Int J Med Sci 2013; 10(12):1615-1624. doi:10.7150/ijms.6635
Interaction of RAS Activation and Lipid Disorders Accelerates the Progression of Glomerulosclerosis
1. Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, P.R. China.
2. Department of Infection Management, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, P.R. China.
3. Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, UK.
Background: The activation of the renin-angiotensin system (RAS) and lipid disorders are major risk factors in progressive chronic kidney disease. This study aimed to investigate the potential synergistic mechanisms of RAS activation and lipid disorders that contribute to glomerulosclerosis. Materials and methods: Human renal mesangial cells (HMCs) were treated with 10-7 mol/L angiotensin II (Ang II) or with 30 μg/ml cholesterol and 1 μg/ml 25-hydroxycholesterol (lipid loading) for 24 hours. Lipid accumulation in the cells was evaluated by Oil Red O staining and intracellular cholesterol quantitative assays. The gene and protein expression of molecules in the low-density lipoprotein receptor (LDLr) pathway, the RAS family, and the extracellular matrix were examined by real-time polymerase chain reaction and Western blotting. The translocation of sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP), which escorts SREBP-2 from the endoplasmic reticulum (ER) to the Golgi, was examined by immunofluorescent staining. Results: Ang II increased lipid droplet accumulation in HMCs. Further analysis revealed that Ang II increased the mRNA and protein expression of LDLr, SCAP, and SREBP-2. This increase was correlated with an enhanced translocation of the SCAP/SREBP-2 complex from the ER to the Golgi in HMCs that was induced by Ang II, thereby activating LDLr gene transcription. Interestingly, lipid loading increased the mRNA and protein expression of angiotensinogen, Ang II, renin, angiotensin-converting enzyme, angiotensin II type 1 receptor, and type 2 receptor in HMCs with increased mRNA and protein expression of collagen I, α-smooth muscle actin, and fibronectin. Conclusions: This study demonstrates that the interaction of RAS activation and lipid disorders accelerates the progression of glomerulosclerosis.
Keywords: renin-angiotensin system, lipid disorder, glomerulosclerosis, low-density lipoprotein receptor, extracellular matrix
Ma KL, Ni J, Wang CX, Liu J, Zhang Y, Wu Y, Lv LL, Ruan XZ, Liu BC. Interaction of RAS Activation and Lipid Disorders Accelerates the Progression of Glomerulosclerosis. Int J Med Sci 2013; 10(12):1615-1624. doi:10.7150/ijms.6635. Available from http://www.medsci.org/v10p1615.htm