title: Modulation of AT-1R/MAPK cascade by an olmesartan treatment attenuates diabetic nephropathy in streptozotocin-induced diabetic mice.
abstract: There is increasing evidence that angiotensin (Ang)-II plays an unprecedented role in diabetic complications. It could also be an important therapeutic target for ameliorating various diseases, especially diabetic nephropathy (DN). We therefore studied the beneficial effects of olmesartan, an Ang-II type 1 receptor (AT-1R) blocker in streptozotocin (150 mg/kg, BW)-induced diabetic kidney disease in mice. The diabetic kidney mice displayed upregulated protein expression levels of AT-1R, AT-2R, ERK-1/2, p-p38 MAPK, p-MAPKAPK-2, ET-1, p-JNK, p-c-Jun, TGF-β1, and gp91-phox, and all of these effects were expectedly downregulated by an olmesartan treatment. Also, immunohistochemical analysis, and Azan-Mallory and HE staining were performed to examine the expression of collagen-III and fibronectin, renal fibrosis, and hypertrophy, respectively. Furthermore, olmesartan treatment significantly abrogated the downregulation of ACE-2 and Ang-(1-7) mas R protein expression in diabetic kidney mice. Considering all these findings together, the AT-1R/MAPK pathway might be a potential therapeutic target in diabetes kidney disease, and olmesartan treatment could have beneficial effects on DN by modulating the AT-1R/MAPK pathway.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
authors.forename: Arun Prasath
authors.initials: AP
authors.lastname: Lakshmanan
authors.forename: Rajarajan A
authors.initials: RA
authors.lastname: Thandavarayan
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
authors.forename: Flori R
authors.initials: FR
authors.lastname: Sari
authors.forename: Harima
authors.initials: H
authors.lastname: Meilei
authors.forename: Vijayasree V
authors.initials: VV
authors.lastname: Giridharan
authors.forename: Vijayakumar
authors.initials: V
authors.lastname: Sukumaran
authors.forename: Vivian
authors.initials: V
authors.lastname: Soetikno
authors.forename: Somasundaram
authors.initials: S
authors.lastname: Arumugam
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodama
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004789:Enzyme Activation; D015870:Gene Expression; D007093:Imidazoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000085962:Angiotensin-Converting Enzyme 2; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D007703:Peptidyl-Dipeptidase A; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D013777:Tetrazoles; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C437965:olmesartan; C000705328:Ace2 protein, mouse