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. BioEssays 25:520–527, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

This renin‐angiotensin system (RAS) interpretation is focused on differences in tissue dependence on RAS and on the topological hierarchy that allows mediators to act only on downstream tissues.Dependence of tissues on RAS: Tested by expectation maximization clustering of the RNA human tissue expression (https://biogps.org/). ACE and vasoconstrictive AT1R clustered with the prorenin receptor. ACE2 and dilatory MAS1 clustered with nine RAS‐related genes, highly expressed in: Liver; Cardiac_Myocytes; Skeletal_Muscle; Uterus; Kidney; Lung; Small_Intestine; Smooth_Muscle.RAS and stress accumulation: While prorenin is active after (...) binding to its receptor, binding of soluble renin increases its enzymatic activity several times. Increased renin secretion multiplies the overall capacity for producing Ang I, leading to hypertension and increased vascular resistance.Coronavirus infection and comorbidities: Cardiorespiratory failure during infection is linked to the previously altered RAS role in lungs and myocardium. Reduced vasodilation by ACE2 lead to vasoconstriction and suboptimal tissue perfusion patterns. Also see the video abstract here https://www.youtube.com/watch?v=Jf0Iped-Mws. (shrink)

The renin-angiotensin system (RAS) is critical in sodium and blood pressure (BP) regulation, and in cardiovascular-renal (CVR) diseases and therapeutics. As a contribution to SAPHIR project, we present a realistic computer model of renin production and circulating RAS, integrated into Guyton’s circulatory model ( GCM ). Juxtaglomerular apparatus, JGA , and Plasma modules were implemented in C ++/M2SL (Multi-formalism Multi-resolution Simulation Library) for fusion with GCM . Matlab © optimization toolboxes were used for parameter identification. In JGA , renin production (...) and granular cells recruitment (GCR) are controlled by perfusion pressure (PP), macula densa (MD), angiotensin II (Ang II), and renal sympathetic activity (RSNA). In Plasma , renin and ACE (angiotensin-converting enzyme) activities are integrated to yield Ang I and II. Model vs. data deviation is given as normalized root mean squared error (nRMSE; n points). Identification: JGA and Plasma parameters were identified against selected experimental data. After fusion with GCM : (1) GCR parameters were identified against Laragh’s PRA-natriuresis nomogram; (2) Renin production parameters were identified against two sets of data ([renin] transients vs. ACE or renin inhibition). Finally, GCR parameters were re-identified vs. Laragh’s nomogram (nRMSE 8%, n = 9). Validation: (1) model BP, PRA and [Ang II] are within reported ranges, and respond physiologically to sodium intake; (2) short-term Ang II infusion induces reported rise in BP and PRA. The modeled circulating RAS, in interaction with an integrated CVR, exhibits a realistic response to BP control maneuvers. This construction will allow for modelling hypertensive and CVR patients, including salt-sensitivity, polymorphisms, and pharmacotherapeutics. (shrink)

“Hypertension in Blacks is a salt disease,” Dr. Anderson1 explained. “Too much salt overloads their renin-angiotensin system and their kidneys can’t handle it. It’s just the way their bodies work....

Any living organism interacts with and responds specifically to environmental molecules by expressing specific olfactory receptors. In this paper, this specificity will be first examined in causal terms with particular emphasis on the mechanisms controlling olfactory gene expression, cell-to-cell interactions and odor-decoding processes. However, this type of explanation does not entirely justify the role olfactory receptors have played during evolution, since they are also expressed ectopically in different organs and/or tissues. Homologous olfactory genes have in fact been found in such (...) diverse cells and/or organs as spermatozoa, testis and kidney where they are assumed to act as chemotactic sensors or renin modulators. To justify their functional diversity, homologous olfactory receptors are assumed to share the same basic role: that of conferring a self-identity to cells or tissues under varying environmental conditions. By adopting this standpoint, the functional attribution as olfactory or chemotactic sensors to these receptors should not be seen either as a cause conditioning receptor gene expression, or as a final effect resulting from genetically predetermined programs, but as a direct consequence of the environmental conditions olfactory receptor genes have explored during evolution. The association of odorant patterns with specific environmental or contextual situations makes their relationship semiotically triadic, due to the emergence of an interpretant capable of perceiving odorants as meaningful signs out of a noisy background. This perspective highlights the importance of odorant-receptor relationships as respect to the properties of the interacting partners. It is our contention that only when taken together can these different explanatory strategies provide a realistic account of how olfactory receptor genes have been structurally and functionally modified during evolution. (shrink)

