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

Jeppe Skov,Jens Sandahl Christiansen,Jørgen Frøkiær,Frederik Persson

doi:10.3389/fendo.2014.00023

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.

Highlights

The renin–angiotensin system (RAS) is classically considered to play key roles in regulating blood pressure as well as water and sodium balance
TISSUE RAS REGULATION Below, we will review the interactions between tissue RAS and some of the main players in metabolic disease [hyperglycemia, obesity, hypertension, exercise, glucagonlike peptide-1 (GLP-1), cortisol, and vitamin D (VitD)]
Tissue RAS is regulated by multiple factors of which we have only mentioned some

Summary

INTRODUCTION

The renin–angiotensin system (RAS) is classically considered to play key roles in regulating blood pressure as well as water and sodium balance. Compared to hormones such as glucagonlike peptide-1 (GLP-1) or cortisol, the RAS may seem only a weak regulator of metabolism We will challenge this perception and argue that the tissue RAS can be considered as the most central player in metabolic regulation. A range of metabolic potent hormones and conditions closely interact with tissue RAS and it is often hard to distinguish direct hormonal actions from actions secondary to tissue RAS stimulation/inhibition Because of this consistent convergence toward tissue RAS and the well-known potent actions of especially ANG II, we hypothesize that the effects are mediated through regulations of tissue RAS. Implications of this hypothesis may change our view on endocrine physiology and explain both the origin of some metabolic diseases and the accompanying complications. TISSUE RAS REGULATION Below, we will review the interactions between tissue RAS and some of the main players in metabolic disease [hyperglycemia, obesity, hypertension, exercise, GLP-1, cortisol, and vitamin D (VitD)]

Tissue RAS hypothesis

Findings

DISCUSSION