A brief history of renin

Abstract

Renin was discovered by the Finnish physiologist, Robert Tigerstedt, working with his medical student, Bergman, in Stockholm in 1898. They showed that saline extracts of fresh rabbit kidney or of an alcohol-dried powder produced an initial fall but then a prolonged rise in blood pressure when injected into rabbits lightly anesthetized with urethane [1, 2]. They also showed that renin could only be extracted from the renal cortex, that it was destroyed at 56°C, precipitated by half-saturated ammonium sulfate, did not dialyze, had little effect on the heart, but also raised blood pressure of the pithed cat. For about three decades, very little else happened. When Myron Prinzmetal went to work with George Pickering, the two could initially not duplicate these findings. It was only when they used saline extracts of alcohol-dried kidney in unanesthetized rabbits that they achieved success. Franz Volhard and his assistants also stumbled on the problem of documenting the existence of renin. However, Volhard’s student, Hessel, eventually reported success in 1938. Greatly facilitating the notion that renin must exist were the renal artery stenosis studies of Harry Goldblat and collaborators in 1934. In 1938, Fasciolo, Houssay, and Taquini showed that renal venous blood from an ischemic kidney produced vasoconstriction. Shortly thereafter, Braun-Menendez, Fasciolo, Leloir, and Munoz showed that the pressor substance was soluble in acetone, thermostable, and dialyzable, in short nothing at all like renin. They named the substance hypertensin. Independently, and in the same year, Irvine Page and Oscar Helmer, working in Indianapolis, IN, USA, found that renin was inactive when perfused in saline through the rabbit’s ear but that activity was restored by blood. They also showed that incubating renin with plasma produced a new substance that they called angiotonin. Both groups demonstrated that renin acts like an enzyme and a plasma protein as a substrate. In 1954, Skeggs, Marsh, Kahn, and Shumway, working at the Veterans Hospital in Cleveland, OH, USA, isolated two products from incubating hog renin with horse serum, hypertensin I and II. The group then showed that hypertensin II consists of the following eight amino-acids: AsparticArginine-Valine-Tyrosine-Isoleucine-Histidine-ProlinePhenylalanine. Hypertensin I is a decapeptide, with two additional amino acids, histidine and leucine, added to the phenylalanine end of the chain. Peart, while working in Pickering’s laboratory, largely confirmed these findings. The North and South Americans agreed to consolidate the nomenclature so that the decaand octapeptides are termed angiotensin (Ang) I and Ang II, respectively. Thus, by 1956, the renin–angiotensin system was pretty well worked out. As a nephrologist, I would like to make a few more comments about Leonard Skeggs, who in my view is a largely unsung hero. Aside from the structure of Ang I and Ang II, Skeggs developed the plate hemodialyser that bears his name in 1948. This same technology was then adapted by Skeggs to develop the first automated device to perform blood chemistries. It was called the SMA-12-60 autoanalyzer. Incidentally, the late Norman Shumway, who also appears on these papers, is much better known for his seminal contributions to cardiac transplantation. In 1958, Franz Gross published a brief history of renin, largely as I have recapitulated here [3]. In that paper, Gross made the startling suggestion that somehow renin stimulated aldostserone. He based this conclusion on data from his own laboratory. His group had found that treating animals J Mol Med (2008) 86:611–613 DOI 10.1007/s00109-008-0354-y