Abstract
Recently, it has been reported that 25% of plasma angiotensinogen (Agt) is derived from fat. Meanwhile, liver-specific Agt knockout (KO) mice have markedly low plasma Agt, which may be due to reduced fat mass. To study the contribution of the fat to plasma Agt, we tested whether increasing fat mass can elevate plasma Agt and blood pressure in liver-Agt KO mice. Epididymal fat mass in liver-Agt KO mice fed a high-fat diet (HFD) was 4.1-fold larger than that in liver-Agt KO mice on a normal-fat diet (NFD). The liver-Agt KO mice on NFD were hypotensive with low levels of plasma Agt (on average, 0.11 vs 2.38 μg/ml). HFD slightly increased plasma Agt (0.17 μg/ml) without increase in blood pressure. To further increase fat mass, liver-Agt KO mice were fed HFD and simultaneously supplemented with low-dose angiotensin II and compared with control mice. Fat mass was comparable between the two groups. However, liver-Agt KO mice had uniformly low plasma Agt (0.09 vs 2.07 μg/ml) and systolic blood pressure (78±12 vs 111±6 mm Hg). In conclusion, adipocyte-derived Agt has essentially no contribution to the plasma concentration and no impact on blood pressure compared to liver-derived Agt.
Highlights
The renin-angiotensin system (RAS) plays a central role in the regulation of blood pressure, and inappropriate activation of RAS is implicated in hypertension and progression of cardiovascular and renal diseases.[1,2]The liver is the major source of angiotensinogen (Agt), the precursor of angiotensin II
In liverAgt KO mice, hepatic Agt mRNA was barely detectable by the real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) method with Ct value >35
This value was not correlated with the plasma Agt concentration, indicating that low plasma Agt is generated in non-hepatic tissues in liver-Agt KO mice
Summary
The renin-angiotensin system (RAS) plays a central role in the regulation of blood pressure, and inappropriate activation of RAS is implicated in hypertension and progression of cardiovascular and renal diseases.[1,2]The liver is the major source of angiotensinogen (Agt), the precursor of angiotensin II. The renin-angiotensin system (RAS) plays a central role in the regulation of blood pressure, and inappropriate activation of RAS is implicated in hypertension and progression of cardiovascular and renal diseases.[1,2]. Adipose tissue has been considered as an important source significantly contributing to plasma Agt. Among them, adipose tissue has been considered as an important source significantly contributing to plasma Agt Supporting this notion is that the level of Agt mRNA normalized by 18S rRNA in adipocytes is 60–80% of that in the liver.[14,15] the content of RNA in the adipose tissue is small, the total mass of the adipose tissue is quite large, i.e. 15–30% of total body weight in healthy subjects. Several studies reported that obese rodents showed increased production and secretion of adipocyte Agt, which was accompanied by increase in plasma Agt.[15,18]
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