Betaine inhibits vascularization via suppression of Akt in the retinas of streptozotocin-induced hyperglycemic rats

Kim,Young‑Giun; Lim,Hyung‑Ho; Lee,Suh‑Ha; Shin,Mal‑Soon; Kim,Chang‑Ju; Yang,Hyeon   Jeong

doi:10.3892/mmr.2015.3613

Betaine inhibits vascularization via suppression of Akt in the retinas of streptozotocin-induced hyperglycemic rats

Authors:
- Young‑Giun Kim
- Hyung‑Ho Lim
- Suh‑Ha Lee
- Mal‑Soon Shin
- Chang‑Ju Kim
- Hyeon Jeong Yang
View Affiliations

Affiliations: Department of Oriental Medical Rehabilitation, Gil Oriental Medical Hospital, College of Oriental Medicine, Gachon University, Incheon 405‑760, Republic of Korea, Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Gyeonggi‑do 130‑701, Republic of Korea, Department of Anesthesiology and Pain Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi‑do 463‑721, Republic of Korea
Published online on: April 15, 2015 https://doi.org/10.3892/mmr.2015.3613
Pages: 1639-1644
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Diabetic retinopathy is a severe microvascular complication amongst patients with diabetes, and is the primary cause of visual loss through neovascularization. Betaine is one of the components of Fructus Lycii. In the present study, the effects of betaine on the expression levels of vascular endothelial growth factor (VEGF) and hypoxia‑inducible factor (HIF)‑1α in association with the Akt pathway were investigated in the retinas of streptozotocin (STZ)‑induced diabetic rats using western blot and immunohistochemical analyses. The results of the present study revealed that the expression levels of VEGF, HIF‑1α, and Akt were increased in the retinas of the STZ‑induced diabetic rats. Betaine treatment attenuated this increase in VEGF and HIF‑1α expression via suppression of diabetes‑induced Akt activation in the retinas of the diabetic rats. The results suggested that betaine may potentially be used to delay the onset of complications associated with diabetic retinopathy via inhibition of retinal neovascularization in patients with diabetes.

