To determine whether the adiponectin receptor (AdipoR) agonist AdipoRon inhibits glutamate-induced neuronal cell death and to investigate the neuroprotective mechanism of AdipoRon in rat primary retinal ganglion cells (RGCs).
Methods:
The expression pattern of AdipoR1 and AdipoR2 in rat retina and primary RGCs was examined by immunostaining. The neuroprotective effect of AdipoRon on glutamate-induced cell death was evaluated in rat primary RGCs. Cellular levels of reactive oxygen species (ROS) were also measured. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), estrogen-related receptor-α (Esrra), mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor α (PPARα), and catalase mRNA levels were examined.
Results:
The expression of AdipoR1 and AdipoR2 was confirmed in rat retina and primary RGCs. AdipoRon significantly increased the survival rate of glutamate-induced cell death and decreased ROS production. Additionally, the mRNA levels of PGC-1α, Esrra, and TFAM were upregulated by AdipoRon.
Conclusions:
These results suggest that AdipoRon has a neuroprotective effect by inhibiting ROS production via upregulation of PGC-1α, Esrra, and TFAM against glutamate-induced RGC death.
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References
1.
Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am. J. Ophthalmol. 126:498–505, 1998.
2.
The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am. J. Ophthalmol. 130:429–440, 2000.
3.
BaltmrA., DugganJ., NizariS., SaltT.E., and CordeiroM.F.Neuroprotection in glaucoma—is there a future role?. Exp. Eye Res. 91:554–566, 2010.
4.
CassonR.J., ChidlowG., EbneterA., et al.Translational neuroprotection research in glaucoma: a review of definitions and principles. Clin. Exp Ophthalmol. 40:350–357, 2012.
5.
ChangE.E., and GoldbergJ.L.Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology. 119:979–986, 2012.
6.
Gil-CamposM., CañeteR.R., and GilA.Adiponectin, the missing link in insulin resistance and obesity. Clin. Nutr. 23:963–974, 2004.
7.
YamauchiT., KamonJ., WakiH., et al.The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 7:941–946, 2001.
8.
YamauchiT., KamonJ., MinokoshiY., et al.Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8:1288–1295, 2002.
9.
FruebisJ., TsaoT.S., JavorschiS., et al.Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc. Natl. Acad. Sci. U. S. A. 98:2005–2010, 2001.
10.
KerstenS., DesvergneB., and WahliW.Roles of PPARs in health and disease. Nature. 405:421–424, 2000.
11.
MaedaN., ShimomuraI., KishidaK., et al.Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat. Med. 8:731–737, 2002.
12.
LuoN., ChungB.H., WangX., et al.Enhanced adiponectin actions by overexpression of adiponectin receptor 1 in macrophages. Atherosclerosis. 228:124–135, 2013.
13.
MasamotoY., AraiS., SatoT., et al.Adiponectin enhances antibacterial activity of hematopoietic cells by suppressing bone marrow inflammation. Immunity. 44:1422–1433, 2016.
14.
TaoL., GaoE., JiaoX., et al.Adiponectin cardioprotection after myocardial ischemia/reperfusion involves the reduction of oxidative/nitrative stress. Circulation. 115:1408–1416, 2007.
15.
ChoiSR., LimJH., KimMY., et al.Adiponectin receptor agonist AdipoRon decreased ceramide, and lipotoxicity, and ameliorated diabetic nephropathy. Metabolism. 85:348–360, 2018.
16.
QiuG., WanR., HuJ., et al.Adiponectin protects rat hippocampal neurons against excitotoxicity. Age. 33:155–165, 2011.
17.
YueL., ZhaoL., LiuH., et al.Adiponectin protects against glutamate-induced excitotoxicity via activating SIRT1-dependent PGC-1α expression in HT22 hippocampal neurons. Oxid. Med. Cell Longev. 2016:2957354, 2016.
18.
Okada-IwabuM., YamauchiT., IwabuM., et al.A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature. 503:493–499, 2013.
19.
KimY., LimJ.H., KimM.Y., et al.The adiponectin receptor agonist AdipoRon ameliorates diabetic nephropathy in a model of type 2 diabetes. J. Am. Soc. Nephrol. 29:1108–1127, 2018.
20.
WangY., WanY., YeG., et al.Hepatoprotective effects of AdipoRon against d-galactosamine-induced liver injury in mice. Eur. J. Pharm. Sci. 93:123–131, 2016.
21.
MalihS., SaidijamM., MansouriK., et al.Promigratory and proangiogenic effects of AdipoRon on bone marrow-derived mesenchymal stem cells: an in vitro study. Biotechnol. Lett. 39:39–44, 2017.
22.
HongK., LeeS., LiR., et al.Adiponectin receptor agonist, AdipoRon, causes vasorelaxation predominantly via a direct smooth muscle action. Microcirculation. 23:207–220, 2016.
