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Diabetologia

Erschienen in:

01.09.2011 | Article

Wld^S protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice

verfasst von: S. S. Zhu, Y. Ren, M. Zhang, J. Q. Cao, Q. Yang, X. Y. Li, H. Bai, L. Jiang, Q. Jiang, Z. G. He, Q. Chen

Erschienen in: Diabetologia | Ausgabe 9/2011

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Abstract

Aims/hypothesis

We aimed to evaluate the effect of the mutant Wld ^S (slow Wallerian degeneration; also known as Wld) gene in experimental diabetes on early experimental peripheral diabetic neuropathy and diabetic retinopathy.

Methods

The experiments were performed in four groups of mice: wild-type (WT), streptozotocin (STZ)-induced diabetic WT, C57BL/Wld ^S and STZ-induced diabetic C57BL/Wld ^S. In each group, intraperitoneal glucose and insulin tolerance tests were performed; blood glucose, glycated haemoglobin and serum insulin were monitored. These mice were also subjected to the following behavioural tests: grasping test, hot-plate test and von Frey aesthesiometer test. For some animals, sciatic–tibial motor nerve conduction velocity, tail sensory nerve conduction velocity and eye pattern electroretinogram were measured. At the end of the experiments, islets were isolated to detect glucose-stimulated insulin secretion, ATP content and extent of apoptosis. The NAD/NADH ratio in islets and retinas was evaluated. Surviving retinal ganglion cells were estimated by immunohistochemistry.

Results

We found that the Wld ^S gene is expressed in islets and protects beta cells against multiple low doses of STZ by increasing the NAD/NADH ratio, maintaining the ATP concentration, and reducing apoptosis. Consistently, significantly higher insulin concentrations, lower blood glucose concentrations, and better glucose tolerance were observed in Wld ^S mice compared with WT mice after STZ treatment. Furthermore, Wld ^S alleviated abnormal sensory responses, nerve conduction, retina dysfunction and reduction of surviving retinal ganglion cells in STZ-induced diabetic models.

Conclusions/interpretation

We provide the first evidence that expression of the Wld ^S gene decreases beta cell destruction and preserves islet function in STZ-induced diabetes, thus revealing a novel protective strategy for diabetic models.

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Yoon JW, Jun HS (2005) Autoimmune destruction of pancreatic beta cells. Am J Ther 12:580–591PubMedCrossRef

Ryan A, Murphy M, Godson C, Hickey FB (2009) Diabetes mellitus and apoptosis: inflammatory cells. Apoptosis 14:1435–1450PubMedCrossRef

Charron MJ, Bonner-Weir S (1999) Implicating PARP and NAD+ depletion in type I diabetes. Nat Med 5:269–270PubMedCrossRef

Lunn ER, Perry VH, Brown MC, Rosen H, Gordon S (1989) Absence of Wallerian degeneration does not hinder regeneration in peripheral nerve. Eur J Neurosci 1:27–33PubMedCrossRef

Glass JD, Brushart TM, George EB, Griffin JW (1993) Prolonged survival of transected nerve fibres in C57BL/Ola mice is an intrinsic characteristic of the axon. J Neurocytol 22:311–321PubMedCrossRef

Conforti L, Tarlton A, Mack TG et al (2000) A Ufd2/D4Cole1e chimeric protein and overexpression of Rbp7 in the slow Wallerian degeneration (WldS) mouse. Proc Natl Acad Sci USA 97:11377–11382PubMedCrossRef

Mack TG, Reiner M, Beirowski B et al (2001) Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nat Neurosci 4:1199–1206PubMedCrossRef

Araki T, Sasaki Y, Milbrandt J (2004) Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305:1010–1013PubMedCrossRef

Wang J, Zhai Q, Chen Y et al (2005) A local mechanism mediates NAD-dependent protection of axon degeneration. J Cell Biol 170:349–355PubMedCrossRef

10.

Sullivan KA, Hayes JM, Wiggin TD et al (2007) Mouse models of diabetic neuropathy. Neurobiol Dis 28:276–285PubMedCrossRef

11.

Kern TS, Barber AJ (2008) Retinal ganglion cells in diabetes. J Physiol 586:4401–4408PubMedCrossRef

12.

Sasaki M, Ozawa Y, Kurihara T et al (2010) Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetes. Diabetologia 53:971–979PubMedCrossRef

13.

Gillingwater TH, Ingham CA, Parry KE et al (2006) Delayed synaptic degeneration in the CNS of Wlds mice after cortical lesion. Brain 129:1546–1556PubMedCrossRef

14.

Sajadi A, Schneider BL, Aebischer P (2004) Wlds-mediated protection of dopaminergic fibers in an animal model of Parkinson disease. Curr Biol 14:326–330PubMed

15.

Samsam M, Mi W, Wessig C et al (2003) The Wlds mutation delays robust loss of motor and sensory axons in a genetic model for myelin-related axonopathy. J Neurosci 23:2833–2839PubMed

16.

Ferri A, Sanes JR, Coleman MP, Cunningham JM, Kato AC (2003) Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease. Curr Biol 13:669–673PubMedCrossRef

17.

