Heat shock protein 70 induction by valproic acid delays photoreceptor cell death by N-methyl-N-nitrosourea in mice.
Retinal degenerative diseases (RDs) are a group of inherited diseases characterized by the loss of photoreceptor cells. Selective photoreceptor loss can be induced in mice by an intraperitoneal injection of N-methyl-N-nitrosourea (MNU) and, because of its selectivity, this model is widely used to study the mechanism of RDs. Although it is known that calcium-calpain activation and lipid peroxidation are involved in the initiation of cell death, the precise mechanisms of this process remain unknown. Heat shock protein 70 (HSP70) has been shown to function as a chaperone molecule to protect cells against environmental and physiological stresses. In this study, we investigated the role of HSP70 on photoreceptor cell death in mice. HSP70 induction by valproic acid, a histone deacetylase inhibitor, attenuated the photoreceptor cell death by MNU through inhibition of apoptotic caspase signals. Furthermore, HSP70 itself was rapidly and calpain-dependently cleaved after MNU treatment. Therefore, HSP70 induction by valproic acid was dually effective against MNU-induced photoreceptor cell loss as a result of its anti-apoptotic actions and its ability to prevent HSP70 degradation. These findings might help lead us to a better understanding of the pathogenic mechanism of RDs. Retinal degenerative diseases are characterized by the loss of photoreceptor cells. We proposed the following cascade for N-methyl-N-nitrosourea (MNU)-induced photoreceptor cell death: MNU gives rise to cleavage of heat shock protein 70 (HSP70); HSP70 induction by valproic acid (VPA) is dually effective against MNU-induced photoreceptor cell loss because of its anti-apoptotic actions and its ability to prevent HSP70 degradation. We hope that the present study heralds a new era in developing therapeutic tools against retinal degenerative diseases.
Department of Molecular Neurobiology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan; Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan.
Yoshiki
Y
Koriyama
Kayo
K
Sugitani
Kazuhiro
K
Ogai
Satoru
S
Kato
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D010786:Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012162:Retinal Degeneration / Q000139:chemically induced / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*
D000477:Alkylating Agents; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D014635:Valproic Acid; D008770:Methylnitrosourea
HSP70; N-methyl-N-nitrosourea; calpain; p-Akt; photoreceptor; valproic acid