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin‐converting enzyme (ACE) is the central component of endocrine and local tissue renin–angiotensin systems (RAS), which also regulate diverse aspects of whole‐body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3‐55C (rather than (...) T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8‐fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role. (shrink)

There is evidence that many peptide growth factors and hormones act in the intracellular space after either internalization or retention in their cells of synthesis. These factors, commonly called intracrines, are structurally diverse while sharing some common functional features. Reports of intracellular peptide hormone binding and action are reviewed here. Also, this laboratory has made proposals regarding the origin and actions of intracrines and these areas are further explored. Intracrine interactions and the relationship of intracrines to transcription factors are discussed. (...) The intracellular/intracrine renin–angiotensin system (iRAS) is reviewed to illustrate the intracrine analogue of a well‐established physiological system. The role of intracrine action in metazoan development is also considered. BioEssays 25:401–409, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

High blood pressure is a disease of unknown cause. Family history of the disease indicates higher risk, but it is not known which genes are involved or how they interact with environmental influences to produce the disorder. Molecular biology offers an approach to problems that have not so far been solved by classical physiology or biochemistry. By analysing polymorphic variation in chromosome markers such as minisatellite sequences, or by restriction fragment polymorphism analysis of candidate genes, attempts are being made to (...) link genetic variations with hypertension. In genetically hypertensive rats, hypertension is associated with a polymorphism of the renin gene and with other loci on chromosomes 10 and 18. The role of these loci in human hypertension remains to be determined. Other genes such as sodium‐lithium countertransport may be involved. Environmental factors such as stress or salt intake could influence the rate or timing of expression of certain genes and thus result in hypertension. (shrink)

Recent evidence, from both epidemiological and animal experimental studies, suggest that the very first environment, the intrauterine, is extremely important in determining the future health of the individual. Genetic and ‘lifestyle’ factors impinge on, and can exacerbate, a ‘programming’ effect of an adverse fetal environment. In this review, we present compelling evidence to suggest that one of the major organs affected by an unfavourable prenatal environment is the kidney. Many of the factors that can affect fetal renal development (i.e. exposure (...) to excess glucocorticoids, insufficient vitamin A, protein/calorie malnutrition (in rats) and alterations in the intrarenal renin angiotensinogen system), also produce hypertension in the adult animal. When nephron number is compromised during kidney development, maladaptive functional changes occur and can lead, eventually, to hypertension and/or renal disease. Surprisingly, it is during the very earliest stages of kidney development that the vulnerability to these effects occurs. BioEssays 25:212–220, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

More than 15 million people have been affected by coronavirus disease 2019 (COVID‐19) and it has caused 640 016 deaths as of July 26, 2020. Currently, no effective treatment option is available for COVID‐19 patients. Though many drugs have been proposed, none of them has shown particular efficacy in clinical trials. In this article, the relationship between the Adrenergic system and the renin‐angiotensin‐aldosterone system (RAAS) is focused in COVID‐19 and a vicious circle consisting of the Adrenergic system‐RAAS‐Angiotensin converting enzyme 2 (...) (ACE2)‐severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) (which is referred to as the “ARAS loop”) is proposed. Hyperactivation of the ARAS loop may be the underlying pathophysiological mechanism in COVID‐19, and beta‐adrenergic blockers are proposed as a potential treatment option. Beta‐adrenergic blockers may decrease the SARS‐CoV‐2 cellular entry by decreasing ACE2 receptors expression and cluster of differentiation 147 (CD147) in various cells in the body. Beta‐adrenergic blockers may decrease the morbidity and mortality in COVID‐19 patients by preventing or reducing acute respiratory distress syndrome (ARDS) and other complications. Retrospective and prospective clinical trials should be conducted to check the validity of the hypothesis. Also see the video abstract here https://youtu.be/uLoy7do5ROo. (shrink)