Abstract
Diabetic retinopathy (DR), a major complication of diabetes caused by vascular damage and pathological proliferation of retinal vessels, often progresses to vision loss. Vascular endothelial growth factor (VEGF) signaling plays a pivotal role in the development of DR, but the exact underlying molecular mechanisms remain ill-defined. Cellular prion protein (PrPc) is a surface protein expressed by vascular endothelial cells, and the increased expression of PrPc is associated with physiological and pathological vascularization. Nevertheless, a role for PrPc in the development of DR has not been appreciated. Here, we addressed this question. We found that the development of streptozocin (STZ)-induced DR, but not the STZ-induced hyperglycemia/diabetes itself, was significantly attenuated in PrPc-KO mice, compared to control wildtype (WT) mice, evident by measurement of retinal vascular leakage, retinal neovascularization, a retinopathy score and visual acuity assessment. Moreover, the attenuation of DR severity seemingly resulted from attenuation of retinal neovascularization via VEGF/ras/rac signaling. Together, our study suggests a previously unappreciated role for PrPc in the development of DR.
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References
Gannon M (2007) BuMP-ing up insulin secretion by pancreatic beta cells. Cell Metab 5(3):157–159. https://doi.org/10.1016/j.cmet.2007.02.003
Pipeleers D, Ling Z (1992) Pancreatic beta cells in insulin-dependent diabetes. Diabetes Metab Rev 8(3):209–227
Hammes HP, Feng Y, Pfister F, Brownlee M (2011) Diabetic retinopathy: targeting vasoregression. Diabetes 60(1):9–16. https://doi.org/10.2337/db10-0454
Engerman RL (1989) Pathogenesis of diabetic retinopathy. Diabetes 38(10):1203–1206
Cao Y (2013) Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity. Cell Metab 18(4):478–489. https://doi.org/10.1016/j.cmet.2013.08.008
Xiao X, Guo P, Chen Z, El-Gohary Y, Wiersch J, Gaffar I, Prasadan K, Shiota C, Gittes GK (2013) Hypoglycemia reduces vascular endothelial growth factor a production by pancreatic Beta cells as a regulator of Beta cell mass. J Biol Chem 288(12):8636–8646. https://doi.org/10.1074/jbc.M112.422949
Xiao X, Prasadan K, Guo P, El-Gohary Y, Fischbach S, Wiersch J, Gaffar I, Shiota C, Gittes GK (2014) Pancreatic duct cells as a source of VEGF in mice. Diabetologia 57(5):991–1000. https://doi.org/10.1007/s00125-014-3179-y
Peggion C, Bertoli A, Sorgato MC (2017) Almost a century of prion protein(s): from pathology to physiology, and back to pathology. Biochem Biophys Res Commun 483(4):1148–1155. https://doi.org/10.1016/j.bbrc.2016.07.118
Atkinson CJ, Zhang K, Munn AL, Wiegmans A, Wei MQ (2016) Prion protein scrapie and the normal cellular prion protein. Prion 10(1):63–82. https://doi.org/10.1080/19336896.2015.1110293
Weiss RB (1982) Streptozocin: a review of its pharmacology, efficacy, and toxicity. Cancer Treat Rep 66(3):427–438
Zhang B, Cowden D, Zhang F, Yuan J, Siedlak S, Abouelsaad M, Zeng L, Zhou X, O’Toole J, Das AS, Kofskey D, Warren M, Bian Z, Cui Y, Tan T, Kresak A, Wyza RE, Petersen RB, Wang GX, Kong Q, Wang X, Sedor J, Zhu X, Zhu H, Zou WQ (2015) Prion protein protects against renal ischemia/reperfusion injury. PLoS ONE 10(9):e0136923. https://doi.org/10.1371/journal.pone.0136923
Xiao X, Chen C, Guo P, Zhang T, Fischbach S, Fusco J, Shiota C, Prasadan K, Dong H, Gittes GK (2017) Forkhead box protein 1 (FoxO1) inhibits accelerated beta cell aging in pancreas-specific SMAD7 mutant mice. J Biol Chem 292(8):3456–3465. https://doi.org/10.1074/jbc.M116.770032
Xiao X, Chen Z, Shiota C, Prasadan K, Guo P, El-Gohary Y, Paredes J, Welsh C, Wiersch J, Gittes GK (2013) No evidence for beta cell neogenesis in murine adult pancreas. J Clin Invest 123(5):2207–2217. https://doi.org/10.1172/JCI66323
Xiao X, Fischbach S, Song Z, Gaffar I, Zimmerman R, Wiersch J, Prasadan K, Shiota C, Guo P, Ramachandran S, Witkowski P, Gittes GK (2016) Transient suppression of TGFbeta receptor signaling facilitates human islet transplantation. Endocrinology 157(4):1348–1356. https://doi.org/10.1210/en.2015-1986
