Modulation of AT-1R/CHOP-JNK-Caspase12 pathway by olmesartan treatment attenuates ER stress-induced renal apoptosis in streptozotocin-induced diabetic mice.
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.
Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Japan.
Arun Prasath
AP
Lakshmanan
Rajarajan A
RA
Thandavarayan
Suresh S
SS
Palaniyandi
Flori R
FR
Sari
Harima
H
Meilei
Vijayasree V
VV
Giridharan
Vivian
V
Soetikno
Kenji
K
Suzuki
Makoto
M
Kodama
Kenichi
K
Watanabe
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000032:analysis; D053454:Caspase 12 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008315:Malondialdehyde / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D000068557:Olmesartan Medoxomil; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051742:Transcription Factor CHOP / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007093:Imidazoles; D008565:Membrane Proteins; D044140:Receptor, Angiotensin, Type 1; D047992:TNF Receptor-Associated Factor 2; D013777:Tetrazoles; D013481:Superoxides; D051742:Transcription Factor CHOP; D008315:Malondialdehyde; D000068557:Olmesartan Medoxomil; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C506440:Casp12 protein, mouse; D053454:Caspase 12