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. 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.

Lipid disorder and intrahepatic renin–angiotensin system activation synergistically contribute to non‐alcoholic fatty liver disease

“…When cholesterol deficiency in cells occurs, the ER protein SCAP escorts SREBP-2 from the ER to the Golgi where it cleaves SREBP-2 into nuclear SREBP-2, thus initiating LDLr gene expression (28). Confocal microscopy showed that Ang II stimulation enhanced SCAP/SREBP-2 complex translocation from the ER to the Golgi, suggesting that Ang II is involved in lipid disorder through disrupting the LDLr pathway, which was consistent with our previous studies and those of others (18). Lu et al (29) found that Ang II can increase LDL oxidation and uptake by macrophages, which then promotes the development of atherosclerosis.…”

“…Our previous studies have verified the positive co‐operative effects of RAS activation with dyslipidaemia in the development of chronic kidney disease and have shown that hyperlipidaemia upregulates the expression of RAS components in the kidney of apolipoprotein gene knockout (ApoE KO) mice and that Ang II stimulation increases cholesterol uptake by mesangial cells through the upregulation of low‐density lipoprotein receptor (LDLr) pathway . However, whether there is a possible interaction of RAS activation with lipid disorder in NAFLD is unknown.…”

Angiotensin II induces cholesterol accumulation and injury in podocytes

“…Ma et al . reported that Ang II induced lipid accumulation in human renal mesangial cells (HMCs) 21 . Borghi et al .…”

Inflammatory stress induces lipid accumulation in multi-organs of <italic>db</italic>/<italic>db</italic> mice

“…Therefore, plasma levels of LDL cholesterol in patients might be a poor marker for the risk of lipid-mediated organ injuries. The factors affecting lipid redistribution include chronic inflammation [18], decreased glomerular filtration rate [18], activation of the reninangiotensin system [19,20], insulin resistance, and drug administration (e.g. steroids and rapamycin) [10].…”