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01.10.2011 | Article

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

verfasst von: J. L. Wilkinson-Berka, G. Tan, K. J. Binger, L. Sutton, K. McMaster, D. Deliyanti, G. Perera, D. J. Campbell, A. G. Miller

Erschienen in: Diabetologia | Ausgabe 10/2011

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Abstract

Aim/hypothesis

We examined whether the renin inhibitor, aliskiren, provides similar or greater protection than ACE inhibition from non-proliferative diabetic retinopathy and from the proliferative neoangiogenesis of oxygen-induced retinopathy.

Methods

Transgenic (mRen-2)27 rats, which overexpress mouse renin and angiotensin in extra-renal tissues, were studied. For diabetic studies, non-diabetic, diabetic (streptozotocin, 55 mg/kg), diabetic + aliskiren (10 mg kg⁻¹ day⁻¹, pump), or diabetic + lisinopril (10 mg kg⁻¹ day⁻¹, drinking water) rats were evaluated over 16 weeks. For oxygen-induced retinopathy studies, rats were exposed to 80% oxygen (22 h/day) from postnatal days 0 to 11, and then room air from postnatal days 12 to 18. Aliskiren (10 or 30 mg kg⁻¹ day⁻¹, pump) or lisinopril (10 mg kg⁻¹ day⁻¹, drinking water) was administered during retinopathy development between postnatal days 12 and 18.

Results

Systolic BP in diabetic (mRen-2)27 rats was reduced with 10 mg kg⁻¹ day⁻¹ aliskiren, but only lisinopril normalised systolic blood pressure. In diabetic (mRen-2)27 rats, 10 mg kg⁻¹ day⁻¹ aliskiren and lisinopril reduced retinal acellular capillaries and leucostasis to non-diabetic levels. In oxygen-induced retinopathy, neoangiogenesis and retinal inflammation (leucostasis, ED-1 immunolabelling) were partially reduced by 10 mg kg⁻¹ day⁻¹ aliskiren and normalised by 30 mg kg⁻¹ day⁻¹ aliskiren, whereas lisinopril normalised neoangiogenesis and reduced leucostasis and ED-1 immunolabelling. Aliskiren and lisinopril normalised retinal vascular endothelial growth factor expression; however, only aliskiren reduced intercellular adhesion molecule-1 to control levels.

Conclusions/interpretation

Aliskiren provided similar or greater retinal protection than ACE inhibition and may be a potential treatment for diabetic retinopathy.

Simo R, Hernandez C (2009) Advances in the medical treatment of diabetic retinopathy. Diabetes Care 32:1556–1562PubMedCrossRef

Berka JL, Stubbs AJ, Wang DZ et al (1995) Renin-containing Muller cells of the retina display endocrine features. Invest Ophthalmol Vis Sci 36:1450–1458PubMed

Sarlos S, Wilkinson-Berka JL (2005) The renin–angiotensin system and the developing retinal vasculature. Invest Ophthalmol Vis Sci 46:1069–1077PubMedCrossRef

Wagner J, Jan Danser AH, Derkx FH et al (1996) Demonstration of renin mRNA, angiotensinogen mRNA, and angiotensin converting enzyme mRNA expression in the human eye: evidence for an intraocular renin–angiotensin system. Br J Ophthalmol 80:159–163PubMedCrossRef

Luetscher JA, Kraemer FB, Wilson DM, Schwartz HC, Bryer-Ash M (1985) Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications. N Engl J Med 312:1412–1417PubMedCrossRef

Danser AH, van den Dorpel MA, Deinum J et al (1989) Renin, prorenin, and immunoreactive renin in vitreous fluid from eyes with and without diabetic retinopathy. J Clin Endocrinol Metab 68:160–167PubMedCrossRef

Moravski CJ, Kelly DJ, Cooper ME et al (2000) Retinal neovascularization is prevented by blockade of the renin–angiotensin system. Hypertension 36:1099–1104PubMed

Moravski CJ, Skinner SL, Stubbs AJ et al (2003) The renin–angiotensin system influences ocular endothelial cell proliferation in diabetes: transgenic and interventional studies. Am J Pathol 162:151–160PubMedCrossRef

Wilkinson-Berka JL, Tan G, Jaworski K, Miller AG (2009) Identification of a retinal aldosterone system and the protective effects of mineralocorticoid receptor antagonism on retinal vascular pathology. Circ Res 104:124–133PubMedCrossRef

10.

