The renin angiotensin system and the metabolic syndrome

Abstract

The renin angiotensin system (RAS) is important for fluid and blood pressure regulation. Recent studies suggest that an overactive RAS is involved in the metabolic syndrome. This article discusses recent advances on how genetic alteration of the RAS affects cardiovascular and metabolic phenotypes, with a special emphasis on the potential role of angiotensin-independent effects of renin.

Fig. 1. The Renin-angiotensin system (RAS)

Angiotensin II effects are predominately mediated by Ang II type 1 receptor (AT1R). In addition to the classical RAS, ACE2 and (pro)renin receptor are new players of this system. See text in detail.

Fig. 2. Mouse renin genes

Renin is encoded by a single gene in humans, rats, and some strains of laboratory mice such as C57BL/6, BALB/c, and C3. However, some laboratory mouse strains (eg. 129, DBA/2J) have 2 renin genes (Ren2 and Ren1d) in tandem on the same chromosome through natural duplication. Tissue expression of these renin genes is different.

Fig. 3. Reduced adipose tissue in mice lacking renin

The Ren1c−/− mice have less than 50% of wild-type adipose tissue weight, as analyzed by MRI. Top panels are saggital sections. Bottom panels are 3D images showing the adipose tissue caudal to the diaphragm constructed from saggital images.

Fig. 4. The energy flow of the Ren1c−/− mice

Mice lacking renin are lean and resistant to diet-induced obesity due to increased energy expenditure and increased fecal energy loss.

Fig. 5. Human (h-) renin does not generate Ang I from mouse (m-) AGT

Human renin does not generate Ang I from mouse AGT. However, h-renin activates MAPK in m-vascular smooth muscle cells possibly via m-(pro)renin receptor.

Fig. 6. Classical RAS pathway and novel effects of (pro)renin mediated by (pro)renin receptor

Prorenin and renin effects via PRR include Ang II-dependent and independent actions. Ang II-dependent actions involve increased catalytic activity of the PRR-bound prorenin to generate Ang I from AGT. Ang II-independent action involves intracellular signaling that triggers activation of an extracellular signal-related protein kinase (ERK1/2) pathway.

Fig. 7. Role of ACE2 in the RAS

ACE2 is a key player in the conversion of Ang II to Ang(1–7) and Ang I to Ang(1–9), and counteract the effects of Ang II. Different from ACE ACE2 does not convert Ang I to Ang II, or regulate plasma bradykinin levels.

Fig. 8. Ang II receptor

Type 1 Ang II receptor (AT1R, AT1aR and AT1bR in mice) medicates the majority of Ang II effects, and regulates muscle contraction, inflammation, insulin levels and cell proliferation, while AT2R regulates apoptosis.