Editorial Focus: A fat contribution to RAS activation and blood pressure control: evidence from angiotensinogen conditional null mice. Focus on: “Adipocyte-specific deficiency of angiotensinogen decreases plasma angiotensinogen concentration and systolic blood pressure in mice.”

Abstract

THE RENIN-ANGIOTENSIN SYSTEM (RAS) is well recognized as a critical regulator of blood pressure and a determinant of cardiovascular homeostasis. The RAS was originally described in the circulation, although the presence of many or all components of the RAS has been documented in a variety of individual tissues including kidney, brain, heart, adrenal gland, and blood vessels (4). The importance of these local versions of the RAS in the development and maintenance of hypertension and associated end-organ damage has been firmly established.Mounting evidence supports the concept that a local RAS is present in the adipose tissue (2). Expression of the angiotensinogen (AGT) gene has been reported in murine adipocyte cell lines as well as in murine and human adipose tissues. Fatty acids, carbaprostacyclin, glucocorticoids, and the sympathetic nervous system appear to positively regulate AGT gene expression in adipocytes by transcriptional mechanisms. The presence in adipose tissue of renin and angiotensin converting enzyme (ACE) expression and activity make possible the local production of angiotensin (ANG) II. Both subtypes of ANG II (AT1 and AT2) receptors are present in adipocytes as demonstrated by the presence of mRNA and protein and also by ligand binding functional and pharmacological studies. In addition to the potential physiological importance of the local adipose RAS, the significance and participation of adiposederived RAS components, particularly AGT, to the circulating RAS has attracted much attention. The study by Yiannikouris et al. (10) provides convincing evidence that adipose-derived AGT contributes to plasma AGT levels and blood pressure regulation.The liver is considered the primary site of AGT synthesis and the main source of circulating AGT. Indeed, Stec et al. (7) found that elimination of hepatic AGT expression was associated with a significant decrease in the plasma level of AGT (Ͼ90% of control levels). However, some evidence suggests that adipose tissue may contribute significantly to plasma AGT levels. This is based on findings using transgenic mice with AGT gene expression restricted to adipose tissue using an adipocyte-specific promoter (aP2) driving the expression of a rat AGT cDNA in AGT-deficient mice (6). Compared with AGT knockout mice, which have no detectable AGT plasma levels and are hypotensive, transgenic mice re-expressing AGT only in the adipose tissue have some circulating AGT (ϳ10% of the wild-type controls), are normotensive, and exhibit restored renal function. A major limitation of this previous study, however, stems from the fact that the expression of AGT was not driven by its own promoter, but by an aP2 promoter. Also, there was a dramatic increase in the expression levels of the AGT in the fat explants of transgenic mice. Therefore, it was not clear whether the AGT found in the plasma of the transgenic mice reflected a physiological contribution of adipocytes to the circulating RAS or an abnormal situation in which adipose tissue was dumping the overproduced AGT into ...