Angiotensin II down-regulates the SR-BI HDL receptor in proximal tubular cells
1 Department of Medicine, University of Jena and 2 Department of Medicine, University of Hamburg, Hamburg, Germany
Correspondence and offprint requests to: Gunter Wolf, MD, Klinik für Innere Medizin III, University of Jena, Erlanger Allee 101, D-007347 Jena, Germany. Email: gwolf{at}med.uni-jena.de
Background. The kidney plays an important role in the metabolism of lipoproteins, but renal cells are also a target of lipids under pathophysiological conditions contributing to organ damage and progression of disease. The majority of studies has focused on the interaction of renal cells with low-density lipoproteins. Relatively little is known of potential metabolism of high-density lipoproteins (HDL) on renal cells However, diverse pathophysiological situations, such as the nephrotic syndrome and acute renal injury, may be associated with an activated renin–angiotensin system as well as altered renal handling of HDL. Therefore, the present study sought to gain insight into the expression of the HDL receptor scavenger receptor class B type I (SR-BI) in cultured renal cells and a potential regulation by angiotensin II (ANG II).
Methods. Different renal cells lines and primary cultures (proximal tubular and mesangial cells) were screened by western blot for the expression of SR-BI. MCT cells, a mouse proximal tubular cell line, were selected for further studies. SR-BI protein and mRNA expression were determined after treatment with various doses of ANG II in the presence or absence of AT1- or AT2-receptor blocker. Uptake of HDL-associated cholesteryl ester into MCT cells was determined. Finally, rats were infused intraperitoneally with ANG II for 3–7 days, proximal tubules were isolated by differential centrifugation and SR-BI protein expression was assessed.
Results. SR-BI protein was expressed in various primary cultures and permanent renal cell lines. ANG II (10–10–10–6 M) treatment for 24 h induced a significant down-regulation of SR-BI protein and mRNA expression in MCT cells. This suppression was attenuated by an AT1-receptor antagonist whereas an AT2-blocker was without effect. MCT cells revealed a high selective uptake of HDL cholesteryl ester that was significantly higher than that in syngeneic mesangial cells. ANG II for 24 h significantly reduced this selective HDL cholesteryl ester uptake into MCT, but not mesangial cells. Finally, ANG II- infusion into rats for 3 and 7 days induced a significant decrease of SR-BI protein expression in isolated tubules.
Conclusions. Our data show that ANG II mediates down-regulation of SR-BI expression on proximal tubular cells in vivo and in vitro. However, the effects were small and additional experiments are necessary to confirm these first observations. The attenuated SR-BI expression is functionally relevant and associated with a decrease in cholesteryl ester uptake. ANG II-mediated suppression may contribute to various pathophysiological situations, such as acute tubular injury, the nephrotic syndrome and atherosclerosis.
Keywords: cholesterol transport; high-density lipoproteins; lipid metabolism; renin–angiotensin system; selective uptake; SR-BI
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