PERK Signaling Pathway Involved in Lactic Acid Induced Astrocyte Damage

Author(s): Jian-Zhong Zhang, Li Jing, Ru Yan, Xiang-Mei Cao, Qing-Ping He, P. Andy Li

Diabetes is an important modifiable risk factor for cerebral ischemic stroke. It increases infraction area and restrains astrocyte activation. Meanwhile, hyperglycemia increase lactic acid and decreases pH. Lactic acid may partially be accountable for the detrimental effects of diabetes on ischemic stroke. The objective of this study was to investigate the effect of lactic acid on astrocyte viability and to explore the potential mechanisms that lactic acid enhances astrocyte cell death. Astrocytes were challenged by various concentrations of lactic acid (0, 2.5, 5，10 and 15 mM). Cell viability and PERK pathway were examined. The results showed that lactic acid resulted in astrocyte death (p<0.05) and activation of GRP78 and PERK (p<0.05). It is concluded that lactate acidosis causes stress to the endoplasmic reticulum.

Acidosis, Astrocyte, Lactic acid, GRP78, PERK

1. Siesjo BK, Katsura KI, Kristian T, Li PA, Siesjo P. Molecular mechanisms of acidosis-mediated damage. In: Baethmann A, Kempski O, Plesnila N, Staub F (Eds.). Mechanisms of Secondary Brain Damage in Cerebral Ischemia and Trauma. 1996; 66:8-14
2. Li PA, Siesjo BK. Role of hyperglycaemia-related acidosis in ischaemic brain damage. Acta Physiol Scand. 1997; 161:567-580
3. Kraig RP, Chesler M. Astrocytic acidosis in hyperglycemic and complete ischemia. J Cereb Blood Flow Metab. 1990; 10:104-14
4. Alvarez-Sabin J, Molina CA, Montaner J, Arenillas LF, Huertas R, Ribo M, Codina A, Quintana M. Effects of admission hyperglycemia on stroke outcome in reperfused tissue plasminogen activator—treated patients. Stroke. 2003;34:1235-1241
5. Li PA, Shamloo M, Katsura K, Smith M-L, Siesjö BK. Critical values for plasma glucose in aggravating ischemic brain damage: correlation to extracellular pH. Neurobiol Dis. 1995; 2: 97-108
6. Li C, Li PA, He QP, Ouyang YB, Siesjö BK. Effects of streptozotcin-induced hyperglycemia on brain damage following transient ischemia. Neurobiol Dis. 1998; 5:117-128
7. Li PA, Liu GJ, He QP, Floyd RA, Siesjo BK. Production of hydroxyl free radical by brain tissues in hyperglycemic rats subjected to transient forebrain ischemia. Free Rad Biol Med. 1999; 27:1033-40
8. Muranyi M, Ding C, He Q, Lin Y, Li PA. Streptozotocin-induced diabetes causes astrocyte death after ischemia and reperfusion injury. Diabetes. 2006; 55:349-55
9. Muranyi M, Fujioka M, He Q, Han A, Yong G, Csiszar K, Li PA. Diabetes activates cell death pathway after transient focal cerebral ischemia. Diabetes 2003; 52:481-486
10. Wang DD, Bordey A. The astrocyte odyssey. Prog Neurobiol. 2008; 86:342-367
11. Dhandapani KM, Hadman M, De Sevilla L, Wade MF, Mahesh VB, Brann DW. Astrocyte protection of neurons - Role of transforming growth factor-beta signaling via a c-Jun-AP-1 protective pathway. J Biol Chem. 2003; 278:43329-39
12. Giffard RG, Monyer H, Choi DW. Selective vulnerability of cultured cortical glia to injury by extracellular acidosis. Brain Res. 1990; 530:138-141
13. Jing L, Mai L, Zhang JZ, Wang JG, Chang Y, Dong JD, Guo FY, Li PA. Diabetes inhibits cerebral ischemia-induced astrocyte activation - an observation in the cingulate cortex. Int J Biol Sci. 2013; 9:980-988
14. Srinivasan K, Sharma SS. 3-Bromo-7-nitroindazole attenuates brain ischemic injury in diabetic stroke via inhibition of endoplasmic reticulum stress pathway involving CHOP. Life Sci. 2012; 90:154-60
15. Rao RV, Peel A, Logvinova A, del Rio G, Hermel E, Yokota T, Goldsmith PC, Ellerby LM, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS Lett 2002;514:122-128
16. Harding HP, Zhang YH, Bertolotti A, Zeng HQ, Ron D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell. 2000; 5:897-904
17. Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. PNAS. 1994; 91:10625-9
18. Takahashi S, Izawa Y, Suzuki N. Astrogliopathy as a loss of astroglial protective function against glycoxidative stress under hyperglycemia. Clin Neurol. 2012: 52:41-51
19. Amin SN, Younan SM, Youssef MF, Rashed LA, Mohamady I. A histological and functional study on hippocampal formation of normal and diabetic rats. F1000Res. 2013;2:151
20. Shao B, Bayraktutan U. Hyperglycaemia promotes human brain microvascular endothelial cell apoptosis via induction of protein kinase C-ßI and prooxidant enzyme NADPH oxidase. Redox Biol. 2014, 28:694-701
21. Dalkara T, Gursoy-Ozdemir Y, Yemisci M. Brain microvascular pericytes in health and disease. Acta Neuropathol. 2011; 122: 1-9
22. Hammes HP, Lin J, Renner O, Shani M, Lundqvist A, Betsholtz C, Brownlee M Deutsch U. Pericytes and the pathogenesis of diabetic retinopathy. Diabetes. 2002; 51: 3107-3112
23. Jing L, He Q, Zhang JZ, Li PA. Temporal profile of astrocytes and changes of oligodendrocyte-based myelin following middle cerebral artery occlusion in diabetic and non-diabetic rats. Int J Biol Sci 2013; 9: 190-199
24. Raghubir R, Nakka VP, Mehta SL. Endoplasmic reticulum stress in brain damage. Methods Enzymol 2011; 489:259-275
25. Banhegyi G, Baumeister P, Benedetti A, Dong D, Fu Y, Lee AS, Li J, Mao C, Margittai E, Ni M, Paschen W, Piccirella S, Senesi S, Sitia R, Wang M, Yang W. Endoplasmic reticulum stress. Ann N Y Acad Sci. 2007; 1113: 58-71
26. Amin A, Choi SK, Galan M, Kassan M, Partyka M, Kadowitz P, Henrion D, Trebak M, Belmadani S, Matrougui K. Chronic inhibition of endoplasmic reticulum stress and inflammation prevents ischaemia-induced vascular pathology in type II diabetic mice. J Pathol. 2012; 227:165-174
27. Srinivasan K, Sharma SS. Sodium phenylbutyrate ameliorates focal cerebral ischemic/reperfusion injury associated with comorbid type 2 diabetes by reducing endoplasmic reticulum stress and DNA fragmentation. Behav Brain Res 2011; 225:110-116