UPM|Mediateca

Prof. Pierre Corvol, Leonardo da Vinci Award. Symposium Artificial Intelligence and Ceremony of Awards. 21 and 22 October 2019. The history of renin is a "success story" as we would like to count many in physiology and medicine: an observation by a physiologist that leads some 80 years later to the use of renin angiotensin system (RAS) blocking drugs that have profoundly revolutionized cardiovascular therapy. At the beginning of the 1970s, little was known about the proteins and the genes of the RAS. The structure and function of three of the major components of this system have been elucidated in part in our laboratory using molecular biology and genetic tools: renin, angiotensinogen – the renin substrate - , and angiotensin I - converting enzyme (ACE). The entire RAS has emerged some 400 million years ago, as shown by phylogenetic studies. This system was essential during the transition of several vertebrate species from salt water to fresh water where salt conservation in the body became essential. This essential function is still relevant in today's man. Many of the RAS proteins have properties that recall their ancestral origin. This is the case with ACE that converts angiotensin I into angiotensin II, the active peptide of the system and inactivates bradykinin, a vasodilator peptide. ACE has evolved from an initial developmental and reproductive function to regulation of body volume and blood pressure in vertebrates. In mice, inactivation of the ACE gene results in a marked decrease in blood pressure, decreased renal function and in two unexpected effects: infertility in male mice and a selective decrease in hematopoiesis. In humans, the renin-angiotensin system has probably also played a major role in adapting to hot and humid climates and in preserving salt. There are several genetic variants of the renin-angiotensin system, some of which, such as angiotensinogen, promote salt retention. One of these variants is very common in the African subjects, slightly less so in Asians and even less so in the Europeans. This ability, determined by genetic factors to keep sodium in a warm country, may have provided a selective advantage during the evolution of the human species. Its persistence can nowadays become a disadvantage in a society where salt intake is often excessive. In humans, a mutation loss of function of any of the major genes of the RAS leads to neonatal death by anuria, probably due to a drop in perfusion pressure in the kidney, showing the importance of the RAS in the maintenance of blood pressure during fetal life. In conclusion, the renin-angiotensin system, as we know it, is a good example of physiological adaptation in vertebrates. Inhibition of this system is indicated in many pathological situations, but inappropriate and excessive inhibition under certain circumstances may compromise the ancestral mechanisms of sodium conservation.