23.
YamagishiR., and AiharaM.Neuroprotective effect of astaxanthin against rat retinal ganglion cell death under various stresses that induce apoptosis and necrosis. Mol. Vis. 20:1796–1805, 2014.
24.
AtlanteA., CalissanoP., BobbaA., et al.Glutamate neurotoxicity, oxidative stress and mitochondria. FEBS Lett. 497:1–5, 2001.
25.
VillenaJ.A., and KralliA.ERRalpha: a metabolic function for the oldest orphan. Trends Endocrinol. Metab. 19:269–276, 2008.
26.
WuZ., PuigserverP., AnderssonU., et al.Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 98:115–124, 1999.
27.
ToyamaT., NakamuraH., HaranoY., et al.PPARalpha ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats. Biochem. Biophys. Res. Commun. 324:697–704, 2004.
28.
LehmanJ.J., BargerP.M., KovacsA., et al.Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J. Clin. Invest. 106:847–856, 2000.
29.
LinJ., WuH., TarrP.T., et al.Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature. 418:797–801, 2002.
30.
St-PierreJ., DroriS., UldryM., et al.Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 127:397–408, 2006.
31.
SchreiberS.N., EmterR., HockM.B., et al.The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis. Proc. Natl. Acad. Sci. U. S. A. 101:6472–6477, 2004.
32.
VillenaJ.A., HockM.B., ChangW.Y., et al.Orphan nuclear receptor estrogen-related receptor alpha is essential for adaptive thermogenesis. Proc. Natl. Acad. Sci. U. S. A. 104:1418–1423, 2007.
33.
RangwalaS.M., LiX., LindsleyL., et al.Estrogen-related receptor alpha is essential for the expression of antioxidant protection genes and mitochondrial function. Biochem. Biophys. Res. Commun. 357:231–236, 2007.
34.
XuS., ZhongM., ZhangL., et al.Overexpression of Tfam protects mitochondria against beta-amyloid-induced oxidative damage in SH-SY5Y cells. FEBS J. 276:3800–3809, 2009.
35.
OkaS., LeonJ., SakumiK., et al.Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer's disease. Sci. Rep. 6:37889, 2016.
36.
ThomasR.R., KhanS.M., SmigrodzkiR.M., et al.RhTFAM treatment stimulates mitochondrial oxidative metabolism and improves memory in aged mice. Aging. 4:620–635, 2012.
37.
AntonopoulosA.S., MargaritisM., Coutinho.P., et al. Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue. Diabetes. 64:2207–2219, 2015.
38.
ShresthaA., and ParkP.H.Globular adiponectin attenuates LPS-induced reactive oxygen species production in HepG2 cells via FoxO3A and HO-1 signaling. Life Sci. 148:71–79, 2016.
39.
LiX., GuoH., ZhaoL., et al.Adiponectin attenuates NADPH oxidase-mediated oxidative stress and neuronal damage induced by cerebral ischemia-reperfusion injury. Biochim. Biophys. Acta. 1863:3265–3276, 2017.
40.
YamamotoK., MaruyamaK., HimoriN., et al.The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Invest. Ophthalmol. Vis. Sci. 55:7126–7136, 2014.
41.
ChidlowG., WoodJ.P.M., and CassonR.J.Investigations into hypoxia and oxidative stress at the optic nerve head in a rat model of glaucoma. Front Neurosci. 11:478, 2017.
42.
NepalS., KimM.J., SubediA., et al.Globular adiponectin inhibits ethanol-induced apoptosis in HepG2 cells through heme oxygenase-1 induction. Biochem. Pharmacol. 84:974–983, 2012.
43.
LiH., YaoW., IrwinM.G., et al.Adiponectin ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction by concomitantly activating Nrf2 and Brg1. Free Radic. Biol. Med. 84:311–321, 2015.
44.
RenY., LiY., YanJ., et al.Adiponectin modulates oxidative stress-induced mitophagy and protects C2C12 myoblasts against apoptosis. Sci. Rep. 7:3209, 2017.
45.
AkimotoM., MaruyamaR., KawabataY., TajimaY., and TakenagaK.Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERK-dependent necroptosis. Cell Death Dis. 9:804, 2018.
46.
AlmasiehM., WilsonAM., MorquetteB., VargasJ.L.C., and PoloA.D.The molecular basis of retinal ganglion cell death in glaucoma. Prog. Retin. Eye Res. 31:152–181, 2012.
47.
ShanabA.Y., NakazawaT., RyuM., et al.Metabolic stress response implicated in diabetic retinopathy: the role of calpain, and the therapeutic impact of calpain inhibitor. Neurobiol. Dis. 48:556–567, 2012.
