Pathogenesis of Microvascular Complications

  • Mogher Khamaisi
  • George L. KingEmail author
  • Kyoungmin Park
  • Qian Li
Reference work entry
Part of the Endocrinology book series (ENDOCR)


Risk factors and protective factors in diabetic microvascular complication.


Advanced glycation end products (AGE) Reactive oxygen species (ROS) Protein kinase C (PKC) Vascular endothelial growth factor (VEGF) Activated protein C (APC) Platelet-derived growth factor (PDGF) Transforming growth factor b (TGF) Heme qxygenase-1 (HO-1) 



The authors would like to acknowledge funding from the Juvenile Diabetes Research Foundation grant 17-2011-474, National Institutes of Health grants 5 R01 DK053105-12, 5 R24 DK090961-02, 1 DP3 DK094333-01, NIH Diabetes Research Center 2 P30 DK036836-26A1, ADA mentor-based fellowship.


  1. Abdouh M, Khanjari A, Abdelazziz N, Ongali B, Couture R, Hassessian HM. Early upregulation of kinin B1 receptors in retinal microvessels of the streptozotocin-diabetic rat. Br J Pharmacol. 2003;140:33–40.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Abdouh M, Talbot S, Couture R, Hassessian HM. Retinal plasma extravasation in streptozotocin-diabetic rats mediated by kinin B(1) and B(2) receptors. Br J Pharmacol. 2008;154:136–43.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Aicher A, Brenner W, Zuhayra M, Badorff C, Massoudi S, Assmus B, Eckey T, Henze E, Zeiher AM, Dimmeler S. Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation. 2003;107:2134–9.PubMedCrossRefPubMedCentralGoogle Scholar
  4. Aiello LM, Cavallerano J. Diabetic retinopathy. Curr Ther Endocrinol Metab. 1997;6:475–85.PubMedPubMedCentralGoogle Scholar
  5. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–7.PubMedCrossRefPubMedCentralGoogle Scholar
  6. Aiello LP, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL 3rd, Klein R. Diabetic retinopathy. Diabetes Care. 1998;21:143–56.PubMedCrossRefPubMedCentralGoogle Scholar
  7. Aiello LP, Davis MD, Girach A, Kles KA, Milton RC, Sheetz MJ, Vignati L, Zhi XE. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology. 2006;113:2221–30.PubMedCrossRefPubMedCentralGoogle Scholar
  8. Aiello LP, Vignati L, Sheetz MJ, Zhi X, Girach A, Davis MD, Wolka AM, Shahri N, Milton RC. Oral protein kinase c beta inhibition using ruboxistaurin: efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the Protein Kinase C beta Inhibitor-Diabetic Retinopathy Study and the Protein Kinase C beta Inhibitor-Diabetic Retinopathy Study 2. Retina. 2011;31:2084–94.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Araki S, Haneda M, Sugimoto T, Isono M, Isshiki K, Kashiwagi A, Koya D. Polymorphisms of the protein kinase C-beta gene (PRKCB1) accelerate kidney disease in type 2 diabetes without overt proteinuria. Diabetes Care. 2006;29:864–8.PubMedCrossRefPubMedCentralGoogle Scholar
  10. Artwohl M, Brunmair B, Furnsinn C, Holzenbein T, Rainer G, Freudenthaler A, Porod EM, Huttary N, Baumgartner-Parzer SM. Insulin does not regulate glucose transport and metabolism in human endothelium. Eur J Clin Investig. 2007;37:643–50.CrossRefGoogle Scholar
  11. Ayo SH, Radnik R, Garoni JA, Troyer DA, Kreisberg JI. High glucose increases diacylglycerol mass and activates protein kinase C in mesangial cell cultures. Am J Phys. 1991;261:F571–7.Google Scholar
  12. Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes. 2003;52:2110–20.PubMedCrossRefPubMedCentralGoogle Scholar
  13. Babazono T, Kapor-Drezgic J, Dlugosz JA, Whiteside C. Altered expression and subcellular localization of diacylglycerol-sensitive protein kinase C isoforms in diabetic rat glomerular cells. Diabetes. 1998;47:668–76.PubMedCrossRefPubMedCentralGoogle Scholar
  14. Bautch VL. Stem cells and the vasculature. Nat Med. 2011;17:1437–43.PubMedCrossRefPubMedCentralGoogle Scholar
  15. Boyd A, Casselini C, Vinik E, Vinik A. Quality of life and objective measures of diabetic neuropathy in a prospective placebo-controlled trial of ruboxistaurin and topiramate. J Diabetes Sci Technol. 2011;5:714–22.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Brovkovych V, Zhang Y, Brovkovych S, Minshall RD, Skidgel RA. A novel pathway for receptor-mediated post-translational activation of inducible nitric oxide synthase. J Cell Mol Med. 2011;15:258–69.PubMedCrossRefPubMedCentralGoogle Scholar
  17. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–20.PubMedCrossRefPubMedCentralGoogle Scholar
  18. Burg MB, Kador PF. Sorbitol, osmoregulation, and the complications of diabetes. J Clin Invest. 1988;81:635–40.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Burnier M, Zanchi A. Blockade of the renin-angiotensin-aldosterone system: a key therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes. J Hypertens. 2006;24:11–25.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Bursell SE, Takagi C, Clermont AC, Takagi H, Mori F, Ishii H, King GL. Specific retinal diacylglycerol and protein kinase C beta isoform modulation mimics abnormal retinal hemodynamics in diabetic rats. Invest Ophthalmol Vis Sci. 1997;38:2711–20.PubMedPubMedCentralGoogle Scholar
  21. Busik JV, Tikhonenko M, Bhatwadekar A, Opreanu M, Yakubova N, Caballero S, Player D, Nakagawa T, Afzal A, Kielczewski J, Sochacki A, Hasty S, Li Calzi S, Kim S, Duclas SK, Segal MS, Guberski DL, Esselman WJ, Boulton ME, Grant MB. Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock. J Exp Med. 2009;206:2897–906.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Busse R, Fleming I. Molecular responses of endothelial tissue to kinins. Diabetes. 1996;45(Suppl 1):S8–13.PubMedCrossRefPubMedCentralGoogle Scholar
  23. Cameron NE, Cotter MA. Effects of protein kinase Cbeta inhibition on neurovascular dysfunction in diabetic rats: interaction with oxidative stress and essential fatty acid dysmetabolism. Diabetes Metab Res Rev. 2002;18:315–23.PubMedCrossRefPubMedCentralGoogle Scholar
  24. Cameron NE, Eaton SE, Cotter MA, Tesfaye S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia. 2001;44:1973–88.PubMedCrossRefPubMedCentralGoogle Scholar
  25. Casellini CM, Barlow PM, Rice AL, Casey M, Simmons K, Pittenger G, Bastyr EJ 3rd, Wolka AM, Vinik AI. A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-beta inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy. Diabetes Care. 2007;30:896–902.PubMedCrossRefPubMedCentralGoogle Scholar