Zhang JZ, Xi X, Gao L, Kern TS (2007) Captopril inhibits capillary degeneration in the early stages of diabetic retinopathy. Curr Eye Res 32:883–889PubMedCrossRef

11.

Miller AG, Tan G, Binger KJ et al (2010) Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-I function. Diabetes 59:3208–3215PubMedCrossRef

12.

Chaturvedi N, Porta M, Klein R et al (2008) Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 372:1394–1402PubMedCrossRef

13.

Sjolie AK, Klein R, Porta M et al (2008) Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet 372:1385–1393PubMedCrossRef

14.

Mauer M, Zinman B, Gardiner R et al (2009) Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 361:40–51PubMedCrossRef

15.

United Kingdom Prospective Diabetes Study Group (1998) Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 317:713–720

16.

Estacio RO, Jeffers BW, Gifford N, Schrier RW (2000) Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 23(Suppl 2):B54–B64PubMed

17.

Patel A, MacMahon S, Chalmers J et al (2007) Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370:829–840PubMedCrossRef

18.

Feldman DL, Jin L, Xuan H et al (2008) Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension 52:130–136PubMedCrossRef

19.

Kelly DJ, Zhang Y, Moe G, Naik G, Gilbert RE (2007) Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats. Diabetologia 50:2398–2404PubMedCrossRef

20.

Mullins JJ, Peters J, Ganten D (1990) Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 344:541–544PubMedCrossRef

21.

Kelly DJ, Skinner SL, Gilbert RE, Cox AJ, Cooper ME, Wilkinson-Berka JL (2000) Effects of endothelin or angiotensin II receptor blockade on diabetes in the transgenic (mRen-2)27 rat. Kidney Int 57:1882–1894PubMedCrossRef

22.

Penn JS, Tolman BL, Henry MM (1994) Oxygen-induced retinopathy in the rat: relationship of retinal nonperfusion to subsequent neovascularization. Invest Ophthalmol Vis Sci 35:3429–3435PubMed

23.

Smith LE, Wesolowski E, McLellan A et al (1994) Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 35:101–111PubMed

24.

Wilkinson-Berka JL, Tan G, Jaworski K, Ninkovic S (2007) Valsartan but not atenolol improves vascular pathology in diabetic Ren-2 rat retina. Am J Hypertens 20:423–430PubMedCrossRef

25.

Wilkinson-Berka JL, Heine R, Tan G et al (2010) RILLKKMPSV influences the vasculature, neurons and glia, and (pro)renin receptor expression in the retina. Hypertension 55:1454–1460PubMedCrossRef

26.

Campbell DJ, Lawrence AC, Towrie A, Kladis A, Valentijn AJ (1991) Differential regulation of angiotensin peptide levels in plasma and kidney of the rat. Hypertension 18:763–773PubMed

27.

Campbell DJ (2008) Interpretation of plasma renin concentration in patients receiving aliskiren therapy. Hypertension 51:15–18PubMedCrossRef

28.

Kern TS, Miller CM, Du Y et al (2007) Topical administration of nepafenac inhibits diabetes-induced retinal microvascular disease and underlying abnormalities of retinal metabolism and physiology. Diabetes 56:373–379PubMedCrossRef

29.

Ishida S, Yamashiro K, Usui T et al (2003) Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease. Nat Med 9:781–788PubMedCrossRef

30.

Nussberger J, Aubert JF, Bouzourene K, Pellegrin M, Hayoz D, Mazzolai L (2008) Renin inhibition by aliskiren prevents atherosclerosis progression: comparison with irbesartan, atenolol, and amlodipine. Hypertension 51:1306–1311PubMedCrossRef

31.

Ino J, Kojima C, Osaka M, Nitta K, Yoshida M (2009) Dynamic observation of mechanically-injured mouse femoral artery reveals an antiinflammatory effect of renin inhibitor. Arterioscler Thromb Vasc Biol 29:1858–1863PubMedCrossRef

32.

Stegbauer J, Lee DH, Seubert S et al (2009) Role of the renin–angiotensin system in autoimmune inflammation of the central nervous system. Proc Natl Acad Sci USA 106:14942–14947PubMedCrossRef

33.

