Tissue Renin–Angiotensin Systems: A Unifying Hypothesis of Metabolic Disease

Abstract

The actions of angiotensin peptides are diverse and locally acting tissue renin–angiotensin systems (RAS) are present in almost all tissues of the body. An activated RAS strongly correlates to metabolic disease (e.g., diabetes) and its complications and blockers of RAS have been demonstrated to prevent diabetes in humans. Hyperglycemia, obesity, hypertension, and cortisol are well-known risk factors of metabolic disease and all stimulate tissue RAS whereas glucagon-like peptide-1, vitamin D, and aerobic exercise are inhibitors of tissue RAS and to some extent can prevent metabolic disease. Furthermore, an activated tissue RAS deteriorates the same risk factors creating a system with several positive feedback pathways. The primary effector hormone of the RAS, angiotensin II, stimulates reactive oxygen species, induces tissue damage, and can be associated to most diabetic complications. Based on these observations, we hypothesize that an activated tissue RAS is the principle cause of metabolic syndrome and type 2 diabetes, and additionally is mediating the majority of the metabolic complications. The involvement of positive feedback pathways may create a self-reinforcing state and explain why metabolic disease initiate and progress. The hypothesis plausibly unifies the major predictors of metabolic disease and places tissue RAS regulation in the center of metabolic control.

Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice

“…Ang I is, hereafter, cleaved by angiotensinconverting enzyme (ACE) to the effector hormone Ang II. It is now evident that the components of RAS, in addition to the classical pathway, are expressed and act locally in multiple tissues [2], such as insulin secretion [3], Y. Zhang and L. Wang contributed equally to this work. glomerular sclerosis [4], renal inflammation [5], atherosclerosis [6], cardiac hypertrophy [7], brain disorders [8], and follicular development and endometrial cancer in female reproductive tract [9].…”

Association of polymorphisms within the Renin-Angiotensin System with metabolic syndrome in a cohort of Chilean subjects

“…In the last years, the study of tissue RAS regulation sustained that this system can be a fundamental participant in metabolic processes and could explain the origin and complications of some metabolic disorders, such as Metabolic Syndrome (MetS) (3). MetS is a condition in which obesity and insulin resistance play major roles for its development, and the presence of this syndrome has been associated with a 2-fold increase in cardiovascular disease risk, and 5-fold increase in diabetes mellitus risk (4).…”

Oxidative stress in adipose tissue as a primary link in pathogenesis of insulin resistance

“…Гипергликемия является одним из признанных активаторов РАС в различных тканях животных и человека [72][73][74]. Ангиотензин II (ANG II) -важнейший элемент РАС -связывается с рецептором клеточной поверхности ANG II типа 1 (AT1R), что приводит к активации NADPH-оксидазы, которая продуцирует супероксидный анион-радикал в ходе одноэлектронного восстановления кислорода и окисления NADPH [75]. Активированная NADPH-оксидаза -главный источник избытка АФК во многих типах клеток [76,77].…”