  26. Catanzaro O, Labal E, Andornino A, Capponi JA, Di Martino I, Sirois P. Blockade of early and late retinal biochemical alterations associated with diabetes development by the selective bradykinin B1 receptor antagonist R-954. Peptides. 2012;34:349–52.PubMedCrossRefPubMedCentralGoogle Scholar
  27. Chen S, Ziyadeh FN. Vascular endothelial growth factor and diabetic nephropathy. Curr Diab Rep. 2008;8:470–6.PubMedCrossRefPubMedCentralGoogle Scholar
  28. Chen CY, Abell AM, Moon YS, Kim KH. An advanced glycation end product (AGE)-receptor for AGEs (RAGE) axis restores adipogenic potential of senescent preadipocytes through modulation of p53 protein function. J Biol Chem. 2012;287:44498–507.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Chen YT, Cheng BC, Ko SF, Chen CH, Tsai TH, Leu S, Chang HW, Chung SY, Chua S, Yeh KH, Chen YL, Yip HK. Value and level of circulating endothelial progenitor cells, angiogenesis factors and mononuclear cell apoptosis in patients with chronic kidney disease. Clin Exp Nephrol. 2013;17:83–91.PubMedCrossRefPubMedCentralGoogle Scholar
  30. Chou E, Suzuma I, Way KJ, Opland D, Clermont AC, Naruse K, Suzuma K, Bowling NL, Vlahos CJ, Aiello LP, King GL. Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states: a possible explanation for impaired collateral formation in cardiac tissue. Circulation. 2002;105:373–9.PubMedCrossRefPubMedCentralGoogle Scholar
  31. Clermont A, Chilcote TJ, Kita T, Liu J, Riva P, Sinha S, Feener EP. Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats. Diabetes. 2011;60:1590–8.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Cotter MA, Cameron NE. Effect of the NAD(P)H oxidase inhibitor, apocynin, on peripheral nerve perfusion and function in diabetic rats. Life Sci. 2003;73:1813–24.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Danis RP, Bingaman DP, Jirousek M, Yang Y. Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY333531. Invest Ophthalmol Vis Sci. 1998;39:171–9.PubMedPubMedCentralGoogle Scholar
  34. de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, Goldsberry A, Houser M, Krauth M, Lambers Heerspink HJ, McMurray JJ, Meyer CJ, Parving HH, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Wittes J, Wrolstad D, Chertow GM. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013a;369:2492–503.PubMedPubMedCentralCrossRefGoogle Scholar
  35. de Zeeuw D, Akizawa T, Agarwal R, Audhya P, Bakris GL, Chin M, Krauth M, Lambers Heerspink HJ, Meyer CJ, McMurray JJ, Parving HH, Pergola PE, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Warnock DG, Wittes J, Chertow GM. Rationale and trial design of bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes: the occurrence of renal events (BEACON). Am J Nephrol. 2013b;37:212–22.PubMedCrossRefPubMedCentralGoogle Scholar
  36. Demaine AG. Polymorphisms of the aldose reductase gene and susceptibility to diabetic microvascular complications. Curr Med Chem. 2003;10:1389–98.PubMedCrossRefPubMedCentralGoogle Scholar
  37. Dhondt J, Peeraer E, Verheyen A, Nuydens R, Buysschaert I, Poesen K, Van Geyte K, Beerens M, Shibuya M, Haigh JJ, Meert T, Carmeliet P, Lambrechts D. Neuronal FLT1 receptor and its selective ligand VEGF-B protect against retrograde degeneration of sensory neurons. FASEB J. 2011;25:1461–73.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular outcomes in type 1 diabetes: The DCCT/EDIC study 30-year follow-up. Diabetes Care. 2016;39:686–93.CrossRefGoogle Scholar
  39. Dorrell MI, Aguilar E, Jacobson R, Trauger SA, Friedlander J, Siuzdak G, Friedlander M. Maintaining retinal astrocytes normalizes revascularization and prevents vascular pathology associated with oxygen-induced retinopathy. Glia. 2010;58:43–54.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Du X, Matsumura T, Edelstein D, Rossetti L, Zsengeller Z, Szabo C, Brownlee M. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 2003;112:1049–57.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O’Brien PC, Melton LJ 3rd, Service FJ. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993;43:817–24.PubMedCrossRefGoogle Scholar
  42. Eichberg J. Protein kinase C changes in diabetes: is the concept relevant to neuropathy? Int Rev Neurobiol. 2002;50:61–82.PubMedCrossRefPubMedCentralGoogle Scholar
  43. Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH, Quaggin SE. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest. 2003;111:707–16.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Fallahzadeh MK, Dormanesh B, Sagheb MM, Roozbeh J, Vessal G, Pakfetrat M, Daneshbod Y, Kamali-Sarvestani E, Lankarani KB. Effect of addition of silymarin to renin-angiotensin system inhibitors on proteinuria in type 2 diabetic patients with overt nephropathy: a randomized, double-blind, placebo-controlled trial. Am J Kidney Dis. 2012;60:896–903.PubMedCrossRefPubMedCentralGoogle Scholar
  45. Feener EP, Zhou Q, Fickweiler W. Role of plasma kallikrein in diabetes and metabolism. Thromb Haemost. 2013;110:434–41.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Fleming TH, Humpert PM, Nawroth PP, Bierhaus A. Reactive metabolites and AGE/RAGE-mediated cellular dysfunction affect the aging process: a mini-review. Gerontology. 2011;57:435–43.PubMedPubMedCentralGoogle Scholar
  47. Foster MC, Hwang SJ, Larson MG, Lichtman JH, Parikh NI, Vasan RS, Levy D, Fox CS. Overweight, obesity, and the development of stage 3 CKD: the Framingham Heart Study. Am J Kidney Dis. 2008;52:39–48.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Fu ZJ, Li SY, Kociok N, Wong D, Chung SK, Lo AC. Aldose reductase deficiency reduced vascular changes in neonatal mouse retina in oxygen-induced retinopathy. Invest Ophthalmol Vis Sci. 2012;53:5698–712.PubMedCrossRefPubMedCentralGoogle Scholar
  49. Funa K, Sasahara M. The roles of PDGF in development and during neurogenesis in the normal and diseased nervous system. J Neuroimmune Pharmacol. 2014;9:168–81.PubMedCrossRefPubMedCentralGoogle Scholar
  50. Gabbay KH. The sorbitol pathway and the complications of diabetes. N Engl J Med. 1973;288:831–6.PubMedCrossRefPubMedCentralGoogle Scholar
