Inhibitors of 3-Hydroxy-3-Methylglutaryl–CoA Reductase Reduce Receptor-Mediated Endocytosis in Opossum Kidney Cells

Abstract

Abstract. Renal proximal tubule cells are responsible for the reabsorption of proteins that are present in the tubular lumen. This occurs by receptor-mediated endocytosis, a process that has a requirement for some GTP-binding proteins. Statins are inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase used for the therapeutic reduction of cholesterol-containing plasma lipoproteins. However, they can also reduce intracellular levels of isoprenoid pyrophosphates that are derived from the product of the enzyme, mevalonate, and are required for the prenylation and normal function of GTP-binding proteins. The hypothesis that inhibition of HMG-CoA reductase in renal proximal tubule cells could reduce receptor mediated-endocytosis was therefore tested. Five different statins inhibited the uptake of FITC-labeled albumin by the proximal tubule-derived opossum kidney cell line in a dose-dependent manner and in the absence of cytotoxicity. The reduction in albumin uptake was related to the degree of inhibition of HMG-CoA reductase. Simvastatin (e.g., statin) inhibited receptor-mediated endocytosis of both FITC-albumin and FITC-␤ 2 -microglobulin to similar extents but without altering the binding of albumin to the cell surface. The effect on albumin endocytosis was prevented by mevalonate and by the isoprenoid geranylgeranyl pyrophosphate but not by cholesterol. Finally, evidence that the inhibitory effect of statins on endocytosis of proteins may be caused by reduced prenylation and thereby decreased function of one or more GTP-binding proteins is provided. These data establish the possibility in principle that inhibition of HMG-CoA reductase by statins in proximal tubule cells may reduce tubular protein reabsorption.Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, the major rate-limiting step of the sterol pathway (1). The statins are widely used for the therapeutic reduction of cholesterol-containing atherogenic lipoproteins (2-4). This is brought about as a result of depletion of intracellular mevalonate leading to reduction of the regulatory sterol pool, which in turn causes upregulation of HMGCoA reductase and other enzymes of the sterol pathway, most importantly the LDL receptors principally in the liver (5-7). However, a range of additional effects of statins on cells that are independent of cholesterol homeostasis has been described; these include, proliferation (8), signal transduction (9), and apoptosis (10). Many of these cholesterol-independent effects of statins have been shown to result from depletion of mevalonate and its nonsterol metabolites, particularly the isoprenoid pyrophosphates, such as farnesol pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), that are required for the posttranslation modification of a variety of cell proteins, including the superfamily of small GTP-binding proteins (11)(12)(13). Endocytosis is one cell function that requires multiple GTP-binding proteins (14,15) a...

ESC/EAS Guidelines for the management of dyslipidaemias

“…The statin-induced reduced pinocytosis is directly related to the inhibition of cholesterol synthesis. 230 In clinical trials the frequency of proteinuria is in general low and in most cases is not higher than for placebo. 231 …”

Statins inhibit aminoglycoside accumulation and cytotoxicity to renal proximal tubule cells

“…Statins can inhibit the function of GTP-binding proteins required for receptor mediated endocytosis of low molecular weight proteins in proximal tubule cells [17,19,21]. We therefore explored the relationship between the inhibition of the geranyl-geranylation of a model GTP-binding protein (Rap1A) and the inhibition of gentamicin-induced cytotoxicity.…”

“…Therefore, by decreasing the intracellular sterol pool, statins can also indirectly inhibit receptor-mediated endocytosis by blocking the post-translational 6 modification of GTP-binding proteins [19]. Indeed, statins can inhibit receptor-mediated endocytosis of proteins in vitro [20] by a mechanism which correlates with the inhibition of cholesterol synthesis and an increase in the intracellular level of unprenylated GTP-binding proteins [21]. Since statins have a relatively safe clinical profile, they represent a possible strategy for the prevention of nephrotoxicity in man through the blockade of AG uptake and accumulation.…”

Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

“…The HK-2 cells were inoculated into a 96-well plate and cultured with AGEs, AGEsCinsulin, AGEsCgliquidone, AGEsCLY33531 or AGEsC8-Br-cAMP for 48 h. FITClabeled human albumin (final concentration of 20 mg/ml, FITC-albumin, Abcam) was then added to the culture medium (Sidaway et al 2004). After 30 min, the culture medium was removed and the cells were washed four times with PBS.…”