View Figures

View References

1	Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Valkonen VP, Salonen R and Salonen JT: Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 27:1036–1041. 2004. View Article : Google Scholar : PubMed/NCBI
2	Qaum T, Xu Q, Joussen AM, Clemens MW, Qin W, Miyamoto K, Hassessian H, Wiegand SJ, Rudge J, Yancopoulos GD and Adamis AP: VEGF-initiated blood-retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci. 42:2408–2413. 2001.PubMed/NCBI
3	Ishida S, Usui T, Yamashiro K, Kaji Y, Ahmed E, Carrasquillo KG, Amano S, Hida T, Oguchi Y and Adamis AP: VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci. 44:2155–2162. 2003. View Article : Google Scholar : PubMed/NCBI
4	Arjamaa O and Nikinmaa M: Oxygen-dependent diseases in the retina: role of hypoxia-inducible factors. Exp Eye Res. 83:473–483. 2006. View Article : Google Scholar : PubMed/NCBI
5	Semenza GL: Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochem Pharmacol. 59:47–53. 2000. View Article : Google Scholar
6	Hewitson KS and Schofield CJ: The HIF pathway as a therapeutic target. Drug Discov Today. 9:704–711. 2004. View Article : Google Scholar : PubMed/NCBI
7	Makino Y, Kanopka A, Wilson WJ, Tanaka H and Poellinger L: Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus. J Biol Chem. 277:32405–32408. 2002. View Article : Google Scholar : PubMed/NCBI
8	Matsuda T, Abe T, Wu JL, Fujiki M and Kobayashi H: Hypoxia-inducible factor-1alpha DNA induced angiogenesis in a rat cerebral ischemia model. Neurol Res. 27:503–508. 2005. View Article : Google Scholar : PubMed/NCBI
9	Yang XM, Wang YS, Zhang J, Li Y, Xu JF, Zhu J, Zhao W, Chu DK and Wiedemann P: Role of PI3K/Akt and MEK/ERK in mediating hypoxia-induced expression of HIF-1alpha and VEGF in laser-induced rat choroidal neovascularization. Invest Ophthalmol Vis Sci. 50:1873–1879. 2009. View Article : Google Scholar
10	Brazil DP and Hemmings BA: Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci. 26:657–664. 2001. View Article : Google Scholar : PubMed/NCBI
11	Shiojima I and Walsh K: Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res. 90:1243–1250. 2002. View Article : Google Scholar : PubMed/NCBI
12	Craig SA: Betaine in human nutrition. Am J Clin Nutr. 80:539–549. 2004.PubMed/NCBI
13	Chang RC and So KF: Use of anti-aging herbal medicine, Lycium barbarum, against aging-associated diseases. What do we know so far? Cell Mol Neurobiol. 28:643–652. 2008. View Article : Google Scholar
14	Chang HK, Shin MS, Yang HY, Lee JW, Kim YS, Lee MH, Kim J, Kim KH and Kim CJ: Amygdalin induces apoptosis through regulation of Bax and Bcl-2 expressions in human DU145 and LNCaP prostate cancer cells. Biol Pharm Bull. 29:1597–1602. 2006. View Article : Google Scholar : PubMed/NCBI
15	Kim DY, Jung SY, Kim CJ, Sung YH and Kim JD: Treadmill exercise ameliorates apoptotic cell death in the retinas of diabetic rats. Mol Med Rep. 7:1745–1750. 2013.PubMed/NCBI
16	Jee YS, Ko IG, Sung YH, Lee JW, Kim YS, Kim SE, Kim BK, Seo JH, Shin MS, Lee HH, et al: Effects of treadmill exercise on memory and c-Fos expression in the hippocampus of the rats with intracerebroventricular injection of streptozotocin. Neurosci Lett. 443:188–192. 2008. View Article : Google Scholar : PubMed/NCBI
17	Shin MS, Kim SK, Kim YS, Kim SE, Ko IG, Kim YS, Kim CJ, Kim YM, Kim BK and Kim TS: Aqueous extract of Anemarrhena rhizome increases cell proliferation and neuro-peptide Y expression in the hippocampal dentate gyrus on streptozotocin-induced diabetic rats. Fitoterapia. 79:323–327. 2008. View Article : Google Scholar : PubMed/NCBI
18	Chen J and Smith LE: Retinopathy of prematurity. Angiogenesis. 10:133–140. 2007. View Article : Google Scholar : PubMed/NCBI
19	Kim JH, Lee BJ, Kim JH, Yu YS, Kim MY and Kim KW: Rosmarinic acid suppresses retinal neovascularization via cell cycle arrest with increase of p21(WAF1) expression. Eur J Pharmacol. 615:150–154. 2009. View Article : Google Scholar : PubMed/NCBI
20	Knopman D and Patterson M: An open-label, 24-week pilot study of the methyl donor betaine in Alzheimer disease patients. Alzheimer Dis Assoc Disord. 15:162–165. 2001. View Article : Google Scholar : PubMed/NCBI
21	Coggeshall RE, Tate S and Carlton SM: Differential expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 in normal and inflamed rats. Neurosci Lett. 355:45–48. 2004. View Article : Google Scholar : PubMed/NCBI
22	Coppey LJ, Davidson EP, Dunlap JA, Lund DD and Yorek MA: Slowing of motor nerve conduction velocity in streptozotocin-induced diabetic rats is preceded by impaired vasodilation in arterioles that overlie the sciatic nerve. Int J Exp Diabetes Res. 1:131–143. 2000. View Article : Google Scholar
23	Cherdshewasart W and Sutjit W: Correlation of antioxidant activity and major isoflavonoid contents of the phytoestrogen-rich Pueraria mirifica and Pueraria lobata tubers. Phytomedicine. 15:38–43. 2008. View Article : Google Scholar
24	Xiong FL, Sun XH, Gan L, Yang XL and Xu HB: Puerarin protects rat pancreatic islets from damage by hydrogen peroxide. Eur J Pharmacol. 529:1–7. 2006. View Article : Google Scholar
25	Hartnett ME, Lappas A, Darland D, McColm JR, Lovejoy S and D’Amore PA: Retinal pigment epithelium and endothelial cell interaction causes retinal pigment epithelial barrier dysfunction via a soluble VEGF-dependent mechanism. Exp Eye Res. 77:593–599. 2003. View Article : Google Scholar : PubMed/NCBI
26	Ferrara N, Gerber HP and LeCouter J: The biology of VEGF and its receptors. Nat Med. 9:669–676. 2003. View Article : Google Scholar : PubMed/NCBI
27	Ozaki H, Seo MS, Ozaki K, Yamada H, Yamada E, Okamoto N, Hofmann F, Wood JM and Campochiaro PA: Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization. Am J Pathol. 156:697–707. 2000. View Article : Google Scholar : PubMed/NCBI
28	Wenger RH: Cellular adaptation to hypoxia: O₂-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O₂-regulated gene expression. FASEB J. 16:1151–1162. 2002. View Article : Google Scholar : PubMed/NCBI
29	Huang Y, Hua K, Zhou X, Jin H, Chen X, Lu X, Yu Y, Zha X and Feng Y: Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadeno-carcinoma. Cell Res. 18:780–791. 2008. View Article : Google Scholar : PubMed/NCBI
30	Dugel PU: Ranibizumab treatment of patients with ocular diseases. Int Ophthalmol Clin. 46:131–140. 2006. View Article : Google Scholar : PubMed/NCBI
31	Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, Zimmer-Galler I, Do DV and Campochiaro PA: Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol. 142:961–969. 2006. View Article : Google Scholar : PubMed/NCBI
32	Vengellur A, Woods BG, Ryan HE, Johnson RS and LaPres JJ: Gene expression profiling of the hypoxia signaling pathway in hypoxia-inducible factor 1alpha null mouse embryonic fibroblasts. Gene Expr. 11:181–197. 2003. View Article : Google Scholar : PubMed/NCBI
33	Lee BL, Kim WH, Jung J, Cho SJ, Park JW, Kim J, Chung HY, Chang MS and Nam SY: A hypoxia-independent up-regulation of hypoxia-inducible factor-1 by AKT contributes to angio-genesis in human gastric cancer. Carcinogenesis. 29:44–51. 2008. View Article : Google Scholar
34	Dimmeler S, Dernbach E and Zeiher AM: Phosphorylation of the endothelial nitric oxide synthase at ser-1177 is required for VEGF-induced endothelial cell migration. FEBS Lett. 477:258–262. 2000. View Article : Google Scholar : PubMed/NCBI
35	Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC and Walsh K: The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 6:1004–1010. 2000. View Article : Google Scholar : PubMed/NCBI
36	Wang Q, Pfister F, Dorn-Beineke A, vom Hagen F, Lin J, Feng Y and Hammes HP: Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina. Diabetologia. 53:1227–1238. 2010. View Article : Google Scholar : PubMed/NCBI