  51. Garcia Soriano F, Virag L, Jagtap P, Szabo E, Mabley JG, Liaudet L, Marton A, Hoyt DG, Murthy KG, Salzman AL, Southan GJ, Szabo C. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med. 2001;7:108–13.PubMedCrossRefPubMedCentralGoogle Scholar
  52. Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res. 2010;106:1319–31.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Geraldes P, Yagi K, Ohshiro Y, He Z, Maeno Y, Yamamoto-Hiraoka J, Rask-Madsen C, Chung SW, Perrella MA, King GL. Selective regulation of heme oxygenase-1 expression and function by insulin through IRS1/phosphoinositide 3-kinase/Akt-2 pathway. J Biol Chem. 2008;283:34327–36.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Geraldes P, Hiraoka-Yamamoto J, Matsumoto M, Clermont A, Leitges M, Marette A, Aiello LP, Kern TS, King GL. Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat Med. 2009;15:1298–306.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Ghosh AK, Quaggin SE, Vaughan DE. Molecular basis of organ fibrosis: potential therapeutic approaches. Exp Biol Med (Maywood). 2013;238:461–81.CrossRefGoogle Scholar
  56. Girolami A, Tezza F, Scandellari R, Vettore S, Girolami B. Associated prothrombotic conditions are probably responsible for the occurrence of thrombosis in almost all patients with congenital FVII deficiency. Critical review of the literature. J Thromb Thrombolysis. 2010;30:172–8.PubMedCrossRefPubMedCentralGoogle Scholar
  57. Goldberg T, Cai W, Peppa M, Dardaine V, Baliga BS, Uribarri J, Vlassara H. Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc. 2004;104:1287–91.PubMedCrossRefPubMedCentralGoogle Scholar
  58. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114:597–605.PubMedCrossRefPubMedCentralGoogle Scholar
  59. Gomes E, Papa L, Hao T, Rockwell P. The VEGFR2 and PKA pathways converge at MEK/ERK1/2 to promote survival in serum deprived neuronal cells. Mol Cell Biochem. 2007;305:179–90.PubMedCrossRefPubMedCentralGoogle Scholar
  60. Gupta A, Gerlitz B, Richardson MA, Bull C, Berg DT, Syed S, Galbreath EJ, Swanson BA, Jones BE, Grinnell BW. Distinct functions of activated protein C differentially attenuate acute kidney injury. J Am Soc Nephrol. 2009;20:267–77.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Hale LJ, Hurcombe J, Lay A, Santamaria B, Valverde AM, Saleem MA, Mathieson PW, Welsh GI, Coward RJ. Insulin directly stimulates VEGF-A production in the glomerular podocyte. Am J Physiol Ren Physiol. 2013;305:F182–8.CrossRefGoogle Scholar
  62. Hamilton RT, Bhattacharya A, Walsh ME, Shi Y, Wei R, Zhang Y, Rodriguez KA, Buffenstein R, Chaudhuri AR, Van Remmen H. Elevated protein carbonylation, and misfolding in sciatic nerve from db/db and Sod1(−/−) mice: plausible link between oxidative stress and demyelination. PLoS One. 2013;8:e65725.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Hammes HP, Lin J, Renner O, Shani M, Lundqvist A, Betsholtz C, Brownlee M, Deutsch U. Pericytes and the pathogenesis of diabetic retinopathy. Diabetes. 2002;51:3107–12.PubMedCrossRefPubMedCentralGoogle Scholar
  64. Han T, Bai J, Liu W, Hu Y. A systematic review and meta-analysis of alpha-lipoic acid in the treatment of diabetic peripheral neuropathy. Eur J Endocrinol. 2012;167:465–71.PubMedCrossRefPubMedCentralGoogle Scholar
  65. Harindhanavudhi T, Mauer M, Klein R, Zinman B, Sinaiko A, Caramori ML. Benefits of Renin-Angiotensin blockade on retinopathy in type 1 diabetes vary with glycemic control. Diabetes Care. 2011;34:1838–42.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Haritoglou C, Gerss J, Hammes HP, Kampik A, Ulbig MW. Alpha-lipoic acid for the prevention of diabetic macular edema. Ophthalmologica. 2011;226:127–37.PubMedCrossRefPubMedCentralGoogle Scholar
  67. Hempel A, Maasch C, Heintze U, Lindschau C, Dietz R, Luft FC, Haller H. High glucose concentrations increase endothelial cell permeability via activation of protein kinase C alpha. Circ Res. 1997;81:363–71.PubMedCrossRefPubMedCentralGoogle Scholar
  68. Hermann C, Assmus B, Urbich C, Zeiher AM, Dimmeler S. Insulin-mediated stimulation of protein kinase Akt: a potent survival signaling cascade for endothelial cells. Arterioscler Thromb Vasc Biol. 2000;20:402–9.PubMedCrossRefPubMedCentralGoogle Scholar
  69. Hernandez SL, Gong JH, Chen L, Wu IH, Sun JK, Keenan HA, King GL. Characterization of circulating and endothelial progenitor cells in patients with extreme-duration type 1 diabetes. Diabetes Care. 2014;37:2193–201.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RA, Warnholtz A, Meinertz T, Griendling K, Harrison DG, Forstermann U, Munzel T. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res. 2001;88:E14–22.CrossRefPubMedGoogle Scholar
  71. Hudson BI, Kalea AZ, Del Mar Arriero M, Harja E, Boulanger E, D’Agati V, Schmidt AM. Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J Biol Chem. 2008;283:34457–68.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Ido Y, McHowat J, Chang KC, Arrigoni-Martelli E, Orfalian Z, Kilo C, Corr PB, Williamson JR. Neural dysfunction and metabolic imbalances in diabetic rats. Prevention by acetyl-L-carnitine. Diabetes. 1994;43:1469–77.PubMedCrossRefPubMedCentralGoogle Scholar
  73. Idris I, Gray S, Donnelly R. Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes. Diabetologia. 2001;44:659–73.PubMedCrossRefPubMedCentralGoogle Scholar
  74. Inoguchi T, Battan R, Handler E, Sportsman JR, Heath W, King GL. Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation. Proc Natl Acad Sci U S A. 1992;89:11059–63.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C – dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes. 2000;49:1939–45.PubMedCrossRefPubMedCentralGoogle Scholar
  76. Isermann B, Vinnikov IA, Madhusudhan T, Herzog S, Kashif M, Blautzik J, Corat MA, Zeier M, Blessing E, Oh J, Gerlitz B, Berg DT, Grinnell BW, Chavakis T, Esmon CT, Weiler H, Bierhaus A, Nawroth PP. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med. 2007;13:1349–58.PubMedCrossRefPubMedCentralGoogle Scholar
  77. Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science. 1996;272:728–31.PubMedCrossRefPubMedCentralGoogle Scholar
