Background Dyslipidemia and local activation of renin-angiotensin system (RAS) play crucial roles in the progression of chronic kidney disease (CKD).The present study was undertaken to investigate possible effects of dyslipidemia on intracellular RAS activation and its underlying mechanism in glomerulosclerosis using human renal mesangial cells (HMCs).Methods HMCs were cultured and divided into Control group (treated with serum free medium) and cholesterol loading group (treated with serum free medium plus 30 μg/mL cholesterol and 1 μg/mL 25-hydroxycholesterol).The lipid accumulation in HMCs was examined by Oil red O staining.The production of extracellular matrix in HMCs was examined by immunohistochemical staining and immunofluorescent staining.The gene and protein expressions of molecules involved in RAS components and the pathway of mammalian target of rapamycin (mTOR) were examined by real-time PCR and Western blot.Results Cholesterol and 25-hydroxycholesterol loading increased lipid accumulation in HMCs, and inhibited protein expression of α-SMA and collagen Ⅳ.Further analysis showed that cholesterol loading upregulated mRNA and protein expression of RAS components (angiotensinogen, angiotensin Ⅱ, rennin, angiotensin-converting enzyme, agiotensin Ⅱ type 1receptor and type 2 receptor) in HMCs.Interestingly, lipid accumulation activated mTOR pathway, characterized by increased mRNA and protein expression, and protein phosphorylation level of mTOR, eukaryotic translation initiation factor 4E binding protein 1 (4EBP1), ribosomal protein S6 kinase 1 (S6K1), which were closely correlated with intracellular RAS activation.Conclusion Cholesterol loading affected mesangial cell functions and stimulated extracellular matrix excretion through intracellular RAS activation, which was correlated with the upregulation of mTOR pathway, suggesting a potential mechanism in the progression of glomerulosclerosis.