title: Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase reduce receptor-mediated endocytosis in opossum kidney cells.
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-beta(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.
authors.affiliation: AstraZeneca, Safety Assessment, 23S37-69, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. james.sidaway@astrazeneca.com
authors.forename: James E
authors.initials: JE
authors.lastname: Sidaway
authors.forename: Robert G
authors.initials: RG
authors.lastname: Davidson
authors.forename: Fergus
authors.initials: F
authors.lastname: McTaggart
authors.forename: Terry C
authors.initials: TC
authors.lastname: Orton
authors.forename: Robert C
authors.initials: RC
authors.lastname: Scott
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Smith
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Brunskill
mesh_terms: D000418:Albumins / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009893:Opossums; D011506:Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D000418:Albumins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011506:Proteins; D011956:Receptors, Cell Surface; D019821:Simvastatin