  78. Jandeleit-Dahm KA, Lassila M, Allen TJ. Advanced glycation end products in diabetes-associated atherosclerosis and renal disease: interventional studies. Ann N Y Acad Sci. 2005;1043:759–66.PubMedCrossRefPubMedCentralGoogle Scholar
  79. Jarajapu YP, Grant MB. The promise of cell-based therapies for diabetic complications: challenges and solutions. Circ Res. 2010;106:854–69.PubMedCrossRefPubMedCentralGoogle Scholar
  80. Jeffery J, Jornvall H. Enzyme relationships in a sorbitol pathway that bypasses glycolysis and pentose phosphates in glucose metabolism. Proc Natl Acad Sci U S A. 1983;80:901–5.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Jeppesen P, Aalkjaer C, Bek T. Bradykinin relaxation in small porcine retinal arterioles. Invest Ophthalmol Vis Sci. 2002;43:1891–6.PubMedPubMedCentralGoogle Scholar
  82. Jiang ZY, He Z, King BL, Kuroki T, Opland DM, Suzuma K, Suzuma I, Ueki K, Kulkarni RN, Kahn CR, King GL. Characterization of multiple signaling pathways of insulin in the regulation of vascular endothelial growth factor expression in vascular cells and angiogenesis. J Biol Chem. 2003;278:31964–71.PubMedCrossRefPubMedCentralGoogle Scholar
  83. Jin Y, Ratnam K, Chuang PY, Fan Y, Zhong Y, Dai Y, Mazloom AR, Chen EY, D'Agati V, Xiong H, Ross MJ, Chen N, Ma'ayan A, He JC. A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat Med. 2012;18:580–8.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Jing G, Wang JJ, Zhang SX. ER stress and apoptosis: a new mechanism for retinal cell death. Exp Diabetes Res. 2012;2012:589589.PubMedCrossRefPubMedCentralGoogle Scholar
  85. Jirousek MR, Gillig JR, Gonzalez CM, Heath WF, McDonald JH 3rd, Neel DA, Rito CJ, Singh U, Stramm LE, Melikian-Badalian A, Baevsky M, Ballas LM, Hall SE, Winneroski LL, Faul MM. (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-d ione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase C beta. J Med Chem. 1996;39:2664–71.PubMedCrossRefPubMedCentralGoogle Scholar
  86. Kador PF, Betts D, Wyman M, Blessing K, Randazzo J. Effects of topical administration of an aldose reductase inhibitor on cataract formation in dogs fed a diet high in galactose. Am J Vet Res. 2006;67:1783–7.PubMedCrossRefPubMedCentralGoogle Scholar
  87. Kagami S, Border WA, Miller DE, Noble NA. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest. 1994;93:2431–7.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Kaiser N, Sasson S, Feener EP, Boukobza-Vardi N, Higashi S, Moller DE, Davidheiser S, Przybylski RJ, King GL. Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. Diabetes. 1993;42:80–9.PubMedCrossRefPubMedCentralGoogle Scholar
  89. Kale S, Karihaloo A, Clark PR, Kashgarian M, Krause DS, Cantley LG. Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. J Clin Invest. 2003;112:42–9.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Kamata K, Sugiura M, Kasuya Y. Decreased Ca2+ influx into the endothelium contributes to the decrease in endothelium-dependent relaxation in the aorta of streptozotocin-induced diabetic mice. Res Commun Mol Pathol Pharmacol. 1995;90:69–74.PubMedPubMedCentralGoogle Scholar
  91. Kanetsuna Y, Takahashi K, Nagata M, Gannon MA, Breyer MD, Harris RC, Takahashi T. Deficiency of endothelial nitric-oxide synthase confers susceptibility to diabetic nephropathy in nephropathy-resistant inbred mice. Am J Pathol. 2007;170:1473–84.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Keenan HA, Costacou T, Sun JK, Doria A, Cavellerano J, Coney J, Orchard TJ, Aiello LP, King GL. Clinical factors associated with resistance to microvascular complications in diabetic patients of extreme disease duration: the 50-year medalist study. Diabetes Care. 2007;30:1995–7.PubMedCrossRefPubMedCentralGoogle Scholar
  93. Keenan JD, Fan AZ, Klein R. Retinopathy in nondiabetic persons with the metabolic syndrome: findings from the Third National Health and Nutrition Examination Survey. Am J Ophthalmol. 2009;147:934–44. 944. e931–932PubMedCrossRefPubMedCentralGoogle Scholar
  94. Khamaisi M, Katagiri S, Keenan H, Park K, Maeda Y, Li Q, Qi W, Thomou T, Eschuk D, Tellechea A, Veves A, Huang C, Orgill DP, Wagers A, King GL. PKCdelta inhibition normalizes the wound-healing capacity of diabetic human fibroblasts. J Clin Invest. 2016;126:837–53.PubMedPubMedCentralCrossRefGoogle Scholar
  95. Kim J, Rushovich EH, Thomas TP, Ueda T, Agranoff BW, Greene DA. Diminished specific activity of cytosolic protein kinase C in sciatic nerve of streptozocin-induced diabetic rats and its correction by dietary myo-inositol. Diabetes. 1991;40:1545–54.PubMedCrossRefPubMedCentralGoogle Scholar
  96. Kim YK, Lee MS, Son SM, Kim IJ, Lee WS, Rhim BY, Hong KW, Kim CD. Vascular NADH oxidase is involved in impaired endothelium-dependent vasodilation in OLETF rats, a model of type 2 diabetes. Diabetes. 2002;51:522–7.PubMedCrossRefPubMedCentralGoogle Scholar
  97. Kim BJ, Lee JK, Schuchman EH, Jin HK, Bae JS. Synergistic vasculogenic effects of AMD3100 and stromal-cell-derived factor-1alpha in vasa nervorum of the sciatic nerve of mice with diabetic peripheral neuropathy. Cell Tissue Res. 2013;354:395–407.PubMedCrossRefPubMedCentralGoogle Scholar
  98. Kojima N, Saito M, Mori A, Sakamoto K, Nakahara T, Ishii K. Role of cyclooxygenase in vasodilation of retinal blood vessels induced by bradykinin in Brown Norway rats. Vasc Pharmacol. 2009;51:119–24.CrossRefGoogle Scholar
  99. Kolte D, Bryant J, Holsworth D, Wang J, Akbari P, Gibson G, Shariat-Madar Z. Biochemical characterization of a novel high-affinity and specific plasma kallikrein inhibitor. Br J Pharmacol. 2011;162:1639–49.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Konishi H, Tanaka M, Takemura Y, Matsuzaki H, Ono Y, Kikkawa U, Nishizuka Y. Activation of protein kinase C by tyrosine phosphorylation in response to H2O2. Proc Natl Acad Sci U S A. 1997;94:11233–7.PubMedPubMedCentralCrossRefGoogle Scholar
  101. Kowluru RA, Zhong Q. Beyond AREDS: is there a place for antioxidant therapy in the prevention/treatment of eye disease? Invest Ophthalmol Vis Sci. 2011;52:8665–71.PubMedPubMedCentralCrossRefGoogle Scholar
  102. Kuhr F, Lowry J, Zhang Y, Brovkovych V, Skidgel RA. Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors. Neuropeptides. 2010;44:145–54.PubMedPubMedCentralCrossRefGoogle Scholar
