Modulation of AT-1R/MAPK cascade by an olmesartan treatment attenuates diabetic nephropathy in streptozotocin-induced diabetic mice

• Published in: Molecular and cellular endocrinology Vol. 348; no. 1; pp. 104 - 111
• Main Authors: Lakshmanan, Arun Prasath, Thandavarayan, Rajarajan A., Watanabe, Kenichi, Sari, Flori R., Meilei, Harima, Giridharan, Vijayasree V., Sukumaran, Vijayakumar, Soetikno, Vivian, Arumugam, Somasundaram, Suzuki, Kenji, Kodama, Makoto
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 02.01.2012
• Subjects: Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Apoptosis - drug effects; AT-1R/MAPK pathway; Attenuation; Diabetes Mellitus, Experimental; Diabetic Nephropathies - prevention & control; Diabetic nephropathy; Enzyme Activation; fibronectins; Fibrosis; Gene Expression; hypertrophy; Imidazoles - pharmacology; immunohistochemistry; Intracellular Signaling Peptides and Proteins - metabolism; Kidney - drug effects; Kidney - pathology; Kidney - physiopathology; Kidney diseases; Kidneys; Male; MAP Kinase Signaling System - drug effects; Mice; Mice, Inbred C57BL; mitogen-activated protein kinase; Modulation; Olmesartan; Oxidative Stress; p38 Mitogen-Activated Protein Kinases - metabolism; Pathways; Peptidyl-Dipeptidase A - genetics; Peptidyl-Dipeptidase A - metabolism; Phosphorylation; protein synthesis; Protein-Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor, Angiotensin, Type 1 - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; streptozotocin; Tetrazoles - pharmacology; transforming growth factor beta 1; AT-1R; AT-1R/MAPK pathway; p-JNK; RAS; Ang-(1–7) mas R; NADPH oxidase; STZ; Diabetic nephropathy; DN; Olmesartan; ACE-2; Ang-II
• ISSN: 0303-7207; 1872-8057; 1872-8057
• DOI: 10.1016/j.mce.2011.07.041

Schematic representation describing the possible pathway modulation by an olmesartan treatment. [Display omitted] ► The levels of Ang-(1–7) mas R and ACE-2 were up-regulated by olmesartan treatment. ► The up-regulated Ang-(1–7) mas R and ACE-2 have positive effects on AT-1R/MAPK pathway. ► Olmesartan (5 mg/kg) attenuates diabetic nephropathy by modulating AT-1R/MAPK pathway. 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.