Research On Multy Systems Protection Of Panax Ginseng Root Total Saponins Based On Angiotensin Converting Enzyme 2

Renin-angiotensin system(RAS),consisting of the angiotensin converting enzyme 1(ACE)/angiotensin ?(Ang ?)/angiotensin type 1 receptor(AT1)axis and the angiotensin converting enzyme 2(ACE2)/angiotensin 1-7(Ang 1-7)/Mas receptor(Mas)axis,is an important and complex body fluid regulation system.The main physiological functions of the ACE/Ang ?/AT1 axis include contraction of vascular smooth muscle,promoting aldosterone and vasopressin release,increasing renal tubular sodium reabsorption,activation of the sympathetic nervous system,promoting cell growth and migration.Abnormal activation of the ACE/Ang II/AT1 axis can cause hypertension,and promote inflammation,oxidative stress and fibrosis and other pathological damage.The effects of the ACE2/Ang 1-7/Mas axis are opposite to the ACE/Ang II/AT1 axis.ACE2 can degrade Ang II and inhibit ATI activation directly.It can also antagonize the effects of AT1 activation by activating Mas with Ang 1-7,the degradation product of Ang II.The two axes are restricted by each other in the body,maintaining the dynamic balance of the RAS.Panax ginseng is one of the most important tonic drugs in Chinese medicine.The main active ingredient of panax ginseng are ginsenosides,the saponins extracted from it.A variety of proprietary Chinese medicines,whose main components are ginsenosides,are widely used in adjuvant therapy of chronic diseases,such as hypertension,diabetes,hyperlipidemia and cancer.The above diseases are all systemic,involving multiple organs and systems in the body.Ginsenosides play a multi-system protection in the process of the adjuvant therapy to them.There are many similarities between this multi-system protection and the effects of the ACE2/Ang 1-7/Mas axis.We speculate that activation of the ACE2/Ang 1-7/Mas axis may be one of the key mechanisms of ginsenosides' multi-system protection.So we carry out this study to verify the hypothesis.First,we treated the spontaneous hypertensive rats(SHR)with panax ginseng root total saponins(GTS)to see whether the ventricular remodeling of SHR could be inhibited and whether this cardio protective effect on SHR was associated with the activation of ACE2/Ang 1-7/Mas axis.We also set an inhibitor control group,using A779,an inhibitor of Mas,to inhibit the activation of Mas.This is for observing whether it can block the cardio protective effects of GTS.The results show that GTS can inhibit the ventricular remodeling of SHR,and this effect does not depend on the regulation of SHR blood pressure,and will not be blocked by A779 either.Mechanism studies show that the cardio protective effect on SHR of GTS is indeed related to ACE2/Ang 1-7/Mas axis,but mainly due to up-regulation of ACE2 expression and Ang ? degradation,inhibiting the activation of AT1.The inhibition the ACE/Ang ?/AT1 axis down-regulation myocardial inflammation,oxidative stress,fibrosis.The activation of Mas by Ang 1-7 played a secondary role in the cardio protective effect on SHR of GTS,as the using of A779 did not block this effect.To further verify the importance of ACE2 on the cardio protective effect of GTS,we constructed the ACE2 knockout mice(KO mice)and established the ventricular remodeling model by subcutaneous sustained releasing Ang ?(1.5mg/kg·d).So we can compared the differences in the cardio protective effects of GTS on KO mice and wild-type mice(WT mice).Results show that GTS can up-regulate the expression of ACE2 and Ang ? degradation,inhibit Ang II-induced ventricular remodeling on WT mice,but there is no such effect on KO mice.These verify that the cardio protective effect of GTS depends on the up-regulation of ACE2,which lead to the degradation of Ang II in myocardial tissue,down-regulating inflammation,oxidative stress and fibrosis.Subcutaneous release of Ang ? can also cause kidney damage,so we obtained the kidneys of the mice of the above research to observe whether GTS has renel protective effect,and whether this effect depends on ACE2.The results showed that GTS could inhibit Ang ?-induced kidney damage in WT mice also by increasing the expression of ACE2 and the degradation of Ang ?,but there is no such effect on KO mice.These verify that the renal protective effect of GTS depends on the up-regulation of ACE2,which lead to the degradation of Ang ? in renal tissue,down-regulating inflammation,oxidative stress and fibrosis.To further verify the renal protective effect of GTS and the association of this effect and ACE2,we used db/db mice with spontaneous type 2 diabetes to observe the effect of GTS on diabetic nephropathy.The results showed that GTS significantly reduced the levels of creatinine and urea nitrogen in the serum of db/db mice,which means renal function improving,and reduced renal pathology change caused by hyperglycemia.This protective effect of kidney does not depend on the regulation of blood glucose.While alleviating the diabetic nephropathy of db/db mice,GTS up-regulate the expression of ACE2 in renal tissue,which lead to the down-regulation of Ang ? levels,as well as the inhibition of inflammation,oxidative stress and fibrosis.These means that upregulating ACE2 in kidney tissue is one of the key mechanisms of GTS's renal protective effect in diabetic nephropathy.The db/db mice do not only suffer from diabetic nephropathy,but also suffer from hyperlipidemia and nonalcoholic fatty liver disease,so we also observed the role GTS play on the non-alcoholic fatty liver disease.The results showed that GTS significantly reduced the activity of glutamic pyruvic transaminase and glutamic oxalacetic transaminase in the serum of db/db mice,which means hepatic function improving,and reduced steatosis of hepatocytes.This protective effect of liver does not depend on the regulation of blood lipids.While alleviating the nonalcoholic fatty liver disease of db/db mice,GTS up-regulate the expression of ACE2 in liver tissue,which lead to the down-regulation of Ang ? levels,as well as the inhibition of inflammation,oxidative stress and fibrosis.These means that upregulating ACE2 in liver tissue is one of the key mechanisms of GTS's hepatic protective effect in nonalcoholic fatty liver disease.The five studies above have shown that GTS has significant protective effects on the circulatory system(heart),urinary system(kidney)and digestive system(liver)under three different pathogenic factors.The up-regulation of the ACE2 expression in tissues,increase the degradation of Ang ?,leading to inhibition of inflammation,oxidative stress and fibrosis in tissues.This is one of the key mechanisms of GTS's multi-system protection.Our presumption in the preceding text has been initially confirmed,but it is necessary to use more animal disease model to verify the relationship between the multiple system protection of ginsenoside and the ACE2/Ang 1-7/Mas axis.At the same time,the protective effect of ginsenoside may also be related to other systemic regulatory mechanisms,which require further study to confirm.