  103. Lassegue B, San Martin A, Griendling KK. Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res. 2012;110:1364–90.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Laursen JB, Somers M, Kurz S, McCann L, Warnholtz A, Freeman BA, Tarpey M, Fukai T, Harrison DG. Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation. 2001;103:1282–8.PubMedCrossRefPubMedCentralGoogle Scholar
  105. Lawson SR, Gabra BH, Nantel F, Battistini B, Sirois P. Effects of a selective bradykinin B1 receptor antagonist on increased plasma extravasation in streptozotocin-induced diabetic rats: distinct vasculopathic profile of major key organs. Eur J Pharmacol. 2005;514:69–78.PubMedCrossRefPubMedCentralGoogle Scholar
  106. Lei H, Rheaume MA, Kazlauskas A. Recent developments in our understanding of how platelet-derived growth factor (PDGF) and its receptors contribute to proliferative vitreoretinopathy. Exp Eye Res. 2010;90:376–81.PubMedCrossRefPubMedCentralGoogle Scholar
  107. Li Calzi S, Neu MB, Shaw LC, Grant MB. Endothelial progenitor dysfunction in the pathogenesis of diabetic retinopathy: treatment concept to correct diabetes-associated deficits. EPMA J. 2010;1:88–100.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Li G, Tang J, Du Y, Lee CA, Kern TS. Beneficial effects of a novel RAGE inhibitor on early diabetic retinopathy and tactile allodynia. Mol Vis. 2011;17:3156–65.PubMedPubMedCentralGoogle Scholar
  109. Lightman S. Does aldose reductase have a role in the development of the ocular complications of diabetes? Eye (Lond). 1993;7(Pt 2):238–41.CrossRefGoogle Scholar
  110. Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997;277:242–5.PubMedCrossRefPubMedCentralGoogle Scholar
  111. Liu H, Luo Y, Zhang T, Zhang Y, Wu Q, Yuan L, Chung SS, Oates PJ, Yang JY. Genetic deficiency of aldose reductase counteracts the development of diabetic nephropathy in C57BL/6 mice. Diabetologia. 2011;54:1242–51.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Lonn E, Yusuf S, Hoogwerf B, Pogue J, Yi Q, Zinman B, Bosch J, Dagenais G, Mann JF, Gerstein HC. Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care. 2002;25:1919–27.PubMedCrossRefPubMedCentralGoogle Scholar
  113. Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, van Zonneveld AJ. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes. 2004;53:195–9.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Ma RC, Tam CH, Wang Y, Luk AO, Hu C, Yang X, Lam V, Chan AW, Ho JS, Chow CC, Tong PC, Jia W, Ng MC, So WY, Chan JC. Genetic variants of the protein kinase C-beta 1 gene and development of end-stage renal disease in patients with type 2 diabetes. JAMA. 2010;304:881–9.PubMedCrossRefPubMedCentralGoogle Scholar
  115. Maeno Y, Li Q, Park K, Rask-Madsen C, Gao B, Matsumoto M, Liu Y, Wu IH, White MF, Feener EP, King GL. Inhibition of insulin signaling in endothelial cells by protein kinase C-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase (PI3K). J Biol Chem. 2012;287:4518–30.PubMedCrossRefPubMedCentralGoogle Scholar
  116. Marceau F, Regoli D. Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov. 2004;3:845–52.PubMedCrossRefPubMedCentralGoogle Scholar
  117. Mark AB, Poulsen MW, Andersen S, Andersen JM, Bak MJ, Ritz C, Holst JJ, Nielsen J, de Courten B, Dragsted LO, Bugel SG. Consumption of a diet low in advanced glycation end products for 4 weeks improves insulin sensitivity in overweight women. Diabetes Care. 2014;37:88–95.PubMedCrossRefPubMedCentralGoogle Scholar
  118. Matsumoto T, Kobayashi T, Kamata K. Relationships among ET-1, PPARgamma, oxidative stress and endothelial dysfunction in diabetic animals. J Smooth Muscle Res. 2008;44:41–55.PubMedCrossRefPubMedCentralGoogle Scholar
  119. Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A, Strand T, Drummond K, Donnelly S, Goodyer P, Gubler MC, Klein R. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 2009;361:40–51.PubMedPubMedCentralCrossRefGoogle Scholar
  120. Meier M, Menne J, Park JK, Holtz M, Gueler F, Kirsch T, Schiffer M, Mengel M, Lindschau C, Leitges M, Haller H. Deletion of protein kinase C-epsilon signaling pathway induces glomerulosclerosis and tubulointerstitial fibrosis in vivo. J Am Soc Nephrol. 2007;18:1190–8.PubMedCrossRefPubMedCentralGoogle Scholar
  121. Menne J, Park JK, Boehne M, Elger M, Lindschau C, Kirsch T, Meier M, Gueler F, Fiebeler A, Bahlmann FH, Leitges M, Haller H. Diminished loss of proteoglycans and lack of albuminuria in protein kinase C-alpha-deficient diabetic mice. Diabetes. 2004;53:2101–9.PubMedCrossRefPubMedCentralGoogle Scholar
  122. Mima A, Kitada M, Geraldes P, Li Q, Matsumoto M, Mizutani K, Qi W, Li C, Leitges M, Rask-Madsen C, King GL. Glomerular VEGF resistance induced by PKCdelta/SHP-1 activation and contribution to diabetic nephropathy. FASEB J. 2012;26:2963–74.PubMedPubMedCentralCrossRefGoogle Scholar
  123. Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation. 2002;105:1541–4.PubMedCrossRefPubMedCentralGoogle Scholar
  124. Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH, Steffes MW. Nephropathy in diabetes. Diabetes Care. 2004;27(Suppl 1):S79–83.PubMedPubMedCentralGoogle Scholar
  125. Motawi TK, Rizk SM, Ibrahim IA, El-Emady YF. Alterations in circulating angiogenic and anti-angiogenic factors in type 2 diabetic patients with neuropathy. Cell Biochem Funct. 2014;32:155–63.PubMedCrossRefPubMedCentralGoogle Scholar
  126. Murakami T, Frey T, Lin C, Antonetti DA. Protein kinase cbeta phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo. Diabetes. 2012;61:1573–83.PubMedPubMedCentralCrossRefGoogle Scholar
  127. Nakagawa T, Sato W, Glushakova O, Heinig M, Clarke T, Campbell-Thompson M, Yuzawa Y, Atkinson MA, Johnson RJ, Croker B. Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J Am Soc Nephrol. 2007;18:539–50.PubMedCrossRefPubMedCentralGoogle Scholar
  128. Nakamura J, Kato K, Hamada Y, Nakayama M, Chaya S, Nakashima E, Naruse K, Kasuya Y, Mizubayashi R, Miwa K, Yasuda Y, Kamiya H, Ienaga K, Sakakibara F, Koh N, Hotta N. A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats. Diabetes. 1999;48:2090–5.PubMedCrossRefPubMedCentralGoogle Scholar