Gillingwater TH, Haley JE, Ribchester RR, Horsburgh K (2004) Neuroprotection after transient global cerebral ischemia in Wld(s) mutant mice. J Cereb Blood Flow Metab 24:62–66PubMedCrossRef

18.

Stevens MJ, Li F, Drel VR et al (2007) Nicotinamide reverses neurological and neurovascular deficits in streptozotocin diabetic rats. J Pharmacol Exp Ther 320:458–464PubMedCrossRef

19.

Bordone L, Motta MC, Picard F et al (2006) Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 4:e31PubMedCrossRef

20.

Ramsey KM, Mills KF, Satoh A, Imai S (2008) Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell 7:78–88PubMedCrossRef

21.

Marcotte PA, Richardson PL, Guo J et al (2004) Fluorescence assay of SIRT protein deacetylases using an acetylated peptide substrate and a secondary trypsin reaction. Anal Biochem 332:90–99PubMedCrossRef

22.

Gale EA, Bingley PJ, Emmett CL, Collier T (2004) European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 363:925–931PubMedCrossRef

23.

Olmos PR, Hodgson MI, Maiz A et al (2006) Nicotinamide protected first-phase insulin response (FPIR) and prevented clinical disease in first-degree relatives of type-1 diabetics. Diabetes Res Clin Pract 71:320–333PubMedCrossRef

24.

de la Lastra CA, Villegas I, Sanchez-Fidalgo S (2007) Poly(ADP-ribose) polymerase inhibitors: new pharmacological functions and potential clinical implications. Curr Pharm Des 13:933–962PubMedCrossRef

25.

Gonzalez C, Menissier de Murcia J, Janiak P et al (2002) Unexpected sensitivity of nonobese diabetic mice with a disrupted poly(ADP-Ribose) polymerase-1 gene to streptozotocin-induced and spontaneous diabetes. Diabetes 51:1470–1476PubMedCrossRef

26.

Pieper AA, Brat DJ, Krug DK et al (1999) Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes. Proc Natl Acad Sci U S A 96:3059–3064PubMedCrossRef

27.

Drel VR, Lupachyk S, Shevalye H et al (2010) New therapeutic and biomarker discovery for peripheral diabetic neuropathy: PARP inhibitor, nitrotyrosine, and tumor necrosis factor-{alpha}. Endocrinology 151:2547–2555PubMedCrossRef

28.

Obrosova IG, Xu W, Lyzogubov VV et al (2008) PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy. Free Radic Biol Med 44:972–981PubMedCrossRef

29.

Onozaki A, Midorikawa S, Sanada H et al (2004) Rapid change of glucose concentration promotes mesangial cell proliferation via VEGF: inhibitory effects of thiazolidinedione. Biochem Biophys Res Commun 317:24–29PubMedCrossRef

30.

Zheng L, Szabo C, Kern TS (2004) Poly(ADP-ribose) polymerase is involved in the development of diabetic retinopathy via regulation of nuclear factor-kappaB. Diabetes 53:2960–2967PubMedCrossRef

31.

Boulton AJ (2004) The diabetic foot: from art to science. The 18th Camillo Golgi lecture. Diabetologia 47:1343–1353PubMedCrossRef

32.

Antonetti DA, Barber AJ, Bronson SK et al (2006) Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes 55:2401–2411PubMedCrossRef

33.

Virag L, Szabo C (2002) The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 54:375–429PubMedCrossRef

34.

Obrosova IG, Li F, Abatan OI et al (2004) Role of poly(ADP-ribose) polymerase activation in diabetic neuropathy. Diabetes 53:711–720PubMedCrossRef

35.

Jagtap P, Szabo C (2005) Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 4:421–440PubMedCrossRef

36.

Pacher P, Szabo C (2008) Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease. Am J Pathol 173:2–13PubMedCrossRef

37.

Ha HC, Hester LD, Snyder SH (2002) Poly(ADP-ribose) polymerase-1 dependence of stress-induced transcription factors and associated gene expression in glia. Proc Natl Acad Sci USA 99:3270–3275PubMedCrossRef

38.

Minchenko AG, Stevens MJ, White L et al (2003) Diabetes-induced overexpression of endothelin-1 and endothelin receptors in the rat renal cortex is mediated via poly(ADP-ribose) polymerase activation. FASEB J 17:1514–1516PubMed

39.

Du X, Matsumura T, Edelstein D et al (2003) Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest 112:1049–1057PubMed

40.

Andrabi SA, Kim NS, Yu SW et al (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci USA 103:18308–18313PubMedCrossRef

41.

Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410:227–230PubMedCrossRef

42.

Canto C, Auwerx J (2009) Caloric restriction, SIRT1 and longevity. Trends Endocrinol Metab 20:325–331PubMedCrossRef

43.

Camins A, Sureda FX, Junyent F et al (2010) Sirtuin activators: designing molecules to extend life span. Biochim Biophys Acta 1799:740–749PubMed

Titel: Wld S protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice
verfasst von: S. S. Zhu
Y. Ren
M. Zhang
J. Q. Cao
Q. Yang
X. Y. Li
H. Bai
L. Jiang
Q. Jiang
Z. G. He
Q. Chen
Publikationsdatum: 01.09.2011
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 9/2011
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-011-2226-1

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