The Contribution Of Hypertension To Diabetic Nephropathy And Retinopathy: The Role Of Inflammation And Oxidative Stress

Diabetes and hypertension frequently coexist and constitute the most notorious combination for the pathogenesis of diabetic nephropathy and retinopathy. Large clinical trials have clearly demonstrated that tight control of glycemia and/or blood pressure significantly reduces the incidence and progression of diabetic retinopathy (DR) and nephropathy. However, the mechanism by which hypertension interacts with diabetes to induce and/or exacerbate nephropathy and retinopathy is very unclear. Substantial evidence implicates the involvement of chronic inflammation and oxidative stress in the pathogenesis of DR and nephropathy. In addition, hypertension causes oxidative stress and inflammation in the kidney and retina. In the present review, we summarized data obtained from our research along with those from other groups to better understand the role of hypertension in the pathogenesis of diabetic nephropathy and retinopathy. It is suggested that oxidative stress and inflammation may be common denominators of kidney and retinal damage in the concomitant presence of diabetes and hypertension. © 2011 The Japanese Society of Hypertension All rights reserved.344413422National High Blood Pressure Education Program Working Group report on hypertension in diabetes (1994) Hypertension, 23, pp. 145-158. , AnonymousGeiss, L.S., Rolka, D.B., Engelgau, M.M., Elevated blood pressure among U.S. adults with diabetes, 1988-1994 (2002) American Journal of Preventive Medicine, 22 (1), pp. 42-48. , DOI 10.1016/S0749-3797(01)00399-3, PII S0749379701003993Jensen, T., Borch-Johnsen, K., Deckert, T., Changes in blood pressure and renal function in patients with type I (insulin-dependent) diabetes mellitus prior to clinical diabetic nephropathy (1987) Diabetes Research, 4 (4), pp. 159-162Parving, H.H., Controlling hypertension in diabetes (2002) Acta Diabetol, 39, pp. S35-S40Tarnow, L., Rossing, P., Gall, M.-A., Nielsen, F.S., Parving, H.-H., Prevalence of arterial hypertension in diabetic patients before and after the JNC-V (1994) Diabetes Care, 17 (11), pp. 1247-1251Stratton, I.M., Cull, C.A., Adler, A.I., Matthews, D.R., Neil, H.A.W., Holman, R.R., Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: A prospective observational study (UKPDS 75) (2006) Diabetologia, 49 (8), pp. 1761-1769. , DOI 10.1007/s00125-006-0297-1Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 (1998) BMJ, 317, pp. 703-713. , The UKPDS Study Group UK Prospective Diabetes Study GroupZoungas, S., De Galan, B.E., Ninomiya, T., Grobbee, D., Hamet, P., Heller, S., MacMahon, S., Travert, F., Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: New results from the ADVANCE trial (2009) Diabetes Care, 32, pp. 2068-2074. , ADVANCE Collaborative GroupGiunti, S., Barit, D., Cooper, M.E., Mechanisms of diabetic nephropathy: Role of hypertension (2006) Hypertension, 48 (4), pp. 519-526. , DOI 10.1161/01.HYP.0000240331.32352.0c, PII 0000426820061000000001Schrier, R.W., Estacio, R.O., Esler, A., Mehler, P., Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes (2002) Kidney International, 61 (3), pp. 1086-1097. , DOI 10.1046/j.1523-1755.2002.00213.xThomas, M.C., Atkins, R.C., Blood pressure lowering for the prevention and treatment of diabetic kidney disease (2006) Drugs, 66 (17), pp. 2213-2234. , http://drugs.adisonline.com/pt/re/drugs/pdfhandler.00003495-200666170- 00005.pdf;jsessionid=F1dGGhWzy9FYfgqm4hSkJ1rpXyhL5sRFrTvryFMQw0qFK3pQQsmH!