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Local renin-angiotensin system and mitogen-activated protein kinase activation in rat aorta
1Department of Pharmacology, Showa College of Pharmaceutical Sciences, Machida, Tokyo, Japan.
Abstract:
We previously reported that endogenous angiotensin II is released to cause mitogen-activated protein (MAP) kinase stimulation in the media portion of the vasculature. In this study, we examined whether a functional renin-angiotensin system is indeed present within the media of the vasculature. In rat aortic strips, endothelium removal produced an increase of MAP kinase activity. The MAP kinase activation was inhibited either by the renin inhibitor pepstatin A or by the angiotensin-converting enzyme inhibitor captopril. The degree of the inhibition of the MAP kinase activation by pepstatin A, captopril and the angiotensin receptor antagonist losartan was almost the same. Pepstatin A inhibited MAP kinase activation induced by renin but not by angiotensin I and angiotensin II. Captopril inhibited the MAP kinase activation induced by angiotensin I but not by angiotensin II. In nephrectomized rat aortic strips, endothelium removal also produced an increase in MAP kinase activity, but the MAP kinase activation was considerably small and minimally inhibited by losartan. Nephrectomy produced a marked decrease in plasma renin activity. These findings suggest that an apparently fully intact and functional renin-angiotensin system is present in the media of the rat vasculature and this system serves to increase MAP kinase activity. It appears that renin plays the determining role in the regulation of angiotensin generation also in the media and the major source of the renin is renin of kidney origin.
Insights
A functional renin-angiotensin system exists in blood vessel walls, stimulating mitogen-activated protein (MAP) kinase activity. Kidney-derived renin is crucial for this vascular system
Area of Science:
- Vascular biology
- Renal physiology
- Molecular signaling
Background:
- Endogenous angiotensin II stimulates mitogen-activated protein (MAP) kinase in vasculature.
- The presence and function of a renin-angiotensin system (RAS) within the vascular media are not fully understood.
Purpose of the Study:
- To investigate the presence of a functional RAS within the vascular media.
- To determine the role of this vascular RAS in regulating MAP kinase activity.
Main Methods:
- Experiments conducted on rat aortic strips with and without endothelium.
- Inhibition of MAP kinase activity using renin inhibitor (pepstatin A), angiotensin-converting enzyme inhibitor (captopril), and angiotensin receptor antagonist (losartan).
- Comparison of MAP kinase activation in normal and nephrectomized rats.
Main Results:
- Endothelium removal increased MAP kinase activity in rat aortic strips.
- Pepstatin A, captopril, and losartan similarly inhibited this MAP kinase activation.
- Pepstatin A inhibited renin-induced, but not angiotensin I/II-induced, MAP kinase activation.
- Captopril inhibited angiotensin I-induced, but not angiotensin II-induced, MAP kinase activation.
- In nephrectomized rats, MAP kinase activation was reduced and minimally affected by losartan, correlating with decreased plasma renin activity.
Conclusions:
- A functional renin-angiotensin system is present in the vascular media.
- This vascular RAS increases MAP kinase activity.
- Renin plays a key role in regulating angiotensin generation within the vascular media, with kidney-derived renin being the primary source.