Endothelial dysfunction as a potential contributor in diabetic nephropathy (original) (raw)

• Bojestig, M., Arnqvist, H. J., Hermansson, G., Karlberg, B. E. & Ludvigsson, J. Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N. Engl. J. Med. 330, 15–18 (1994).
  Article CAS PubMed Google Scholar
• Hovind, P. et al. Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes. Diabetes Care 26, 1258–1264 (2003).
  Article PubMed Google Scholar
• Saito, Y. et al. Mesangiolysis in diabetic glomeruli: its role in the formation of nodular lesions. Kidney Int. 34, 389–396 (1988).
  Article CAS PubMed Google Scholar
• Stout, L. C., Kumar, S. & Whorton, E. B. Insudative lesions—their pathogenesis and association with glomerular obsolescence in diabetes: a dynamic hypothesis based on single views of advancing human diabetic nephropathy. Hum. Pathol. 25, 1213–1227 (1994).
  Article CAS PubMed Google Scholar
• Jensen, T. Increased plasma concentration of von Willebrand factor in insulin dependent diabetics with incipient nephropathy. BMJ 298, 27–28 (1989).
  Article CAS PubMed PubMed Central Google Scholar
• Jensen, T., Bjerre-Knudsen, J., Feldt-Rasmussen, B. & Deckert, T. Features of endothelial dysfunction in early diabetic nephropathy. Lancet 1, 461–463 (1989).
  Article CAS PubMed Google Scholar
• Stehouwer, C. D. et al. Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet 340, 319–323 (1992).
  Article CAS PubMed Google Scholar
• Stehouwer, C. D., Stroes, E. S., Hackeng, W. H., Mulder, P. G. & Den Ottolander, G. J. von Willebrand factor and development of diabetic nephropathy in IDDM. Diabetes 40, 971–976 (1991).
  Article CAS PubMed Google Scholar
• Parving, H. H. et al. Macro-microangiopathy and endothelial dysfunction in NIDDM patients with and without diabetic nephropathy. Diabetologia 39, 1590–1597 (1996).
  Article CAS PubMed Google Scholar
• Fioretto, P. et al. Heterogeneous nature of microalbuminuria in NIDDM: studies of endothelial function and renal structure. Diabetologia 41, 233–236 (1998).
  Article CAS PubMed Google Scholar
• Nieuwdorp, M. et al. Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 55, 1127–1132 (2006).
  Article CAS PubMed Google Scholar
• Nieuwdorp, M. et al. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 55, 480–486 (2006).
  Article CAS PubMed Google Scholar
• Dávila-Esqueda, M. E., Vertiz-Hernández, A. A. & Martínez-Morales, F. Comparative analysis of the renoprotective effects of pentoxifylline and vitamin E on streptozotocin-induced diabetes mellitus. Ren. Fail. 27, 115–122 (2005).
  Article PubMed Google Scholar
• Toyoda, M., Najafian, B., Kim, Y., Caramori, M. L. & Mauer, M. Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy. Diabetes 56, 2155–2160 (2007).
  Article CAS PubMed Google Scholar
• Fioretto, P. et al. Patterns of renal injury in NIDDM patients with microalbuminuria. Diabetologia 39, 1569–1576 (1996).
  Article CAS PubMed Google Scholar
• Gambara, V., Mecca, G., Remuzzi, G. & Bertani, T. Heterogeneous nature of renal lesions in type II diabetes. J. Am. Soc. Nephrol. 3, 1458–1466 (1993).
  CAS PubMed Google Scholar
• White, K. E. & Bilous, R. W. Type 2 diabetic patients with nephropathy show structural-functional relationships that are similar to type 1 disease. J. Am. Soc. Nephrol. 11, 1667–1673 (2000).
  CAS PubMed Google Scholar
• Lane, P. H., Steffes, M. W., Fioretto, P. & Mauer, S. M. Renal interstitial expansion in insulin-dependent diabetes mellitus. Kidney Int. 43, 661–667 (1993).
  Article CAS PubMed Google Scholar
• Shibata, R. et al. Involvement of asymmetric dimethylarginine (ADMA) in tubulointerstitial ischaemia in the early phase of diabetic nephropathy. Nephrol. Dial. Transplant. 24, 1162–1169 (2009).
  Article CAS PubMed Google Scholar
• Bangstad, H. J., Seljeflot, I., Berg, T. J. & Hanssen, K. F. Renal tubulointerstitial expansion is associated with endothelial dysfunction and inflammation in type 1 diabetes. Scand. J. Clin. Lab. Invest. 69, 138–144 (2009).