  129. Nakamura S, Chikaraishi Y, Tsuruma K, Shimazawa M, Hara H. Ruboxistaurin, a PKCbeta inhibitor, inhibits retinal neovascularization via suppression of phosphorylation of ERK1/2 and Akt. Exp Eye Res. 2010;90:137–45.PubMedCrossRefPubMedCentralGoogle Scholar
  130. Naruse K, Rask-Madsen C, Takahara N, Ha SW, Suzuma K, Way KJ, Jacobs JR, Clermont AC, Ueki K, Ohshiro Y, Zhang J, Goldfine AB, King GL. Activation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance. Diabetes. 2006;55:691–8.PubMedCrossRefPubMedCentralGoogle Scholar
  131. Neuenschwander H, Takahashi Y, Kador PF. Dose-dependent reduction of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by the aldose reductase inhibitor M79175. J Ocul Pharmacol Ther. 1997;13:517–28.PubMedCrossRefPubMedCentralGoogle Scholar
  132. Newton AC. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem J. 2003;370:361–71.PubMedPubMedCentralCrossRefGoogle Scholar
  133. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787–90.PubMedCrossRefPubMedCentralGoogle Scholar
  134. Ohshiro Y, Ma RC, Yasuda Y, Hiraoka-Yamamoto J, Clermont AC, Isshiki K, Yagi K, Arikawa E, Kern TS, King GL. Reduction of diabetes-induced oxidative stress, fibrotic cytokine expression, and renal dysfunction in protein kinase Cbeta-null mice. Diabetes. 2006;55:3112–20.PubMedCrossRefPubMedCentralGoogle Scholar
  135. Oliver FJ, de la Rubia G, Feener EP, Lee ME, Loeken MR, Shiba T, Quertermous T, King GL. Stimulation of endothelin-1 gene expression by insulin in endothelial cells. J Biol Chem. 1991;266:23251–6.PubMedPubMedCentralGoogle Scholar
  136. Orsenigo F, Giampietro C, Ferrari A, Corada M, Galaup A, Sigismund S, Ristagno G, Maddaluno L, Koh GY, Franco D, Kurtcuoglu V, Poulikakos D, Baluk P, McDonald D, Grazia Lampugnani M, Dejana E. Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo. Nat Commun. 2012;3:1208.PubMedPubMedCentralCrossRefGoogle Scholar
  137. Othman A, Ahmad S, Megyerdi S, Mussell R, Choksi K, Maddipati KR, Elmarakby A, Rizk N, Al-Shabrawey M. 12/15-Lipoxygenase-derived lipid metabolites induce retinal endothelial cell barrier dysfunction: contribution of NADPH oxidase. PLoS One. 2013;8:e57254.PubMedPubMedCentralCrossRefGoogle Scholar
  138. Park L, Raman KG, Lee KJ, Lu Y, Ferran LJ Jr, Chow WS, Stern D, Schmidt AM. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med. 1998;4:1025–31.PubMedCrossRefPubMedCentralGoogle Scholar
  139. Park K, Li Q, Rask-Madsen C, Mima A, Mizutani K, Winnay J, Maeda Y, D’Aquino K, White MF, Feener EP, King GL. Serine phosphorylation sites on IRS2 activated by angiotensin II and protein kinase C to induce selective insulin resistance in endothelial cells. Mol Cell Biol. 2013;33:3227–41.PubMedPubMedCentralCrossRefGoogle Scholar
  140. Park K, Mima A, Li Q, Rask-Madsen C, He P, Mizutani K, Katagiri S, Maeda Y, Wu IH, Khamaisi M, Preil SR, Maddaloni E, Sorensen D, Rasmussen LM, Huang PL, King GL. Insulin decreases atherosclerosis by inducing endothelin receptor B expression. JCI Insight. 2016;1:e86574.PubMedPubMedCentralCrossRefGoogle Scholar
  141. Parmer TG, Ward MD, Hait WN. Effects of rottlerin, an inhibitor of calmodulin-dependent protein kinase III, on cellular proliferation, viability, and cell cycle distribution in malignant glioma cells. Cell Growth Differ. 1997;8:327–34.PubMedPubMedCentralGoogle Scholar
  142. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.PubMedCrossRefPubMedCentralGoogle Scholar
  143. Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS. Regression of microalbuminuria in type 1 diabetes. N Engl J Med. 2003;348:2285–93.PubMedCrossRefPubMedCentralGoogle Scholar
  144. Petersen M, Thorikay M, Deckers M, van Dinther M, Grygielko ET, Gellibert F, de Gouville AC, Huet S, ten Dijke P, Laping NJ. Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis. Kidney Int. 2008;73:705–15.PubMedCrossRefPubMedCentralGoogle Scholar
  145. Phipps JA, Clermont AC, Sinha S, Chilcote TJ, Bursell SE, Feener EP. Plasma kallikrein mediates angiotensin II type 1 receptor-stimulated retinal vascular permeability. Hypertension. 2009;53:175–81.PubMedPubMedCentralCrossRefGoogle Scholar
  146. Plesnila N, Schulz J, Stoffel M, Eriskat J, Pruneau D, Baethmann A. Role of bradykinin B2 receptors in the formation of vasogenic brain edema in rats. J Neurotrauma. 2001;18:1049–58.PubMedCrossRefPubMedCentralGoogle Scholar
  147. Pouliot M, Talbot S, Senecal J, Dotigny F, Vaucher E, Couture R. Ocular application of the kinin B1 receptor antagonist LF22-0542 inhibits retinal inflammation and oxidative stress in streptozotocin-diabetic rats. PLoS One. 2012;7:e33864.PubMedPubMedCentralCrossRefGoogle Scholar
  148. Pruneau D, Belichard P, Sahel JA, Combal JP. Targeting the kallikrein-kinin system as a new therapeutic approach to diabetic retinopathy. Curr Opin Investig Drugs. 2010;11:507–14.PubMedPubMedCentralGoogle Scholar
  149. Ramasamy R, Goldberg IJ. Aldose reductase and cardiovascular diseases, creating human-like diabetic complications in an experimental model. Circ Res. 2010;106:1449–58.PubMedPubMedCentralCrossRefGoogle Scholar
  150. Ramasamy R, Yan SF, Schmidt AM. RAGE: therapeutic target and biomarker of the inflammatory response – the evidence mounts. J Leukoc Biol. 2009;86:505–12.PubMedCrossRefPubMedCentralGoogle Scholar
  151. Rask-Madsen C, King GL. Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab. 2013;17:20–33.PubMedPubMedCentralCrossRefGoogle Scholar
  152. Rask-Madsen C, Li Q, Freund B, Feather D, Abramov R, Wu IH, Chen K, Yamamoto-Hiraoka J, Goldenbogen J, Sotiropoulos KB, Clermont A, Geraldes P, Dall’Osso C, Wagers AJ, Huang PL, Rekhter M, Scalia R, Kahn CR, King GL. Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. Cell Metab. 2010;11:379–89.PubMedPubMedCentralCrossRefGoogle Scholar
  153. Reddy VP, Obrenovich ME, Atwood CS, Perry G, Smith MA. Involvement of Maillard reactions in Alzheimer disease. Neurotox Res. 2002;4:191–209.PubMedCrossRefPubMedCentralGoogle Scholar
  154. Ruiz S, Pergola PE, Zager RA, Vaziri ND. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 2013;83:1029–41.PubMedPubMedCentralCrossRefGoogle Scholar
  155. Ruscetti F, Varesio L, Ochoa A, Ortaldo J. Pleiotropic effects of transforming growth factor-beta on cells of the immune system. Ann N Y Acad Sci. 1993;685:488–500.PubMedCrossRefGoogle Scholar
