title: Interaction of RAS activation and lipid disorders accelerates the progression of glomerulosclerosis.
abstract: 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.
  
  
  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.
authors.affiliation: 1. Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing City, Jiangsu Province, P.R. China.
authors.forename: Kun-Ling
authors.initials: KL
authors.lastname: Ma
authors.forename: Jie
authors.initials: J
authors.lastname: Ni
authors.forename: Chang-Xian
authors.initials: CX
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Wu
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Lv
authors.forename: Xiong-Zhong
authors.initials: XZ
authors.lastname: Ruan
authors.forename: Bi-Cheng
authors.initials: BC
authors.lastname: Liu
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage* / Q000378:metabolism; D002784:Cholesterol / Q000008:administration & dosage; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000008:administration & dosage; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis; D050356:Lipid Metabolism / Q000187:drug effects*; D008565:Membrane Proteins / Q000096:biosynthesis; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000096:biosynthesis / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000096:biosynthesis; D051779:Sterol Regulatory Element Binding Proteins / Q000096:biosynthesis; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D006888:Hydroxycholesterols; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D044140:Receptor, Angiotensin, Type 1; D018110:Receptors, Lipoprotein; C497390:SREBF2 protein, human; C102196:SREBP cleavage-activating protein; D051782:Sterol Regulatory Element Binding Protein 2; D051779:Sterol Regulatory Element Binding Proteins; D000804:Angiotensin II; C007997:25-hydroxycholesterol; D002784:Cholesterol; D018631:ras Proteins
keywords: extracellular matrix; glomerulosclerosis; lipid disorder; low-density lipoprotein receptor; renin-angiotensin system