Irbesartan inhibits advanced glycation end product (AGE)-induced proximal tubular cell injury in vitro by suppressing receptor for AGEs (RAGE) expression.
Renin-angiotensin system (RAS) plays a central role in the development and progression of diabetic nephropathy. Further, there is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) axis also contributes to diabetic nephropathy. However, the pathophysiological crosstalk between the RAS and AGE-RAGE system in tubular cell injury, which is more important than glomerulopathy in terms of renal prognosis in diabetic nephropathy, remains unknown. In this study, we examined whether and how irbesartan, an angiotensin II type 1 receptor blocker (ARB), inhibited the AGE-induced tubular cell apotptosis and damage in vitro. Gene expression was analyzed by quantitative real-time reverse transcription-polymerase chain reactions. Intracellular formation of reactive oxygen species (ROS) was measured with dihydroethidium staining. Apoptosis levels were evaluated for DNA fragments with an enzyme-linked immunosorbent assay kit and for caspase-3 activity. Irbesartan inhibited the AGE-induced up-regulation of RAGE mRNA levels and subsequently reduced ROS generation in human proximal tubular cells. AGEs induced apoptosis and increased inflammatory, thrombogenic and fibrogenic gene expressions in tubular cells, which were also blocked by the treatment with irbesartan. Our present data suggest that there exists a crosstalk between the RAS and AGE-RAGE system in tubular cell apoptosis and damage. Blockade of the RAS by irbesartan may play a protective role against tubular injury in diabetes by attenuating the deleterious effects of AGEs via down-regulation of RAGE.
Matsui
Takanori
T
Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume 830-0011, Fukuoka, Japan.
Yamagishi
Sho-Ichi
S
Takeuchi
Masayoshi
M
Ueda
Seiji
S
Fukami
Kei
K
Okuda
Seiya
S
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D000077405:Irbesartan; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012710:Serum Albumin, Bovine / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013777:Tetrazoles; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; C505407:CASP3 protein, human; D053148:Caspase 3; D000077405:Irbesartan