title: Pravastatin inhibits advanced glycation end products (AGEs)-induced proximal tubular cell apoptosis and injury by reducing receptor for AGEs (RAGE) level.
abstract: Advanced glycation end products (AGEs) and their receptor (RAGE) axis play a role in diabetic nephropathy. Statins have been shown to ameliorate renal function and reduce proteinuria in patients with chronic kidney disease. However, the effects of statin on AGEs-induced tubular cell damage remain unknown. We examined here whether and how pravastatin could block the AGEs-RAGE-elicited tubular cell injury in vitro. Gene expression level was evaluated by real-time reverse-transcription polymerase chain reactions. Reactive oxygen species (ROS) generation was measured with dihydroethidium staining. Apoptosis was analyzed in an enzyme-linked immunosorbent assay. Asymmetric dimethylarginine (ADMA) expression was evaluated by immunostaining. Pravastatin dose-dependently inhibited the AGEs-induced up-regulation of RAGE mRNA level, ROS generation and apoptosis in human renal proximal tubular cells. Further, AGEs decreased mRNA level of dimethylarginine dimethylaminohydrolase-2, an enzyme that mainly degrades asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase and subsequently increased ADMA generation in tubular cells, both of which were also prevented by pravastatin. Geranylgeranyl pyrophosphate (GGPP) treatment blocked all of the effects of pravastatin on tubular cells. We found that rosuvastatin also significantly blocked the AGEs-induced increase in RAGE mRNA level and ROS generation, both of which were prevented by GGPP. Our present study suggests that pravastatin could inhibit the AGEs-induced apoptosis and ADMA generation in tubular cells by suppressing RAGE expression probably via inhibition of GGPP synthesis. Pravastatin may exert beneficial effects on tubular damage in diabetic nephropathy by blocking the AGEs-RAGE axis.
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishibashi
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ohta
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Tanoue
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Seiji
authors.initials: S
authors.lastname: Ueda
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Seiya
authors.initials: S
authors.lastname: Okuda
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005464:Fluorobenzenes / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017035:Pravastatin / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005464:Fluorobenzenes; D017127:Glycation End Products, Advanced; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013449:Sulfonamides; C018524:N,N-dimethylarginine; D000068718:Rosuvastatin Calcium; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase; D017035:Pravastatin