- 565972194!-949856144!8091!-1, DOI 10.2165/00003495-200666170-00005Klein, R., Knudtson, M.D., Lee, K.E., Gangnon, R., Klein, B.E., The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes (2008) Ophthalmology, 115, pp. 1859-1868Klein, R., Lee, K.E., Gangnon, R.E., Klein, B.E., The 25-year incidence of visual impairment in type 1 diabetes mellitus the wisconsin epidemiologic study of diabetic retinopathy (2010) Ophthalmology, 117, pp. 63-70Rodrigues, T.C., Canani, L.H., Viatroski, R.S., Hoffmann, L.H., Esteves, J.F., Gross, J.L., Masked hypertension, nocturnal blood pressure and retinopathy in normotensive patients with type 1 diabetes (2010) Diabetes Res Clin Pract, 87, pp. 240-245Korner, A., Jaremko, G., Eklof, A.-C., Aperia, A., Rapid development of glomerulosclerosis in diabetic Dahl salt-sensitive rats (1997) Diabetologia, 40 (4), pp. 367-373. , DOI 10.1007/s001250050689Mauer, S.M., Steffes, M.W., Azar, S., The effects of Goldblatt hypertension on development of the glomerular lesions of diabetes mellitus in the rat (1978) Diabetes, 27 (7), pp. 738-744Wakisaka, M., Nunoi, K., Iwase, M., Kikuchi, M., Maki, Y., Yamamoto, K., Sadoshima, S., Fujishima, M., Early development of nephropathy in a new model of spontaneously hypertensive rat with non-insulin-dependent diabetes mellitus (1988) Diabetologia, 31, pp. 291-296Cooper, M.E., Allen, T.J., O'Brien, R.C., Macmillan, P.A., Clarke, B., Jerums, G., Doyle, A.E., Effects of genetic hypertension on diabetic nephropathy in the rat - functional and structural characteristics (1988) Journal of Hypertension, 6 (12), pp. 1009-1016. , DOI 10.1097/00004872-198812000-00009Dosso, A.A., Leuenberger, P.M., Rungger-Brandle, E., Remodeling of retinal capillaries in the diabetic hypertensive rat (1999) Investigative Ophthalmology and Visual Science, 40 (10), pp. 2405-2410Hammes, H.-P., Brownlee, M., Edelstein, D., Saleck, M., Martin, S., Federlin, K., Aminoguanidine inhibits the development of accelerated diabetic retinopathy in the spontaneous hypertensive rat (1994) Diabetologia, 37 (1), pp. 32-35Gin, T., Troy Lim Joon, Panagiotopoulos, S., Cooper, M., Taylor, H., Jerums, G., Organ specificity of antihypertensive therapy on ocular albumin vascular clearance and albuminuria in the hypertensive diabetic rat (1996) Investigative Ophthalmology and Visual Science, 37 (2), pp. 281-289Righetti, A.E., Boer-Lima, P.A., Lopes De Faria, J.B., The presence of genetic hypertension stimulates early renal accumulation of fibronectin in experimental diabetes mellitus (2001) Diabetologia, 44 (11), pp. 2088-2091. , DOI 10.1007/s001250100014Lopes De Faria, J.M., Silva, K.C., Boer, P.A., Cavalcanti, T.C., Rosales, M.A., Ferrari, A.L., Lopes De Faria, J.B., A decrease in retinal progenitor cells is associated with early features of diabetic retinopathy in a model that combines diabetes and hypertension (2008) Mol Vis, 14, pp. 1680-1691Wolf, G., Cell cycle regulation in diabetic nephropathy (2000) Kidney Int, 77, pp. S59-S66Wolf, G., Schroeder, R., Thaiss, F., Ziyadeh, F.N., Helmchen, U., Stahl, R.A.K., Glomerular expression of p27(Kip1) in diabetic db/db mouse: Role of hyperglycemia (1998) Kidney International, 53 (4), pp. 869-879. , DOI 10.1111/j.1523-1755.1998.00829.xWolf, G., Schanze, A., Stahl, R.A.K., Shankland, S.J., Amann, K., p27 Kip1 knockout mice are protected from diabetic nephropathy: Evidence for p27 Kip1 haplotype insufficiency (2005) Kidney International, 68 (4), pp. 1583-1589. , DOI 10.1111/j.1523-1755.2005.00570.x, PII 4494761Silveira, L.A., Bacchi, C.E., Pinto, G.A., Lopes De Faria, J.B., The genetics of hypertension modifies the renal cell replication response induced by experimental diabetes (2002) Diabetes, 51 (5), pp. 1529-1534Carmines, P.K., The renal vascular response to diabetes (2010) Curr Opin Nephrol Hypertens, 19, pp. 85-90Gruden, G., Zonca, S., Hayward, A., Thomas, S., Maestrini, S., Gnudi, L., Viberti, G., Mechanical stretch-induced fibronectin and transforming growth factor- β1 production in human mesangial cells is p38 mitogen-activated protein kinase-dependent (2000) Diabetes, 49 (4), pp. 655-661Rassam, S.M., Patel, V., Kohner, E.M., The effect of experimental hypertension on retinal vascular autoregulation in humans: A mechanism for the progression of diabetic retinopathy (1995) Exp Physiol, 80, pp. 53-68Aiello, L.P., Avery, R.L., Arrigg, P.G., Keyt, B.A., Jampel, H.D., Shah, S.T., Pasquale, L.R., King, G.L., Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders (1994) New England Journal of Medicine, 331 (22), pp. 1480-1487. , DOI 10.1056/NEJM199412013312203Seko, Y., Seko, Y., Fujikura, H., Pang, J., Tokoro, T., Shimokawa, H., Induction of vascular endothelial growth factor after application of mechanical stress to retinal pigment epithelium of the rat in vitro (1999) Invest Ophthalmol Vis Sci, 40, pp. 3287-3291Suzuma, I., Hata, Y., Clermont, A., Pokras, F., Rook, S.L., Suzuma, K., Feener, E.P., Aiello, L.P., Cyclic stretch and hypertension induce retinal expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2: Potential mechanisms for exacerbation of diabetic retinopathy by hypertension (2001) Diabetes, 50 (2), pp. 444-454Suzuma, I., Suzuma, K., Ueki, K., Hata, Y., Feener, E.P., King, G.L., Aiello, L.P., Stretch-induced retinal vascular endothelial growth factor expression is mediated by phosphatidylinositol 3-kinase and protein kinase C (PKC)-ζ but not by stretch-induced ERK1/2, Akt, Ras, or classical/novel PKC pathways (2002) Journal of Biological Chemistry, 277 (2), pp. 1047-1057. , DOI 10.1074/jbc.M105336200Suzuma, I., Murakami, T., Suzuma, K., Kaneto, H., Watanabe, D., Ojima, T., Honda, Y., Yoshimura, N., Cyclic stretch-induced reactive oxygen species generation enhances apoptosis in retinal pericytes through c-Jun NH2-terminal kinase activation (2007) Hypertension, 49 (2), pp. 347-354. , DOI 10.1161/01.HYP.0000253535.26659.2f, PII 0000426820070200000020Beltramo, E., Berrone, E., Giunti, S., Gruden, G., Perin, P.C., Porta, M., Effects of mechanical stress and high glucose on pericyte proliferation, apoptosis and contractile phenotype (2006) Experimental Eye Research, 83 (4), pp. 989-994. , DOI 10.1016/j.exer.2006.05.008, PII S0014483506002612Mizutani, M., Kern, T.S., Lorenzi, M., Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy (1996) Journal of Clinical Investigation, 97 (12), pp. 2883-2890Pfister, F., Feng, Y., Vom Hagen, F., Hoffmann, S., Molema, G., Hillebrands, J.L., Shani, M., Hammes, H.P., Pericyte migration: A novel mechanism of pericyte loss in experimental diabetic retinopathy (2008) Diabetes, 57, pp. 2495-2502Yasuda, T., Kondo, S., Homma, T., Harris, R.C., Regulation of extracellular matrix by mechanical stress in rat glomerular mesangial cells (1996) Journal of Clinical Investigation, 98 (9), pp. 1991-2000Cortes, P., Zhao, X., Riser, B.L., Narins, R.G., Role