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

Arun Lakshmanan, Rajarajan A. Thandavarayan, Suresh S. Palaniyandi, Flori R. Sari, Harima Meilei, Vijayasree V. Giridharan, Vivian Soetikno, Kenji Suzuki, Makoto Kodama, Kenichi Watanabe

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Abstract

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.

Original languageEnglish
Pages (from-to)627-634
Number of pages8
JournalEuropean Journal of Pharmaceutical Sciences
Volume44
Issue number5
DOIs
Publication statusPublished - 18 Dec 2011
Externally publishedYes

Fingerprint

MAP Kinase Signaling System
Streptozocin
Apoptosis
Kidney
Angiotensin II
Therapeutics
NADPH Oxidase
Superoxides
Proteins
olmesartan
TNF Receptor-Associated Factor 2
Staining and Labeling
In Situ Nick-End Labeling
Diabetic Nephropathies
Lipid Peroxidation
Animal Models
Western Blotting
Immunohistochemistry

Keywords

  • Apoptosis
  • Diabetic nephropathy
  • Endoplasmic reticulum stress
  • Olmesartan

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Modulation of AT-1R/CHOP-JNK-Caspase12 pathway by olmesartan treatment attenuates ER stress-induced renal apoptosis in streptozotocin-induced diabetic mice. / Lakshmanan, Arun; Thandavarayan, Rajarajan A.; Palaniyandi, Suresh S.; Sari, Flori R.; Meilei, Harima; Giridharan, Vijayasree V.; Soetikno, Vivian; Suzuki, Kenji; Kodama, Makoto; Watanabe, Kenichi.

In: European Journal of Pharmaceutical Sciences, Vol. 44, No. 5, 18.12.2011, p. 627-634.

Research output: Contribution to journalArticle

Lakshmanan, Arun ; Thandavarayan, Rajarajan A. ; Palaniyandi, Suresh S. ; Sari, Flori R. ; Meilei, Harima ; Giridharan, Vijayasree V. ; Soetikno, Vivian ; Suzuki, Kenji ; Kodama, Makoto ; Watanabe, Kenichi. / Modulation of AT-1R/CHOP-JNK-Caspase12 pathway by olmesartan treatment attenuates ER stress-induced renal apoptosis in streptozotocin-induced diabetic mice. In: European Journal of Pharmaceutical Sciences. 2011 ; Vol. 44, No. 5. pp. 627-634.
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