  Article CAS PubMed Google Scholar
• Kosugi, T. et al. Lowering blood pressure blocks mesangiolysis and mesangial nodules, but not tubulointerstitial injury, in diabetic eNOS knockout mice. Am. J. Pathol. 174, 1221–1229 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Temm, C. & Dominguez, J. H. Microcirculation: nexus of comorbidities in diabetes. Am. J. Physiol. Renal Physiol. 293, F486–F493 (2007).
  Article CAS PubMed Google Scholar
• Brodsky, S. V., Morrishow, A. M., Dharia, N., Gross, S. S. & Goligorsky, M. S. Glucose scavenging of nitric oxide. Am. J. Physiol. Renal Physiol. 280, F480–F486 (2001).
  Article CAS PubMed Google Scholar
• Bucala, R., Tracey, K. J. & Cerami, A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J. Clin. Invest. 87, 432–438 (1991).
  Article CAS PubMed PubMed Central Google Scholar
• Khosla, U. M. et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 67, 1739–1742 (2005).
  Article PubMed Google Scholar
• Xiong, Y., Lei, M., Fu, S. & Fu, Y. Effect of diabetic duration on serum concentrations of endogenous inhibitor of nitric oxide synthase in patients and rats with diabetes. Life Sci. 77, 149–159 (2005).
  Article CAS PubMed Google Scholar
• Ceriello, A. et al. Detection of nitrotyrosine in the diabetic plasma: evidence of oxidative stress. Diabetologia 44, 834–838 (2001).
  Article CAS PubMed Google Scholar
• Noiri, E. et al. Association of eNOS Glu298Asp polymorphism with end-stage renal disease. Hypertension 40, 535–540 (2002).
  Article CAS PubMed Google Scholar
• Liu, Y. et al. T-786C polymorphism of the endothelial nitric oxide synthase gene is associated with albuminuria in the diabetes heart study. J. Am. Soc. Nephrol. 16, 1085–1090 (2005).
  Article CAS PubMed Google Scholar
• Neugebauer, S., Baba, T. & Watanabe, T. Association of the nitric oxide synthase gene polymorphism with an increased risk for progression to diabetic nephropathy in type 2 diabetes. Diabetes 49, 500–503 (2000).
  Article CAS PubMed Google Scholar
• Shin Shin, Y. et al. Relations between eNOS Glu298Asp polymorphism and progression of diabetic nephropathy. Diabetes Res. Clin. Pract. 65, 257–265 (2004).
  Article CAS PubMed Google Scholar
• Zanchi, A. et al. Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. Kidney Int. 57, 405–413 (2000).
  Article CAS PubMed Google Scholar
• Degen, B., Schmidt, S. & Ritz, E. A polymorphism in the gene for the endothelial nitric oxide synthase and diabetic nephropathy. Nephrol. Dial. Transplant. 16, 185 (2001).
  Article CAS PubMed Google Scholar
• Lin, S., Qu, H. & Qiu, M. Allele A in intron 4 of ecNOS gene will not increase the risk of diabetic nephropathy in type 2 diabetes of Chinese population. Nephron 91, 768 (2002).
  Article PubMed Google Scholar
• Rippin, J. D. et al. Nitric oxide synthase gene polymorphisms and diabetic nephropathy. Diabetologia 46, 426–428 (2003).
  Article CAS PubMed Google Scholar
• Shimizu, T., Onuma, T., Kawamori, R., Makita, Y. & Tomino, Y. Endothelial nitric oxide synthase gene and the development of diabetic nephropathy. Diabetes Res. Clin. Pract. 58, 179–185 (2002).
  Article CAS PubMed Google Scholar
• Hohenstein, B. et al. Analysis of NO-synthase expression and clinical risk factors in human diabetic nephropathy. Nephrol. Dial. Transplant. 23, 1346–1354 (2008).
  Article CAS PubMed Google Scholar
• Sugimoto, H. et al. Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy. Diabetologia 41, 1426–1434 (1998).
  Article CAS PubMed Google Scholar
• Brodsky, S. V., Gao, S., Li, H. & Goligorsky, M. S. Hyperglycemic switch from mitochondrial nitric oxide to superoxide production in endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 283, H2130–H2139 (2002).
  Article CAS PubMed Google Scholar
• Komers, R. et al. Altered endothelial nitric oxide synthase targeting and conformation and caveolin-1 expression in the diabetic kidney. Diabetes 55, 1651–1659 (2006).
  Article CAS PubMed Google Scholar
• Mogyorosi, A. & Ziyadeh, F. N. Increased decorin mRNA in diabetic mouse kidney and in mesangial and tubular cells cultured in high glucose. Am. J. Physiol. 275, F827–F832 (1998).