of glomerular mechanical strain in the pathogenesis of diabetic nephropathy (1997) Kidney International, 51 (1), pp. 57-68Riser, B.L., Ladson-Wofford, S., Sharba, A., Cortes, P., Drake, K., Guerin, C.J., Jerry, Y., Narins, R.G., TGF-β receptor expression and binding in rat mesangial cells: Modulation by glucose and cyclic mechanical strain (1999) Kidney International, 56 (2), pp. 428-439. , DOI 10.1046/j.1523-1755.1999.00600.xRiser, B.L., Denichilo, M., Cortes, P., Baker, C., Grondin, J.M., Yee, J., Narins, R.G., Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis (2000) Journal of the American Society of Nephrology, 11 (1), pp. 25-38Giunti, S., Pinach, S., Arnaldi, L., Viberti, G., Perin, P.C., Camussi, G., Gruden, G., The MCP-1/ CCR2 system has direct proinflammatory effects in human mesangial cells (2006) Kidney Int, 69, pp. 856-863Gruden, G., Setti, G., Hayward, A., Sugden, D., Duggan, S., Burt, D., Buckingham, R.E., Viberti, G., Mechanical stretch induces monocyte chemoattractant activity via an NF-κB-dependent monocyte chemoattractant protein-1-mediated pathway in human mesangial cells: Inhibition by rosiglitazone (2005) Journal of the American Society of Nephrology, 16 (3), pp. 688-696. , DOI 10.1681/ASN.2004030251Kuroiwa, T., Lee, E.G., Danning, C.L., Illei, G.G., McInnes, I.B., Boumpas, D.T., CD40 ligand-activated human monocytes amplify glomerular inflammatory responses through soluble and cell-to-cell contact-dependent mechanisms (1999) Journal of Immunology, 163 (4), pp. 2168-2175Mene, P., Pugliese, F., Cinotti, G.A., Adhesion of U-937 monocytes induces cytotoxic damage and subsequent proliferation of cultured human mesangial cells (1996) Kidney International, 50 (2), pp. 417-423Gruden, G., Thomas, S., Burt, D., Zhou, W., Chusney, G., Gnudi, L., Viberti, G., Interaction of angiotensin II and mechanical stretch on vascular endothelial growth factor production by human mesangial cells (1999) Journal of the American Society of Nephrology, 10 (4), pp. 730-737Thomas, S., Vanuystel, J., Gruden, G., Rodriguez, V., Burt, D., Gnudi, L., Hartley, B., Viberti, G., Vascular endothelial growth factor receptors in human mesangium in vitro and in glomerular disease (2000) Journal of the American Society of Nephrology, 11 (7), pp. 1236-1243Amemiya, T., Sasamura, H., Mifune, M., Kitamura, Y., Hirahashi, J., Hayashi, M., Saruta, T., Vascular endothelial growth factor activates MAP kinase and enhances collagen synthesis in human mesangial cells (1999) Kidney International, 56 (6), pp. 2055-2063. , DOI 10.1046/j.1523-1755.1999.00796.xGnudi, L., Viberti, G.C., Raij, L., Rodriguez, V., Burt, D., Cortes, P., Hartley, B., Gruden, G., GLUT-1 overexpression: Link between hemodynamic and metabolic factors in glomerular injury? (2003) Hypertension, 42 (1), pp. 19-24. , DOI 10.1161/01.HYP.0000075949.19968.EFHeilig, C.W., Concepcion, L.A., Riser, B.L., Freytag, S.O., Zhu, M., Cortes, P., Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype (1995) J Clin Invest, 96, pp. 1802-1814Shankland, S.J., The podocyte's response to injury: Role in proteinuria and glomerulosclerosis (2006) Kidney International, 69 (12), pp. 2131-2147. , DOI 10.1038/sj.ki.5000410, PII 5000410White, K.E., Bilous, R.W., Cordonnier, D.J., Pinel, N., Barro, C., Halimi, S., Chopinet, P., Mezin, P., Structural alterations to the podocyte are related to proteinuria in type 2 diabetic patients (2004) Nephrology Dialysis Transplantation, 