title: Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation.
abstract: There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) interaction evokes oxidative stress generation and subsequently elicits inflammatory and fibrogenic reactions, thereby contributing to the development and progression of diabetic nephropathy. We have previously found that nifedipine, a calcium-channel blocker (CCB), inhibits the AGE-induced mesangial cell damage in vitro. However, effects of nifedipine on proximal tubular cell injury remain unknown. We examined here whether and how nifedipine blocked the AGE-induced tubular cell damage. Nifedipine, but not amlodipine, a control CCB, inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-gamma (PPARgamma). GW9662 treatment alone was found to increase RAGE mRNA levels in tubular cells. Further, nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-kappaB activation and increases in intercellular adhesion molecule-1 and transforming growth factor-beta gene expression in tubular cells, all of which were blocked by GW9662. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-oxidative and anti-inflammatory agent against AGEs in tubular cells by suppressing RAGE expression via PPARgamma activation.
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Seiji
authors.initials: S
authors.lastname: Ueda
authors.forename: Kei
authors.initials: K
authors.lastname: Fukami
authors.forename: Seiya
authors.initials: S
authors.lastname: Okuda
mesh_terms: D000813:Anilides / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000517:prevention & control*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D002121:Calcium Channel Blockers; D017127:Glycation End Products, Advanced; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009543:Nifedipine