  CAS PubMed Google Scholar
• Flyvbjerg, A., Bennett, W. F., Rasch, R., Kopchick, J. J. & Scarlett, J. A. Inhibitory effect of a growth hormone receptor antagonist (G120K-PEG) on renal enlargement, glomerular hypertrophy, and urinary albumin excretion in experimental diabetes in mice. Diabetes 48, 377–382 (1999).
  Article CAS PubMed Google Scholar
• Inada, A. et al. A model for diabetic nephropathy: advantages of the inducible cAMP early repressor transgenic mouse over the streptozotocin-induced diabetic mouse. J. Cell Physiol. 215, 383–391 (2008).
  Article CAS PubMed Google Scholar
• Breyer, M. D. et al. Mouse models of diabetic nephropathy. J. Am. Soc. Nephrol. 16, 27–45 (2005).
  Article PubMed Google Scholar
• Fujimoto, M. et al. Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy. Biochem. Biophys. Res. Commun. 305, 1002–1007 (2003).
  Article CAS PubMed Google Scholar
• Wang, A. et al. Interference with TGF-beta signaling by _Smad3_-knockout in mice limits diabetic glomerulosclerosis without affecting albuminuria. Am. J. Physiol. Renal Physiol. 293, F1657–F1665 (2007).
  Article CAS PubMed Google Scholar
• Tay, Y. C. et al. Can murine diabetic nephropathy be separated from superimposed acute renal failure? Kidney Int. 68, 391–398 (2005).
  Article PubMed Google Scholar
• Kanetsuna, Y. et al. Deficiency of endothelial nitric-oxide synthase confers susceptibility to diabetic nephropathy in nephropathy-resistant inbred mice. Am. J. Pathol. 170, 1473–1484 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Nakagawa, T. et al. Diabetic eNOS knockout mice develop advanced diabetic nephropathy. J. Am. Soc. Nephrol 18, 539–550 (2007).
  Article CAS PubMed Google Scholar
• Brosius, F. C. 3rd et al. Mouse models of diabetic nephropathy. J. Am. Soc. Nephrol. 20, 2503–2512 (2009).
  Article PubMed Google Scholar
• Borch-Johnsen, K., Kreiner, S. & Deckert, T. Mortality of type 1 (insulin-dependent) diabetes mellitus in Denmark: a study of relative mortality in 2,930 Danish type 1 diabetic patients diagnosed from 1933 to 1972. Diabetologia 29, 767–772 (1986).
  Article CAS PubMed Google Scholar
• Groop, P. H. et al. The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes. Diabetes 58, 1651–1658 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Nakagawa, T., Kosugi, T., Haneda, M., Rivard, C. J. & Long, D. A. Abnormal angiogenesis in diabetic nephropathy. Diabetes 58, 1471–1478 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Ichinose, K. et al. 2-(8-Hydroxy-6-methoxy-1-oxo-1h-2-benzopyran-3-yl) propionic acid, an inhibitor of angiogenesis, ameliorates renal alterations in obese type 2 diabetic mice. Diabetes 55, 1232–1242 (2006).
  Article CAS PubMed Google Scholar
• Ichinose, K. et al. Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model. Diabetes 54, 2891–2903 (2005).
  Article CAS PubMed Google Scholar
• Yamamoto, Y. et al. Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. Diabetes 53, 1831–1840 (2004).
  Article CAS PubMed Google Scholar
• Guo, M. et al. A stereological study of the renal glomerular vasculature in the db/db mouse model of diabetic nephropathy. J. Anat. 207, 813–821 (2005).
  Article PubMed PubMed Central Google Scholar
• Nakagawa, T. Uncoupling of the VEGF-endothelial nitric oxide axis in diabetic nephropathy: an explanation for the paradoxical effects of VEGF in renal disease. Am. J. Physiol. Renal Physiol. 292, F1665–F1672 (2007).
  Article CAS PubMed Google Scholar
• Nakagawa, T. et al. Uncoupling of vascular endothelial growth factor with nitric oxide as a mechanism for diabetic vasculopathy. J. Am. Soc. Nephrol. 17, 736–745 (2006).
  Article CAS PubMed Google Scholar
• Huang, P. L. et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377, 239–242 (1995).
  Article CAS PubMed Google Scholar
• Barber, A. J. et al. The Ins2 Akita mouse as a model of early retinal complications in diabetes. Invest. Ophthalmol. Vis. Sci. 46, 2210–2218 (2005).
  Article PubMed Google Scholar
• Feit-Leichman, R. A. et al. Vascular damage in a mouse model of diabetic retinopathy: relation to neuronal and glial changes. Invest. Ophthalmol. Vis. Sci. 46, 4281–4287 (2005).
  Article PubMed Google Scholar
• Barber, A. J., Antonetti, D. A. & Gardner, T. W. Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes. The Penn State Retina Research Group. Invest. Ophthalmol. Vis. Sci. 41, 3561–3568 (2000).
