| The renin-angiotensin system (RAS) plays a major role in regulating blood pressure and cardiovascular function. Likewise, over- activity of the RAS has been linked to the development of hypertension as well as cardiovascular hypertrophy and remodeling. With the development and progress of molecular and cell biologic technology, it was found that in addition to the classic circulating RAS, increasing evidence supports the existence of local tissue RAS (heart, vessel and kidney etc) that appear to participate in cardiovascular homeostasis and in the pathogenesis of cardiovascular disorders via multiple autocrine and paracrine functions. The existence of renin substrate and angiotensin-converting enzyme mRNA expression shows the major components of RAS can be synthesized in local tissue. Other hand, evidence that administration of ACE inhibitor or angiotensin receptor blocker that inhibition of the RAS achieves cardiovascular organ damage protection features that go beyond blood pressure indirectly supports the role of RAS at the local tissue level.Although circulating RAS were studied in depth in relation to arterial hypertension and cardiovascular diseases, however, whether the local tissue RAS is involved in the organ damage associated with hypertension is not well established and limited information on their interrelationships between circulating RAS and local tissue RAS in causing hypertension and related end organ damage. Therefore, the aim of this study was to investigate:1. The gene expression of the various component of RAS in the local tissue, such as heart, aorta and kidney, in spontaneously hypertensive rats (SHR);2. The roles of circulating Ang II and the gene expression of the various component of local RAS in the end organ damage. In addition, to elucidate whether the changes of the component of local RAS gene expression could be due to blood pressure development rather than genetic factor, the gene expression of RAS in kidney was also studied in SHR at age of 5, 14 and 53 weeks. SHR and WKY rats were used in this study. The blood pressure and baroreflex sensitivity were measured in conscious state. After haemodynamic monitoring and BRS studies, the animal was weighed, anesthetized, and killed by decapitation. The aorta, heart and kidney were immediately excised and rinsed in cold physiological saline for histopathological examination. The mRNA levels of angiotensinogen, renin, ACE, ACE2, AT1, AT2 in local tissue were determined using quantitative real-time polymerase chain reaction. The plasma was collected for the determination of angiotensin II concentration using the radioimmunoassay kit.The main finding of this study are as following:1. Hemodynamics Changes, plasma Ang II and ET-1 concentration and end organ damage in SHR:Compared with WKY rats, SBP and DBP as well as systolic BPV and diastolic BPV were significantly higher in SHR. While, HP, HPV and BRS were significantly lower in SHR. Plasma Ang II and ET-1 concentrations were obviously higher in SHR. SHR exhibited obvious end organ damage characterized by increases in LVW/BW (reflecting left ventricular hypertrophy), AW/length (reflecting aortic hypertrophy) and GSS (reflecting renal damage).2. Expression of RAS mRNA in the heart, aorta and kidney from SHR:Compared with WKY rats, the mRNA levels of angiotensinogen, renin, ACE2, AT1 and AT2 in the heart of SHR rats increased by 313.93%, 212.18%, 119.33%, 214.50% and 249.66% respectively. The ACE mRNA was not different in the heart between SHR and W KY rats; The mRNA levels of ACE, ACE2, AT1 and AT2 in the aorta of SHR rats increased by 116.04%, 86.04%, 106.57% and 110.28% respectively, when compared with WKY. The angiotensinogen and renin mRNA was not different in the aorta between SHR and WKY rats; However, the mRNA levels of angiotensinogen, renin, ACE, ACE2 and AT2 in the SHR kidney decreased by 73.50%, 60.20%, 84.07%, 83.45% and 89.54% respectively, when compared with WKY rats. The AT1 mRNA in the kidney of SHR and WKY was not significantly different.3. Relationships between RAS mRNA expression in the heart, aorta, kidney and hemodynamics parameter in SHR:BP was positively related to ACE, ACE2, angiotensinogen mRNA expression in heart and negatively related to ACE, ACE2 mRNA expression in SHR kidney; BPV was positively related to angiotensinogen, renin, ACE, ACE2, AT2 mRNA expression in heart and ACE, ACE2 mRNA expression in aorta, negatively related to ACE2 mRNA expression in SHR kidney; BRS was positively related to ACE2 mRNA expression in heart and negatively related to angiotensinogen, ACE, ACE2 mRNA expression in SHR kidney.4. Relationships between RAS mRNA expression in the heart, aorta, kidney and organ damages in SHR:LVW/BW (reflecting left ventricular hypertrophy) was positively related to ACE and ACE2 mRNA expression in heart. AW/length (reflecting aortic hypertrophy) was positively related to renin and ACE2 mRNA in aorta. GSS (reflecting renal damage) was negatively related to angiotensinogen and ACE2 mRNA in kidney.5. Expression of RAS mRNA in the SHR kidney at 5 weeks, 14 weeks and 53 weeks of age:Compare with WKY, the mRNA levels of renin, ACE2 and AT1 at 5 weeks of age of SHR rats was significantly increased. However, at the same time, ACE mRNA expression was selectively lower in SHR and there was not significantly different in angiotensinogen and AT2 mRNA expression between SHR and WKY.At 14 weeks and 53 weeks of age, the level of angiotensinogen, renin, ACE, ACE2 and AT2 gene expression were reduced in the adult SHR kidney. However, no significant change in the gene expression of AT1 was observed in SHR.In conclusion, our finding demonstrated that the change of RAS mRNA expression was unidirectional within one organ, such as heart, aorta or kidney in SHR. The RAS gene expression upregulated in cardiovascular tissue and downregulated in kidney but not circulating RAS might contribute to hypertensive organ damage. Moreover, ACE2 and AT2 seemed not to be pivotal molecule in RAS and partly withstand the effect of ACE and AT1 respectively in SHR. In addition, the change of renal ACE gene expression in SHR was probably determined by inherited factor and the change of other component of RAS gene expression might be secondary to hypertension.
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