Robert Tigerstedt and the Discovery of Renin.

The year 2022 marks the 125th anniversary of the discovery of the first element of the renin-angiotensin-aldosterone system. The importance of this event on the further development of nephrology, cardiology, and endocrinology left us compelled to reminisce about it and its main author, Robert Tigerstedt (1853-1923), who was one of Scandinavia's most famous scientists. He studied medicine at the University of Helsinki, Finland. His doctoral dissertation On the Mechanical Stimulation of the Nervous System and 10 other original publications made him famous among the neurophysiological community. From 1881, he worked in the Physiology Department at Karolinska Institute, Stockholm, where he created a modern laboratory and became a professor at age 33 years. After meeting Carl Ludwig in Leipzig, he became interested in central blood circulation. In 1886, with Per Bergman, he started a series meticulously performed experiments with extracts of the rabbit kidney cortex, which, when injected into other rabbits, increased their blood pressure. The hypothetical responsible substance was called renin. The results were presented at the International Congress of Medicine in Moscow in 1887. Forty years later, Harry Goldblatt confirmed Tigerstedt's theory that "the substance which comes from kidneys increases the blood pressure." After he returned to Finland in 1901, Tigerstedt headed the Physiology Institute in Helsinki. His further activities included scientific work, teaching, and socially oriented issues like healthy nutrition and conditions in prison camps. He was also interested in the history of medicine and was a member of the Nobel Committee. His Textbook of Human Physiology was published in numerous editions in many languages. He also authored the renowned Textbook of Physiological Methodology and Physiology of Circulation. Tigerstedt published over 200 scientific papers and was an honorary doctor at many universities. He was known for his strong personality, critical judgment, idealism, humor, and warm heart.

Renin: from 'pro' to promoter.

Renin is the rate-limiting enzyme in a cascade that leads to production of angiotensin II, which is perhaps our most important regulator of salt and water balance and blood pressure. In this personal perspective, I describe how I entered the renin field 33 years ago by discovering that proteases increased the level of renin activity in biological fluids, so revealing the existence of a 'pro' form of the molecule. This led me on a journey that encapsulated all of the major milestones in molecular discovery for renin. These included (1) the elucidation of the steps in renin biosynthesis, (2) the cloning of renin cDNA and its gene, (3) demonstration of the structure of the renin protein, (4) using the renin gene in the first genetic studies in hypertension, (5) finding the mechanism by which the major controller, cyclic AMP, regulates the promoter, (6) showing that a strong enhancer and its weak promoter control this physiologically regulatable gene in accord with the variegation (on/off switching) model, and (7) being the first to identify molecules involved in posttranscriptional control. The renin molecule, its gene and molecular control are now very well understood, but more fine details on the topic of renin continue to emerge to delight 'reninologists' and others.

History about the discovery of the renin-angiotensin system.

The history of the discovery of the renin-angiotensin system began in 1898 with the studies made by Tigerstedt and Bergman, who reported the pressor effect of renal extracts; they named the renal substance renin based on its origin. In 1934, Harry Goldblatt induced experimental hypertension in dogs by clamping a renal artery. About 1936, simultaneously in the Medical School of the University of Buenos Aires, Argentina, and in the Eli-Lilly Laboratories in Indianapolis, 2 independent groups of researchers, using the Goldblatt technique to produce experimental hypertension, demonstrated renal secretion of a pressor agent similar to renin. In the following years, both teams described the presence of a new compound in the renal vein blood of ischemic kidneys. This agent was extracted from blood with 70% acetone and had a short pressor effect. The final conclusion was that renin acted enzymatically on a plasma protein to produce the new substance. In Buenos Aires, it was called hypertensin; in the United States, angiotonin. In 1958, Eduardo Braun Menéndez from Argentina and Irving H. Page from the United States agreed to name it angiotensin.

[The renin saga]. / La saga de la renina.

This saga is the story of a scientific development. From the search of a mechanism to explain high blood pressure, research was orientated to the functions of an omnipresent biochemical system. And from the search to elucidate the etiology of arterial hypertension, research has ended up studying the local, functional and structural activity of the renin-angiotensin system and the possibilities of interfering with its actions. Since Bright, left ventricular hypertrophy became associated with nephrosclerosis. Later on, clinical studies led Volhard and Fahr to associate nephrosclerosis to high blood pressure while biochemical research led Tigerstedt and Bergmann to demonstrate that renin was associated to high blood pressure. Two teams of investigators, one in Argentina and one in USA discovered the biochemical mechanism by which renin acted on arterioles and later on, two other teams, one in USA and one in England, discovered the biochemical steps leading to the synthesis of angiotensin II. Since Goldblatt's experimental design resulting in a reliable method to obtain arterial hypertension, more than 20 years had to elapse before renal artery stenosis became established as the main cause of clinical secondary arterial hypertension. The renin-angiotensin system became part of a very complex array of substances able to regulate local circulation directly or indirectly and angiotensin has become involved in the remodeling of the smooth muscles of arterioles and myocardium.

La saga de la renina / The renin saga

Esta saga será historia de un conocimiento si sólo refiere los hechos y será un cuento al añadirle la interpretación que ayude a la comprensión, una saga es más cuento que historia. Iniciada la investigación para la búsqueda de causas de hipertensión arterial, los resultados han llevado al estudio de acciones locales funcionales y estructurales y al análisis de mecanismos de acción que han permitido una extensa utilización de modos de inhibir el sistema renina-angiotensina. En esta historia, un ejemplo paradigmático de la evolución del conocimiento científico, la búsqueda de un mecanismo que explicara la hipertensión há llevado a la búsqueda de funciones para un sistema de presencia ubicua.

[A 100-year perspective on renal function and hypertension. Anti-renin therapy has made hypertensive renal failure a rarity]. / 100 års perspektiv på njurfunktion och hypertoni. Anti-reninterapi har gjort hypertensiv njursvikt till en raritet.

One hundred years ago, in 1898, Professor Robert Tigerstedt, Karolinska institutet, Sweden, discovered renin. The subsequent elaboration in 1960 of the renin-angiotensin-aldosterone system signalled the start of modern hypertension research. The kidney takes part in blood pressure regulation in a number of ways. Indications are that increased renovascular resistance due to increased renin-angiotensin activity is of importance for the barostatic function of the kidneys and for the pathogenesis of human hypertension. Several commonly used, efficacious and well tolerated antihypertensive agents act by blocking the renin-angiotensin system, thus normalising kidney function. A number of current large-scale trials--utilising ACE inhibitors and angiotensin receptor antagonists--will, it is hoped, elucidate the proper role of 'anti-renin therapy' in the treatment of hypertension. Thanks to effective modern management of hypertension, renal failure due to hypertensive kidney disease is rare in Sweden today.

Evolution of renin.

After the development of blood pressure measurements in humans, the association of high blood pressure with renal disease was established. Injection of extracts of various organs in an attempt to replace their secretions was common in the 19th century, and it was therefore natural for Tigerstedt and Bergman to investigate the effects of renal extracts. In this way, they discovered renin. This paper covers the methods by which its mode of action was uncovered, as well as its relation to renal ischemia and hypertension.