Modulation of AT-1R/CHOP-JNK-Caspase12 pathway by olmesartan treatment attenuates ER stress-induced renal apoptosis in streptozotocin-induced diabetic mice

• Published in: European journal of pharmaceutical sciences Vol. 44; no. 5; pp. 627 - 634
• Main Authors: Lakshmanan, Arun Prasath, Thandavarayan, Rajarajan A., Palaniyandi, Suresh S., Sari, Flori R., Meilei, Harima, Giridharan, Vijayasree V., Soetikno, Vivian, Suzuki, Kenji, Kodama, Makoto, Watanabe, Kenichi
• Format: Journal Article
• Language: English
• Published: Kindlington Elsevier B.V 18-12-2011; Elsevier
• Subjects: Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animals; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Blood Glucose - analysis; Caspase 12 - metabolism; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetic nephropathy; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic reticulum stress; General pharmacology; Heat-Shock Proteins - metabolism; Imidazoles - pharmacology; Imidazoles - therapeutic use; JNK Mitogen-Activated Protein Kinases - metabolism; Kidney - drug effects; Kidney - metabolism; Lipid Peroxidation - drug effects; Malondialdehyde - metabolism; Medical sciences; Membrane Proteins - metabolism; Mice; Olmesartan; Olmesartan Medoxomil; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - metabolism; Receptor, Angiotensin, Type 1 - metabolism; Superoxides - metabolism; Tetrazoles - pharmacology; Tetrazoles - therapeutic use; TNF Receptor-Associated Factor 2 - metabolism; Transcription Factor CHOP - metabolism; Diabetic nephropathy; Olmesartan; Endoplasmic reticulum stress; Apoptosis; Endocrinopathy; Antineoplastic agent; Imidazole derivatives; Tetrazole derivatives; Kidney; Streptozotocin; Kidney disease; Urinary system disease; Pharmaceutical technology; Diabetes mellitus; Rodentia; Stress; Concomitant disease; Vertebrata; Antibiotic; Mammalia; Treatment; Mouse; Biphenyl derivatives; Cell death; Animal; Antihypertensive agent; Sartan derivatives; Angiotensin antagonist
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2011.10.009

There is evidence that the activation of renal angiotensin (Ang)-II plays a critical role in the pathogenesis of diabetic kidney diseases (DN) via the ER stress-induced renal apoptosis. Since, the potential negative role of Ang-II in the pathogenesis of ER stress-mediated apoptosis is poorly understood; we evaluated whether treatment of mice with AT-1R specific blocker, olmesartan is associated with the reduction of ER stress-induced renal apoptosis in streptozotocin (STZ)-induced diabetic animal model. We employed western blot analysis to measure the renal protein expressions level of NADPH oxidase subunits, ER chaperone GRP78 and the ER-associated apoptosis proteins. Furthermore, TUNEL staining was used to measure the renal apoptosis. Additionally, dihydroethidium staining and TBARS assay, and immunohistochemistry were performed to measure the renal superoxide radical production and lipid peroxidation, and activation of an Ang-II, respectively. The diabetic kidney mice were found to have increased protein expressions of NADPH oxidase subunits, GRP78 and ER-associated apoptosis proteins, such as TRAF2, IRE-1α, CHOP, p-JNK and procaspase-12, in comparison to normal mice, and which were significantly blunted by the olmesartan treatment in diabetic kidney mice. Furthermore, the diabetic kidney mice were found to have significant increment in renal apoptosis, superoxide radical production, MDA level and activation of an Ang-II and which were also attenuated by the olmesartan treatment. Considering all the findings, it is suggested that the AT-1R specific blocker-olmesartan treatment could be a potential therapy in treating ER stress-induced renal apoptosis via the modulation of AT-1R/CHOP-JNK-Caspase12 pathway in STZ-induced diabetic mice.