Effect And Mechanism Of The Ang-(1-7) On Human Mesangial Cells Injury Induced By Low Density Lipoprotein

Objective: Hyperlipidemia is an independent risk factor for renaldisease, and lipid deposition is associated with glomerulosclerosis. Theangiotensin converting enzyme2-angiotensin-(1-7)-Mas axis(ACE2-Ang-(1-7)-Mas axis), a recently identified branch of therenin-angiotensin system (RAS), has been reported to participate in lipidmetabolic regulation but its mechanism remains unclear. We hypothesizedAng-(1-7) would reduce lipid uptake in human mesangial cells (HMC) byregulating the low density lipoprotein receptor-sterol regulatory elementbinding proteins-SREBP cleavage activating protein (LDLr-SREBPs-SCAP)negative feedback system, and improve glomerulosclerosis by regulatingthe transforming growth factor-β1.Methods: HMC were divided into six groups: control group, LDLgroup, LDL+Ang-(1-7) group, LDL+Ang-(1-7)+A-779group, Ang-(1-7)group and A-779group. Lipid deposition in HMC was detected by Oil RedO staining and intracellular cholesterol content was measured using anenzymatic assay. The expression of ACE2, LDLr, SREBP2, SCAP and TGF-β1were evaluated by real-time PCR and Western blot analysis.Results: ACE2was undetected in HMC. The administration of LDLcaused a normal LDLr-SREBPs-SCAP negative feedback effect.Exogenous Ang-(1-7) enhanced this negative feedback effect viadown-regulating LDLr, SREBP2, and SCAP expression, and effectivelyinhibited LDL-induced lipid deposition and cholesterol increases, and thensignificantly decreased the high LDL-induced production of TGF-β1. Theeffect of Ang-(1-7) was reversed by treatment with the Mas receptorantagonist A-779. However, HMC treated with Ang-(1-7) alone activatedthe TGF-β1expression.Conclusions:①Ang-(1-7) inhibits LDL accumulation anddecreases cholesterol levels via modulating the LDLr-SREBPs-SCAPnegative feedback system, decreases the expression of TGF-β1induced byLDL, and then effectively improves the renal fibrosis caused by lipids.②The effect of Ang-(1-7) was mediated by the Mas receptor.③HMCtreated with Ang-(1-7) alone activated the TGF-β1expression whichexhibits a dual regulatory effect of Ang-(1-7).