Xiao X, Fischbach S, Zhang T, Chen C, Sheng Q, Zimmerman R, Patnaik S, Fusco J, Ming Y, Guo P, Shiota C, Prasadan K, Gangopadhyay N, Husain SZ, Dong H, Gittes GK (2017) SMAD3/Stat3 signaling mediates beta-cell epithelial-mesenchymal transition in chronic pancreatitis-related diabetes. Diabetes 66(10):2646–2658. https://doi.org/10.2337/db17-0537
Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, Song Z, El-Gohary Y, Prasadan K, Shiota C, Gittes GK (2014) M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci USA 111(13):E1211-1220. https://doi.org/10.1073/pnas.1321347111
Xiao X, Guo P, Shiota C, Prasadan K, El-Gohary Y, Wiersch J, Gaffar I, Gittes GK (2013) Neurogenin3 activation is not sufficient to direct duct-to-beta cell transdifferentiation in the adult pancreas. J Biol Chem 288(35):25297–25308. https://doi.org/10.1074/jbc.M113.484022
Xiao X, Wiersch J, El-Gohary Y, Guo P, Prasadan K, Paredes J, Welsh C, Shiota C, Gittes GK (2013) TGFbeta receptor signaling is essential for inflammation-induced but not beta-cell workload-induced beta-cell proliferation. Diabetes 62(4):1217–1226. https://doi.org/10.2337/db12-1428
Lee CA, Li G, Patel MD, Petrash JM, Benetz BA, Veenstra A, Amengual J, von Lintig J, Burant CJ, Tang J, Kern TS (2014) Diabetes-induced impairment in visual function in mice: contributions of p38 MAPK, rage, leukocytes, and aldose reductase. Invest Ophthalmol Vis Sci 55(5):2904–2910. https://doi.org/10.1167/iovs.13-11659
Higgins RD, Yu K, Sanders RJ, Nandgaonkar BN, Rotschild T, Rifkin DB (1999) Diltiazem reduces retinal neovascularization in a mouse model of oxygen induced retinopathy. Curr Eye Res 18(1):20–27
Cai X, Xu H, Chen ZJ (2017) Prion-Like Polymerization in Immunity and Inflammation. Cold Spring Harb Perspect Biol 9 (4). https://doi.org/10.1101/cshperspect.a023580
Bueler H, Fischer M, Lang Y, Bluethmann H, Lipp HP, DeArmond SJ, Prusiner SB, Aguet M, Weissmann C (1992) Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356(6370):577–582. https://doi.org/10.1038/356577a0
Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49(11):1603–1616. https://doi.org/10.1016/j.freeradbiomed.2010.09.006
Zanetti F, Carpi A, Menabo R, Giorgio M, Schulz R, Valen G, Baysa A, Massimino ML, Sorgato MC, Bertoli A, Di Lisa F (2014) The cellular prion protein counteracts cardiac oxidative stress. Cardiovasc Res 104(1):93–102. https://doi.org/10.1093/cvr/cvu194
Oh JM, Choi EK, Carp RI, Kim YS (2012) Oxidative stress impairs autophagic flux in prion protein-deficient hippocampal cells. Autophagy 8(10):1448–1461. https://doi.org/10.4161/auto.21164
Watt NT, Taylor DR, Gillott A, Thomas DA, Perera WS, Hooper NM (2005) Reactive oxygen species-mediated beta-cleavage of the prion protein in the cellular response to oxidative stress. J Biol Chem 280(43):35914–35921. https://doi.org/10.1074/jbc.M507327200
Yun CW, Yun S, Lee JH, Han YS, Yoon YM, An D, Lee SH (2016) Silencing prion protein in HT29 human colorectal cancer cells enhances anticancer response to fucoidan. Anticancer Res 36(9):4449–4458. https://doi.org/10.21873/anticanres.10989
Chen MC, Hsu WL, Hwang PA, Chou TC (2015) Low molecular weight fucoidan inhibits tumor angiogenesis through downregulation of HIF-1/VEGF signaling under hypoxia. Mar Drugs 13(7):4436–4451. https://doi.org/10.3390/md13074436
Al-Hilal TA, Chung SW, Choi JU, Alam F, Park J, Kim SW, Kim SY, Ahsan F, Kim IS, Byun Y (2016) Targeting prion-like protein doppel selectively suppresses tumor angiogenesis. J Clin Invest 126(4):1251–1266. https://doi.org/10.1172/JCI83427
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Zhu, L., Xu, J., Liu, Y. et al. Prion protein is essential for diabetic retinopathy-associated neovascularization. Angiogenesis 21, 767–775 (2018). https://doi.org/10.1007/s10456-018-9619-4
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DOI: https://doi.org/10.1007/s10456-018-9619-4