  156. Sainz IM, Pixley RA, Colman RW. Fifty years of research on the plasma kallikrein-kinin system: from protein structure and function to cell biology and in-vivo pathophysiology. Thromb Haemost. 2007;98:77–83.PubMedCrossRefPubMedCentralGoogle Scholar
  157. Sakaguchi T, Yan SF, Yan SD, Belov D, Rong LL, Sousa M, Andrassy M, Marso SP, Duda S, Arnold B, Liliensiek B, Nawroth PP, Stern DM, Schmidt AM, Naka Y. Central role of RAGE-dependent neointimal expansion in arterial restenosis. J Clin Invest. 2003;111:959–72.PubMedPubMedCentralCrossRefGoogle Scholar
  158. Schmidt AM, Hori O, Brett J, Yan SD, Wautier JL, Stern D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb. 1994;14:1521–8.PubMedCrossRefGoogle Scholar
  159. Sheetz MJ, Aiello LP, Davis MD, Danis R, Bek T, Cunha-Vaz J, Shahri N, Berg PH. The effect of the oral PKC beta inhibitor ruboxistaurin on vision loss in two phase 3 studies. Invest Ophthalmol Vis Sci. 2013;54:1750–7.PubMedCrossRefPubMedCentralGoogle Scholar
  160. Shiba T, Inoguchi T, Sportsman JR, Heath WF, Bursell S, King GL. Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation. Am J Phys. 1993;265:E783–93.Google Scholar
  161. Sivaskandarajah GA, Jeansson M, Maezawa Y, Eremina V, Baelde HJ, Quaggin SE. Vegfa protects the glomerular microvasculature in diabetes. Diabetes. 2012;61:2958–66.PubMedPubMedCentralCrossRefGoogle Scholar
  162. Sogawa K, Nagaoka T, Izumi N, Nakabayashi S, Yoshida A. Acute hyperglycemia-induced endothelial dysfunction in retinal arterioles in cats. Invest Ophthalmol Vis Sci. 2010;51:2648–55.PubMedCrossRefPubMedCentralGoogle Scholar
  163. Soltoff SP. Rottlerin: an inappropriate and ineffective inhibitor of PKCdelta. Trends Pharmacol Sci. 2007;28:453–8.PubMedCrossRefPubMedCentralGoogle Scholar
  164. Srivastava SK, Hair GA, Das B. Activated and unactivated forms of human erythrocyte aldose reductase. Proc Natl Acad Sci U S A. 1985;82:7222–6.PubMedPubMedCentralCrossRefGoogle Scholar
  165. Stevens MJ, Dananberg J, Feldman EL, Lattimer SA, Kamijo M, Thomas TP, Shindo H, Sima AA, Greene DA. The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. J Clin Invest. 1994;94:853–9.PubMedPubMedCentralCrossRefGoogle Scholar
  166. Sun JK, Keenan HA, Cavallerano JD, Asztalos BF, Schaefer EJ, Sell DR, Strauch CM, Monnier VM, Doria A, Aiello LP, King GL. Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: the joslin 50-year medalist study. Diabetes Care. 2011;34:968–74.PubMedPubMedCentralCrossRefGoogle Scholar
  167. Suzuma K, Takahara N, Suzuma I, Isshiki K, Ueki K, Leitges M, Aiello LP, King GL. Characterization of protein kinase C beta isoform’s action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization. Proc Natl Acad Sci U S A. 2002;99:721–6.PubMedPubMedCentralCrossRefGoogle Scholar
  168. Sytze Van Dam P, Cotter MA, Bravenboer B, Cameron NE. Pathogenesis of diabetic neuropathy: focus on neurovascular mechanisms. Eur J Pharmacol. 2013;719:180–6.PubMedCrossRefPubMedCentralGoogle Scholar
  169. Tanaka S, Yoshimura Y, Kawasaki R, Kamada C, Horikawa C, Ohashi Y, Araki A, Ito H, Akanuma Y, Yamada N, Yamashita H, Sone H. Fruit intake and incident diabetic retinopathy with type 2 diabetes. Epidemiology. 2013;24:204–11.PubMedCrossRefPubMedCentralGoogle Scholar
  170. Taniguchi K, Xia L, Goldberg HJ, Lee KW, Shah A, Stavar L, Masson EA, Momen A, Shikatani EA, John R, Husain M, Fantus IG. Inhibition of Src kinase blocks high glucose-induced EGFR transactivation and collagen synthesis in mesangial cells and prevents diabetic nephropathy in mice. Diabetes. 2013;62:3874–86.PubMedPubMedCentralCrossRefGoogle Scholar
  171. Tebay LE, Robertson H, Durant ST, Vitale SR, Penning TM, Dinkova-Kostova AT, Hayes JD. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med. 2015;88:108–46.PubMedPubMedCentralCrossRefGoogle Scholar
  172. Thallas-Bonke V, Thorpe SR, Coughlan MT, Fukami K, Yap FY, Sourris KC, Penfold SA, Bach LA, Cooper ME, Forbes JM. Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-alpha-dependent pathway. Diabetes. 2008;57:460–9.PubMedCrossRefPubMedCentralGoogle Scholar
  173. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86.CrossRefGoogle Scholar
  174. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342:381–9.PubMedCentralCrossRefGoogle Scholar
  175. The PKC-DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes. 2005;54:2188–97.CrossRefGoogle Scholar
  176. Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, Widder JD, Tsikas D, Ertl G, Bauersachs J. Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes. 2007;56:666–74.PubMedPubMedCentralCrossRefGoogle Scholar
  177. Trueblood N, Ramasamy R. Aldose reductase inhibition improves altered glucose metabolism of isolated diabetic rat hearts. Am J Phys. 1998;275:H75–83.CrossRefGoogle Scholar
  178. Tsuchiya K, Tanaka J, Shuiqing Y, Welch CL, DePinho RA, Tabas I, Tall AR, Goldberg IJ, Accili D. FoxOs integrate pleiotropic actions of insulin in vascular endothelium to protect mice from atherosclerosis. Cell Metab. 2012;15:372–81.PubMedPubMedCentralCrossRefGoogle Scholar
  179. Tuttle KR, Anderson PW. A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C beta inhibition. Am J Kidney Dis. 2003;42:456–65.PubMedCrossRefPubMedCentralGoogle Scholar
  180. Tuttle KR, Bakris GL, Toto RD, McGill JB, Hu K, Anderson PW. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care. 2005;28:2686–90.PubMedCrossRefPubMedCentralGoogle Scholar
  181. Tutuncu NB, Bayraktar M, Varli K. Reversal of defective nerve conduction with vitamin E supplementation in type 2 diabetes: a preliminary study. Diabetes Care. 1998;21:1915–8.PubMedCrossRefPubMedCentralGoogle Scholar
  182. Uzar E, Tamam Y, Evliyaoglu O, Tuzcu A, Beyaz C, Acar A, Aydin B, Tasdemir N. Serum prolidase activity and oxidative status in patients with diabetic neuropathy. Neurol Sci. 2012;33:875–80.PubMedCrossRefPubMedCentralGoogle Scholar
  183. Veron D, Bertuccio CA, Marlier A, Reidy K, Garcia AM, Jimenez J, Velazquez H, Kashgarian M, Moeckel GW, Tufro A. Podocyte vascular endothelial growth factor (Vegf(1)(6)(4)) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes. Diabetologia. 2011;54:1227–41.PubMedPubMedCentralCrossRefGoogle Scholar
