Abstract
Angiotensin II (Ang II) is a risk factor for the initiation and progression of chronic kidney disease (CKD), as elevated Ang II levels can lead to podocyte injury. However, there have been no studies on the role of Ang II in lipid metabolism or on podocyte injury caused by lipid dysfunction. Our study showed that Ang II induced lipid droplet (LD) accumulation and expression of the LD marker adipose differentiation-related protein (ADRP) in podocytes, and the extent of lipid deposition could be alleviated by losartan. Our study also demonstrated that Ang II increased the content of cholesterol in podocytes, which is an LD component, and this change was accompanied by decreased expression of the cholesterol efflux-related molecule ATP-binding cassette transporter-1 (ABCA1) and increased expression of the cholesterol uptake-related molecule LDL receptor (LDLR) and the cholesterol synthesis-related molecules sterol regulatory element-binding protein (SREBP1 and SREBP2) and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR). Pretreating podocytes with methyl-β-cyclodextrin (CD), which induces cholesterol efflux, decreased Ang II-mediated cholesterol accumulation and Ang II-induced podocyte apoptosis and maintained the podocyte cytoskeleton and spreading. These results suggested that Ang II induced podocyte cholesterol accumulation by regulating the expression of cholesterol metabolism-related molecules and that the subsequent cholesterol metabolism dysfunction resulted in podocyte injury.
Highlights
Podocytes are visceral glomerular epithelial cells consisting of a cell body and major and minor foot processes
De novo synthesis is mainly controlled by the rate-limiting enzyme hydroxy-3methylglutaryl CoA reductase (HMGCR), which can be regulated on a transcriptional level by SREBP1 and SREBP2, while cholesterol influx is mediated by LDL receptor (LDLR), and cholesterol efflux is primarily mediated by ABCA13, 4
Experimental studies have shown that glomerular capillary hypertension and impaired filtration function with subsequent protein overload play a pathogenic role in the progression of chronic kidney disease (CKD); renin-angiotensin system (RAS) inhibition can reduce proteinuria more effectively than non-RAS inhibition therapy when comparable BP control is provided[17, 18]
Summary
Podocytes are visceral glomerular epithelial cells consisting of a cell body and major and minor foot processes. Podocyte-specific proteins, such as podocin, can bind and recruit cholesterol to contribute to SD formation[3] These features highlight the importance of cholesterol homeostasis in podocytes and suggest that cholesterol serves as an important regulator in the development of proteinuria kidney diseases. CD is a well-known cholesterol efflux inducer that has a strong affinity for the membrane surface and destabilizes the local packing of cholesterol in the plasma membrane to promote cholesterol extraction[12]. This characteristic is exploited by hydroxy-propyl-β-cyclodextrin (HPBCD), which has been approved by the U.S Food and Drug Administration (FDA) for the treatment of Niemann-Pick disease[4]. We hypothesized that Ang II would induce podocyte cholesterol accumulation and injury and that CD-induced cholesterol efflux would protect podocytes from Ang II-mediated damage
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