have to and to In a in which we the dependence of and we found that at those at which a in distal of that these were studies with the channel as well as with from that channel that knockout mice have very or no The identical of of that their role in NaCl activity than any other effects of or is an early epithelial in the by in had that the NaCl activity is by with an of about the for Na or are so that the is with the of we believe that this may as to the is regulated by changes in and it is apparently Na in this is the notion that of in the are comparable to those in the This notion has by the of and who have that the of the the most in had a much only when in It is still which of the epithelial cell changes that are on activity of are part of the juxtaglomerular NaCl has to of Na and an increase of cell an increase in cell and cell All of these changes could be in with the of cell because were found to increase cell a is to which of the and that have by the work of most those of and to be in or of a role in juxtaglomerular until with the of and of the other have in the or studies some on the of the and others in the role for by has established that on the of studies of an of the of and found in and of The of and in is in a to the function of the to or secretion has for the and It is widely that an increase in NaCl causes changes in the of the that the function of and Because of the the most notion is that these changes are changes in the and of a number of such have on the of but evidence and therefore a has to It is in this of that the of knockout mice has and to be example, mice with knockout in the have that is not a major in this under evidence in in and in has as in the example, the the to an in NaCl in an in in which the was and in which changes of the served as end on the that the may the through this as by in with the of mice with a knockout in this In fact, of flow or nephron GFR were found to be in mice The dependence of on the of was in of knockout mice that was by and studied in the laboratory of we that an increase in NaCl causes the in the of and that through causes The of still to be is by and it could be by one of the that are found in many may be from have provided some evidence that may in fact be in a NaCl through a and an of by an of has by is for it is that it a major role in the of secretion by low example, the of secretion by to a major extent by the was found to be in of knockout mice The conclusion that of is not the for the of by low NaCl with studies in the in which the addition of to the did not a major of secretion the other have in the of secretion for a of in secretion was by the in the that the by low NaCl The interpretation of these was not clear because were not to the only known at the development was the by that as well as the of the that of with the the in the used as a had no such role for in the is also by studies from laboratory in which the of on activity was found to be in knockout mice, it was in the of The of this on the extent to which the of through the believe that it is this that causes the of the system in patients with a by the mechanisms that a low NaCl with an of we a cell in from the NaCl a increase in the of from these and a of that these effects were by a low a of Na had no of was also by and The of was by the with the same as by the that it was from of was followed by rapid of and and the of and the of by low of did not or changes of It be out that this to NaCl does not to be to but it to be by In a decrease in NaCl and and of secretion and the and by the same to be by of the The first determination of the changes in the of filtration by NaCl was by and In their the signal from to a in a in nephron filtration a in flow and a in nephron filtration these that this an increase in on and could have or It has also that may the filtration the by has now in in in the and in the nephron Because has as being for one would that the effects of in are with the known of the In fact, to the from a at of and that was particularly in the glomerular of the was not seen in from knockout mice, that it was These observations observations by and in a from the kidney. In in which the and were the most of was in the very of the to the where the is to the of the This of the is also the that is particularly to and is therefore the where and observations in of by and of the of the notion that the by and by the same of by of has well and an through the has for at least 30 the with which is by the degree of of This is by observations that the magnitude of the on of and in or knockout mice or with or a given to the is much than and the glomerular to an is Conversely, an increase in by for example, to the to and this may to some extent be the for the of the to The of the and is still from would that the of through and causes an of from that may a with glomerulus under and with a at In this the region of was to be the glomerulus the first of the to the region of the first and indicate the of the before and of NaCl and at the as the signal that in of or increase in NaCl an epithelial cell that of cell and an increase of These or some other consequences of the in the juxtaglomerular of and the of the of on and this in of of and decrease in NaCl an epithelial that of of and of activity and of This is followed by the in the juxtaglomerular of and the of on and this in and and more one could envisage in which the one when the NaCl is or when NaCl is In this the cell is a cell through the of the other when the NaCl and therefore is the cell is an The of NaCl at the is to of an increase in the of in the juxtaglomerular apparatus and of the The of NaCl at the is to an increase of in the and an of from his The Kidney, Homer Smith about the juxtaglomerular apparatus has the and its associated the juxtaglomerular he that it has an important but some have that this apparatus in the of the renal blood in He had not his about the role of this now can be that it at least the that were the topic of this it and in the of Homer The first of is that man must be free to the in his own which is to say that he must all a The of is that no have a is with a case it is to be as a body of which has and found to be but which is the held to and and indeed! the major from the the of and the The with has a of much in all of my I for the provided by and and I with the with Walter and are to my and and and