  184. Vinik AI, Bril V, Kempler P, Litchy WJ, Tesfaye S, Price KL, Bastyr EJ 3rd. Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial. Clin Ther. 2005;27:1164–80.PubMedCrossRefPubMedCentralGoogle Scholar
  185. Voelker J, Berg PH, Sheetz M, Duffin K, Shen T, Moser B, Greene T, Blumenthal SS, Rychlik I, Yagil Y, Zaoui P, Lewis JB. Anti-TGF-beta1 antibody therapy in patients with diabetic nephropathy. J Am Soc Nephrol. 2017;28(3):953–62.Google Scholar
  186. Wang H, Wang AX, Liu Z, Chai W, Barrett EJ. The trafficking/interaction of eNOS and caveolin-1 induced by insulin modulates endothelial nitric oxide production. Mol Endocrinol. 2009;23:1613–23.PubMedPubMedCentralCrossRefGoogle Scholar
  187. Wang N, Zheng Z, Jin HY, Xu X. Treatment effects of captopril on non-proliferative diabetic retinopathy. Chin Med J. 2012;125:287–92.PubMedPubMedCentralGoogle Scholar
  188. Wei Y, Gong J, Yoshida T, Eberhart CG, Xu Z, Kombairaju P, Sporn MB, Handa JT, Duh EJ. Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia-reperfusion injury. Free Radic Biol Med. 2011;51:216–24.PubMedPubMedCentralCrossRefGoogle Scholar
  189. Welsh GI, Hale LJ, Eremina V, Jeansson M, Maezawa Y, Lennon R, Pons DA, Owen RJ, Satchell SC, Miles MJ, Caunt CJ, McArdle CA, Pavenstadt H, Tavare JM, Herzenberg AM, Kahn CR, Mathieson PW, Quaggin SE, Saleem MA, Coward RJ. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab. 2010;12:329–40.PubMedPubMedCentralCrossRefGoogle Scholar
  190. Wilkinson-Berka JL, Tan G, Binger KJ, Sutton L, McMaster K, Deliyanti D, Perera G, Campbell DJ, Miller AG. Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat. Diabetologia. 2011;54:2724–35.PubMedCrossRefPubMedCentralGoogle Scholar
  191. Wu XH, Chen X, Zhang SL, Pang L, To C, Wang TT, Hohman TC, Filep JG, Chan JS. Molecular mechanism(s) of insulin action on the expression of the angiotensinogen gene in kidney proximal tubular cells. J Renin-Angiotensin-Aldosterone Syst. 2000;1:166–74.PubMedCrossRefPubMedCentralGoogle Scholar
  192. Wu YB, Li HQ, Ren MS, Li WT, Lv XY, Wang L. CHOP/ORP150 ratio in endoplasmic reticulum stress: a new mechanism for diabetic peripheral neuropathy. Cell Physiol Biochem. 2013;32:367–79.PubMedCrossRefPubMedCentralGoogle Scholar
  193. Xia P, Inoguchi T, Kern TS, Engerman RL, Oates PJ, King GL. Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia. Diabetes. 1994;43:1122–9.PubMedCrossRefGoogle Scholar
  194. Yamagishi S, Uehara K, Otsuki S, Yagihashi S. Differential influence of increased polyol pathway on protein kinase C expressions between endoneurial and epineurial tissues in diabetic mice. J Neurochem. 2003;87:497–507.PubMedCrossRefPubMedCentralGoogle Scholar
  195. Yamamoto Y, Kato I, Doi T, Yonekura H, Ohashi S, Takeuchi M, Watanabe T, Yamagishi S, Sakurai S, Takasawa S, Okamoto H, Yamamoto H. Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. J Clin Invest. 2001;108:261–8.PubMedPubMedCentralCrossRefGoogle Scholar
  196. Yan J, Tie G, Park B, Yan Y, Nowicki PT, Messina LM. Recovery from hind limb ischemia is less effective in type 2 than in type 1 diabetic mice: roles of endothelial nitric oxide synthase and endothelial progenitor cells. J Vasc Surg. 2009;50:1412–22.PubMedPubMedCentralCrossRefGoogle Scholar
  197. Yan SF, Ramasamy R, Schmidt AM. Soluble RAGE: therapy and biomarker in unraveling the RAGE axis in chronic disease and aging. Biochem Pharmacol. 2010;79:1379–86.PubMedPubMedCentralCrossRefGoogle Scholar
  198. Yayama K, Okamoto H. Angiotensin II-induced vasodilation via type 2 receptor: role of bradykinin and nitric oxide. Int Immunopharmacol. 2008;8:312–8.PubMedCrossRefPubMedCentralGoogle Scholar
  199. Yeung CM, Lo AC, Cheung AK, Chung SS, Wong D, Chung SK. More severe type 2 diabetes-associated ischemic stroke injury is alleviated in aldose reductase-deficient mice. J Neurosci Res. 2010;88:2026–34.PubMedPubMedCentralGoogle Scholar
  200. Yi X, Schubert M, Peachey NS, Suzuma K, Burks DJ, Kushner JA, Suzuma I, Cahill C, Flint CL, Dow MA, Leshan RL, King GL, White MF. Insulin receptor substrate 2 is essential for maturation and survival of photoreceptor cells. J Neurosci. 2005;25:1240–8.PubMedCrossRefPubMedCentralGoogle Scholar
  201. Yokota T, Ma RC, Park JY, Isshiki K, Sotiropoulos KB, Rauniyar RK, Bornfeldt KE, King GL. Role of protein kinase C on the expression of platelet-derived growth factor and endothelin-1 in the retina of diabetic rats and cultured retinal capillary pericytes. Diabetes. 2003;52:838–45.PubMedCrossRefPubMedCentralGoogle Scholar
  202. You YH, Okada S, Ly S, Jandeleit-Dahm K, Barit D, Namikoshi T, Sharma K. Role of Nox2 in diabetic kidney disease. Am J Physiol Ren Physiol. 2013;304:F840–8.CrossRefGoogle Scholar
  203. Zhang H, Davies KJ, Forman HJ. Oxidative stress response and Nrf2 signaling in aging. Free Radic Biol Med. 2015;88:314–36.PubMedPubMedCentralCrossRefGoogle Scholar
  204. Zhao HJ, Wang S, Cheng H, Zhang MZ, Takahashi T, Fogo AB, Breyer MD, Harris RC. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol. 2006;17:2664–9.PubMedPubMedCentralCrossRefGoogle Scholar
  205. Zhong Q, Mishra M, Kowluru RA. Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2013;54:3941–8.PubMedPubMedCentralCrossRefGoogle Scholar
  206. Ziyadeh FN, Hoffman BB, Han DC, Iglesias-De La Cruz MC, Hong SW, Isono M, Chen S, McGowan TA, Sharma K. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A. 2000;97:8015–20.PubMedPubMedCentralCrossRefGoogle Scholar
  207. Zou Y, Komuro I, Yamazaki T, Kudoh S, Aikawa R, Zhu W, Shiojima I, Hiroi Y, Tobe K, Kadowaki T, Yazaki Y. Cell type-specific angiotensin II-evoked signal transduction pathways: critical roles of Gbetagamma subunit, Src family, and Ras in cardiac fibroblasts. Circ Res. 1998;82:337–45.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Mogher Khamaisi
    • 1
    • 2
  • George L. King
    • 1
    Email author
  • Kyoungmin Park
    • 1
  • Qian Li
    • 1
  1. 1.Section of Vascular Cell Biology, Joslin Diabetes CenterHarvard Medical SchoolBostonUSA
  2. 2.Institutes of Endocrinology, Diabetes and Metabolism and Internal Medicine DRambam Health Care Campus and RB Rappaport Faculty of Medicine-TechnionHaifaIsrael

Personalised recommendations