Cardillo Piccolino F, Zingirian M, Mosci C (1987) Classification of proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 225:245–250PubMedCrossRef

34.

Engerman RL, Kern TS (1995) Retinopathy in animal models of diabetes. Diabetes Metab Rev 11:109–120PubMedCrossRef

35.

Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner EM (2004) Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol 122:1631–1640PubMedCrossRef

36.

Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK (2008) Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 358:2433–2446PubMedCrossRef

37.

Westermann D, Riad A, Lettau O et al (2008) Renin inhibition improves cardiac function and remodeling after myocardial infarction independent of blood pressure. Hypertension 52:1068–1075PubMedCrossRef

38.

Phipps JA, Wilkinson-Berka JL, Fletcher EL (2007) Retinal dysfunction in diabetic ren-2 rats is ameliorated by treatment with valsartan but not atenolol. Invest Ophthalmol Vis Sci 48:927–934PubMedCrossRef

39.

Ristori C, Filippi L, Dal Monte M et al (2011) Role of the adrenergic system in a mouse model of oxygen-induced retinopathy: antiangiogenic effects of beta-adrenoreceptor blockade. Invest Ophthalmol Vis Sci 52:155–170PubMedCrossRef

40.

Lieth E, Barber AJ, Xu B et al (1998) Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. Penn State Retina Research Group. Diabetes 47:815–820PubMedCrossRef

41.

Liu K, Akula JD, Hansen RM, Moskowitz A, Kleinman MS, Fulton AB (2006) Development of the electroretinographic oscillatory potentials in normal and ROP rats. Invest Ophthalmol Vis Sci 47:5447–5452PubMedCrossRef

42.

Fletcher EL, Phipps JA, Ward MM, Vessey KA, Wilkinson-Berka JL (2010) The renin–angiotensin system in retinal health and disease: its influence on neurons, glia and the vasculature. Prog Retin Eye Res 29:284–311PubMedCrossRef

43.

Kurihara T, Ozawa Y, Nagai N et al (2008) Angiotensin II type 1 receptor signaling contributes to synaptophysin degradation and neuronal dysfunction in the diabetic retina. Diabetes 57:2191–2198PubMedCrossRef

44.

Silva KC, Rosales MA, Biswas SK, Lopes de Faria JB, Lopes de Faria JM (2009) Diabetic retinal neurodegeneration is associated with mitochondrial oxidative stress and is improved by an angiotensin receptor blocker in a model combining hypertension and diabetes. Diabetes 58:1382–1390PubMedCrossRef

45.

Downie LE, Pianta MJ, Vingrys AJ, Wilkinson-Berka JL, Fletcher EL (2008) AT1 receptor inhibition prevents astrocyte degeneration and restores vascular growth in oxygen-induced retinopathy. Glia 56:1076–1090PubMedCrossRef

46.

Downie LE, Hatzopoulos KM, Pianta MJ et al (2010) Angiotensin type-1 receptor inhibition is neuroprotective to amacrine cells in a rat model of retinopathy of prematurity. J Comp Neurol 518:41–63PubMedCrossRef

47.

Campbell DJ, Kelly DJ, Wilkinson-Berka JL, Cooper ME, Skinner SL (1999) Increased bradykinin and “normal” angiotensin peptide levels in diabetic Sprague–Dawley and transgenic (mRen-2)27 rats. Kidney Int 56:211–221PubMedCrossRef

48.

Campbell DJ, Rong P, Kladis A, Rees B, Ganten D, Skinner SL (1995) Angiotensin and bradykinin peptides in the TGR(mRen-2)27 rat. Hypertension 25:1014–1020PubMed

49.

Tokita Y, Franco-Saenz R, Mulrow PJ (1995) Reversal of the suppressed kidney renin level in the hypertensive transgenic rat TGR(mRen-2)27 by angiotensin converting enzyme inhibition. Am J Hypertens 8:1031–1039PubMedCrossRef

50.

Pilz B, Shagdarsuren E, Wellner M et al (2005) Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension 46:569–576PubMedCrossRef

Titel: Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat
verfasst von: J. L. Wilkinson-Berka
G. Tan
K. J. Binger
L. Sutton
K. McMaster
D. Deliyanti
G. Perera
D. J. Campbell
A. G. Miller
Publikationsdatum: 01.10.2011
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 10/2011
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-011-2239-9

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