  CAS PubMed Google Scholar
• Rungger-Brändle, E., Dosso, A. A. & Leuenberger, P. M. Glial reactivity, an early feature of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 41, 1971–1980 (2000).
  PubMed Google Scholar
• Mizutani, M., Gerhardinger, C. & Lorenzi, M. Müller cell changes in human diabetic retinopathy. Diabetes 47, 445–449 (1998).
  Article CAS PubMed Google Scholar
• Li, Q. et al. Diabetic eNOS knockout mice develop accelerated retinopathy. Invest. Ophthalmol. Vis. Sci. 51, 5240–5246 (2010).
  Article PubMed PubMed Central Google Scholar
• Feng, D. et al. von Willebrand factor and retinal circulation in early-stage retinopathy of type 1 diabetes. Diabetes Care 23, 1694–1698 (2000).
  Article CAS PubMed Google Scholar
• Quiroz, Y. et al. Mycophenolate mofetil prevents salt-sensitive hypertension resulting from nitric oxide synthesis inhibition. Am. J. Physiol. Renal Physiol. 281, F38–F47 (2001).
  Article CAS PubMed Google Scholar
• Edwards, R. M. & Trizna, W. Modulation of glomerular arteriolar tone by nitric oxide synthase inhibitors. J. Am. Soc. Nephrol. 4, 1127–1132 (1993).
  CAS PubMed Google Scholar
• Patzak, A. et al. Nitric oxide counteracts angiotensin II induced contraction in efferent arterioles in mice. Acta Physiol. Scand. 181, 439–444 (2004).
  Article CAS PubMed Google Scholar
• Sánchez-Lozada, L. G. et al. Mild hyperuricemia induces glomerular hypertension in normal rats. Am. J. Physiol. Renal Physiol. 283, F1105–F1110 (2002).
  Article PubMed Google Scholar
• Ferrara, N. Vascular endothelial growth factor: basic science and clinical progress. Endocr. Rev. 25, 581–611 (2004).
  Article CAS PubMed Google Scholar
• Flyvbjerg, A., Schrijvers, B. F., De Vriese, A. S., Tilton, R. G. & Rasch, R. Compensatory glomerular growth after unilateral nephrectomy is VEGF dependent. Am. J. Physiol. Endocrinol. Metab. 283, E362–E366 (2002).
  Article CAS PubMed Google Scholar
• de Vriese, A. S. et al. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J. Am. Soc. Nephrol. 12, 993–1000 (2001).
  CAS Google Scholar
• Flyvbjerg, A. et al. Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody. Diabetes 51, 3090–3094 (2002).
  Article CAS PubMed Google Scholar
• Sato, W. et al. The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy. Lab. Invest. 88, 949–961 (2008).
  Article CAS PubMed Google Scholar
• Bussolati, B. et al. Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide. Am. J. Pathol. 159, 993–1008 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Kang, D. H., Hughes, J., Mazzali, M., Schreiner, G. F. & Johnson, R. J. Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J. Am. Soc. Nephrol. 12, 1448–1457 (2001).
  CAS PubMed Google Scholar
• Shimizu, A. et al. Vascular endothelial growth factor165 resolves glomerular inflammation and accelerates glomerular capillary repair in rat anti-glomerular basement membrane glomerulonephritis. J. Am. Soc. Nephrol. 15, 2655–2665 (2004).
  Article CAS PubMed Google Scholar
• Matsushita, K. et al. Nitric oxide regulates exocytosis by _S_-nitrosylation of _N_-ethylmaleimide-sensitive factor. Cell 115, 139–150 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Nakayama, T. et al. Endothelial von Willebrand factor release due to eNOS deficiency predisposes to thrombotic microangiopathy in mouse aging kidney. Am. J. Pathol. 176, 2198–2208 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Farquhar, A., MacDonald, M. K. & Ireland, J. T. The role of fibrin deposition in diabetic glomerulosclerosis: a light, electron and immunofluorescence microscopy study. J. Clin. Pathol. 25, 657–667 (1972).
  Article CAS PubMed PubMed Central Google Scholar
• Morgan, C. L. et al. The prevalence of multiple diabetes-related complications. Diabet. Med. 17, 146–151 (2000).
  Article CAS PubMed Google Scholar
• El-Asrar, A. M., Al-Rubeaan, K. A., Al-Amro, S. A., Moharram, O. A. & Kangave, D. Retinopathy as a predictor of other diabetic complications. Int. Ophthalmol. 24, 1–11 (2001).
  Article CAS PubMed Google Scholar
• Rossing, P., Hougaard, P. & Parving, H. H. Risk factors for development of incipient and overt diabetic nephropathy in type 1 diabetic patients: a 10-year prospective observational study. