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Published online April 28, 2008
Diabetes 57:2181-2190, 2008
DOI: 10.2337/db07-1431
© 2008 by the American Diabetes Association
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Protein Kinase C-{delta} Mediates Neuronal Apoptosis in the Retinas of Diabetic Rats via the Akt Signaling Pathway

Young-Hee Kim1, Yoon-Sook Kim1, Chang-Hwan Park1, In-Yong Chung2, Ji-Myong Yoo2, Jae-Geun Kim3, Byung-Ju Lee3, Sang-Soo Kang1, Gyeong-Jae Cho1, and Wan-Sung Choi1

1 Department of Anatomy and Neurobiology, School of Medicine, Institute of Health Science, Gyeongsang National University, Jinju, Gyeongnam, South Korea
2 Department of Ophthalmology, School of Medicine, Institute of Health Science, Gyeongsang National University, Jinju, Gyeongnam, South Korea
3 Department of Biological Sciences, College of Natural Sciences, University of Ulsan, Ulsan, South Korea

Corresponding author: Wan Sung Choi, choiws{at}gnu.ac.kr

OBJECTIVE—Protein kinase C (PKC)-{delta}, an upstream regulator of the Akt survival pathway, contributes to cellular dysfunction in the pathogenesis of diabetes. Herein, we examined the role of PKC-{delta} in neuronal apoptosis through Akt in the retinas of diabetic rats.

RESEARCH DESIGN AND METHODS—We used retinas from 24- and 35-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) diabetic and Long-Evans Tokushima Otsuka (LETO) nondiabetic rats. To assess whether PKC-{delta} affects Akt signaling and cell death in OLETF rat retinas, we examined 1) PKC-{delta} activity and apoptosis; 2) protein levels of phosphatidylinositol 3-kinase (PI 3-kinase) p85, heat shock protein 90 (HSP90), and protein phosphatase 2A (PP2A); 3) Akt phosphorylation; and 4) Akt binding to HSP90 or PP2A in LETO and OLETF retinas in the presence or absence of rottlerin, a highly specific PKC-{delta} inhibitor, or small interfering RNAs (siRNAs) for PKC-{delta} and HSP90.

RESULTS—In OLETF retinas from 35-week-old rats, ganglion cell death, PKC-{delta} and PP2A activity, and Akt-PP2A binding were significantly increased and Akt phosphorylation and Akt-HSP90 binding were decreased compared with retinas from 24-week-old OLETF and LETO rats. Rottlerin and PKC-{delta} siRNA abrogated these effects in OLETF retinas from 35-week-old rats. HSP90 siRNA significantly increased ganglion cell death and Akt-PP2A complexes and markedly decreased HSP90-Akt binding and Akt phosphorylation in LETO retinas from 35-week-old rats compared with those from nontreated LETO rats.

CONCLUSIONS—PKC-{delta} activation contributes to neuro-retinal apoptosis in diabetic rats by inhibiting Akt-mediated signaling pathways.


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