19 (6), pp. 1437-1440. , DOI 10.1093/ndt/gfh129Endlich, N., Kress, K.R., Reiser, J., Uttenweiler, D., Kriz, W., Mundel, P., Endlich, K., Podocytes respond to mechanical stress in vitro (2001) Journal of the American Society of Nephrology, 12 (3), pp. 413-422Endlich, N., Endlich, K., Stretch, tension and adhesion- adaptive mechanisms of the actin cytoskeleton in podocytes (2006) Eur J Cell Biol, 85, pp. 229-234Dessapt, C., Baradez, M.O., Hayward, A., Dei Cas, A., Thomas, S.M., Viberti, G., Gnudi, L., Mechanical forces and TGFbeta1 reduce podocyte adhesion through alpha3beta1 integrin downregulation (2009) Nephrol Dial Transplant, 24, pp. 2645-2655Patey, N., Halbwachs-Mecarelli, L., Droz, D., Lesavre, P., Noel, L.H., Distribution of integrin subunits in normal human kidney (1994) Cell Adhesion and Communication, 2 (2), pp. 159-167Ruoslahti, E., Integrins (1991) J Clin Invest, 87, pp. 1-5Durvasula, R.V., Shankland, S.J., Activation of a local renin angiotensin system in podocytes by glucose (2008) Am J Physiol Renal Physiol, 294, pp. F830-F839Durvasula, R.V., Petermann, A.T., Hiromura, K., Blonski, M., Pippin, J., Mundel, P., Pichler, R., Shankland, S.J., Activation of a local tissue angiotensin system in podocytes by mechanical strain (2004) Kidney International, 65 (1), pp. 30-39. , DOI 10.1111/j.1523-1755.2004.00362.xMiceli, I., Burt, D., Tarabra, E., Camussi, G., Perin, P.C., Gruden, G., Stretch reduces nephrin expression via an angiotensin II-AT(1)-dependent mechanism in human podocytes: Effect of rosiglitazone (2010) Am J Physiol Renal Physiol, 298, pp. F381-F390Doublier, S., Salvidio, G., Lupia, E., Ruotsalainen, V., Verzola, D., Deferrari, G., Camussi, G., Nephrin expression is reduced in human diabetic nephropathy: Evidence for a distinct role for glycated albumin and angiotensin II (2003) Diabetes, 52 (4), pp. 1023-1030. , DOI 10.2337/diabetes.52.4.1023Bonnet, F., Cooper, M.E., Kawachi, H., Allen, T.J., Boner, G., Cao, Z., Irbesartan normalises the deficiency in glomerular nephrin expression in a model of diabetes and hypertension (2001) Diabetologia, 44 (7), pp. 874-877. , DOI 10.1007/s001250100546Amazonas, R.B., Sanita Rde, A., Kawachi, H., De Faria, J.B., Prevention of hypertension with or without renin-angiotensin system inhibition precludes nephrin loss in the early stage of experimental diabetes mellitus (2007) Nephron Physiol, 107, pp. 57-64Gorin, Y., Block, K., Hernandez, J., Bhandari, B., Wagner, B., Barnes, J.L., Abboud, H.E., Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney (2005) Journal of Biological Chemistry, 280 (47), pp. 39616-39626. , DOI 10.1074/jbc.M502412200Susztak, K., Raff, A.C., Schiffer, M., Bottinger, E.P., Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy (2006) Diabetes, 55 (1), pp. 225-233. , http://diabetes.diabetesjournals.org/cgi/reprint/55/1/225, DOI 10.2337/diabetes.55.1.225Brownlee, M., The pathobiology of diabetic complications: A unifying mechanism (2005) Diabetes, 54 (6), pp. 1615-1625. , DOI 10.2337/diabetes.54.6.1615Jones, D.P., Redefining oxidative stress (2006) Antioxidants and Redox Signaling, 8 (9-10), pp. 1865-1879. , DOI 10.1089/ars.2006.8.1865Halliwell, B., Whiteman, M., Measuring reactive species and oxidative damage in vivo and in cell culture: How should you do it and what do the results mean? (2004) British Journal of Pharmacology, 142 (2), pp. 231-255. , DOI 10.1038/sj.bjp.0705776Hinokio, Y., Suzuki, S., Hirai, M., Chiba, M., Hirai, A., Toyota, T., Oxidative