Local RAS

Abstract

The concept of a circulating RAS is well established and known to play an endocrine role in the regulation of fluid homeostasis (see Section 4.1, Chapter 4). However, it is more appropriate to view the RAS in the contemporary notion as an “angiotensin-generating system”, which consists of angiotensinogen, angiotensin-generating enzymes, and angiotensins, as well as their receptors. Some RASs can be termed as “complete”, having renin and ACE involved in the biosynthesis of angiotensin II peptide, i.e. in a renin and/or ACE-dependent manner which is exemplified in the circulating RAS. On the other hand, some RAS can be termed as “partial”, having alternate enzymes to renin and ACE, such as chymase and ACE2 (see Section 4.3, Chapter 4) available for the generation of angiotensin II and other bioactive angiotensin peptides in the biosynthetic cascade, i.e. in a renin and/or ACE-independent manner. Complete vs. partial RASs can be exemplified in the so-called intrinsic angiotensin-generating system or local RAS; for example, a local and functional RAS with renin and ACE-dependent but a renin-independent pathway have been indentified in the pancreas and carotid body, respectively. In the past two decades, local RASs have gained increasing recognition especially with regards to their clinical importance. Distinct from the circulating RAS, these functional local RASs exist in such diverse tissues and organs as the pancreas, liver, intestine, heart, kidney, vasculature, carotid body, and adipose, as well as the nervous, reproductive, and digestive systems. Taken into previous findings from our laboratory and others together, Table 5.1 is a summary of some recently identified local RASs in various levels of tissues and organs.

Fig. 5.1

Representation of the relationship of circulating RAS and carotid RAS involved in the regulation of cardiopulmonary function (modified from Leung et al., 2003)

Fig. 5.2

Western blot analysis of some major RAS component expression in the liver of lean m+/db (m+) and diabetic db/db (db) mice. a Expression of AT1R protein. Expression of AT2R protein. b Expression of ACE protein. Expression of renin protein. The expression levels of AT1R, ACE and renin were upregulated in db/db mouse liver while AT2R had a reduced protein expression when compared with their respective controls

Fig. 5.3

The expression and localization of AT1R in stellate cells (Reelin as a marker) and hepatocytes (albumin marker) and Kupffer cells (ED2 as a marker) from the liver of obese diabetic db/db mice and control lean db/m+ mice. Immunoreactivity of AT1R was immunolabeled with specific liver cell markers of stellate cells, Reelin (a), of hepatocytes, Albumin (b) and of Kupffer cells, ED2 (c). AT1R immunoreactivity was stained with red; Reelin, albumin and ED2 immunoreactivity was stained with green (see arrows). Overlay of the immunofluorescence labeling of db/db livers showing more intense immunostaining for AT1R was observed in both stellate cells and Kupffer cells but not in hepatocytes (merged images), when compared with their respective control livers. DAPI was used as a marker for cell nuclei (blue). Original magnification, ×630 (For interpretation of the references to colour in this figure legend, please be referred to the online version)

Fig. 5.4

A schematic diagram proposing the potential mechanism of an enterocyte RAS-mediated SGLT1 dependent glucose uptake at the BBM under normal (a) and diabetic condition (b)

Fig. 5.5

Expression and regulation of ACE2-angiotensin (1–7)-mas receptor under high (25 mM) and normal (5.6 mM) in Caco-2 cell line. a ACE2 gene and protein expression. b Mas receptor protein expression. c ¹⁴C-glucose uptake in response to angiotensin (1–7). d GLUT2 gene expression