DNA damage in diabetes mellitus: Its association with diabetic complications (1999) Diabetologia, 42 (8), pp. 995-998. , DOI 10.1007/s001250051258Nishikawa, T., Sasahara, T., Kiritoshi, S., Sonoda, K., Senokuchi, T., Matsuo, T., Kukidome, D., Araki, E., Evaluation of urinary 8-hydroxydeoxy-guanosine as a novel biomarker of macrovascular complications in type 2 diabetes (2003) Diabetes Care, 26 (5), pp. 1507-1512. , DOI 10.2337/diacare.26.5.1507Hinokio, Y., Suzuki, S., Hirai, M., Suzuki, C., Suzuki, M., Toyota, T., Urinary excretion of 8-oxo-7, 8-dihydro-2¢-deoxyguanosine as a predictor of the development of diabetic nephro-pathy (2002) Diabetologia, 45, pp. 877-882Wang, Q., Pfister, F., Dorn-Beineke, A., Vom Hagen, F., Lin, J., Feng, Y., Hammes, H.P., Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina (2010) Diabetologia, 53, pp. 1227-1238Furuta, T., Saito, T., Ootaka, T., Soma, J., Obara, K., Abe, K., Yoshinaga, K., The role of macrophages in diabetic glomerulosclerosis (1993) American Journal of Kidney Diseases, 21 (5), pp. 480-485Utimura, R., Fujihara, C.K., Mattar, A.L., Malheiros, D.M.A.C., Noronha, I.D.L., Zatz, R., Mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes (2003) Kidney International, 63 (1), pp. 209-216. , DOI 10.1046/j.1523-1755.2003.00736.xTone, A., Shikata, K., Sasaki, M., Ohga, S., Yozai, K., Nishishita, S., Usui, H., Makino, H., Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats (2005) Diabetologia, 48 (11), pp. 2402-2411. , DOI 10.1007/s00125-005-1945-6Yozai, K., Shikata, K., Sasaki, M., Tone, A., Ohga, S., Usui, H., Okada, S., Makino, H., Methotrexate prevents renal injury in experimental diabetic rats via anti-inflammatory actions (2005) Journal of the American Society of Nephrology, 16 (11), pp. 3326-3338. , DOI 10.1681/ASN.2004111011Okada, S., Shikata, K., Matsuda, M., Ogawa, D., Usui, H., Kido, Y., Nagase, R., Makino, H., Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes (2003) Diabetes, 52 (10), pp. 2586-2593. , DOI 10.2337/diabetes.52.10.2586Chow, F.Y., Nikolic-Paterson, D.J., Ozols, E., Atkins, R.C., Rollin, B.J., Tesch, G.H., Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice (2006) Kidney International, 69 (1), pp. 73-80. , DOI 10.1038/sj.ki.5000014, PII 5000014Kern, T.S., Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy (2007) Exp Diabetes Res, 2007, p. 95103McLeod, D.S., Lefer, D.J., Merges, C., Lutty, G.A., Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid (1995) Am J Pathol, 147, pp. 642-653Limb, G.A., Hickman-Casey, J., Hollifield, R.D., Chignell, A.H., Vascular adhesion molecules in vitreous from eyes with proliferative diabetic retinopathy (1999) Investigative Ophthalmology and Visual Science, 40 (10), pp. 2453-2457Hernandez, C., Segura, R.M., Fonollosa, A., Carrasco, E., Francisco, G., Simo, R., Interleukin-8, monocyte chemoattractant protein-1 and IL-10 in the vitreous fluid of patients with proliferative diabetic retinopathy (2005) Diabetic Medicine, 22 (6), pp. 719-722. , DOI 10.1111/j.1464-5491.2005.01538.xSilva, K.C., Pinto, C.C., Biswas, S.K., Souza, D.S., Lopes De Faria, J.B., Lopes De Faria, J.M., Prevention of hypertension abrogates early inflammatory events in the retina of diabetic hypertensive rats (2007) Experimental Eye Research, 85 (1), pp. 123-129. , DOI 10.1016/j.exer.2007.03.008, PII S0014483507000899Calcutt, N.A., Cooper, M.E., Kern, T.S., Schmidt, A.M., Therapies for hyperglycaemia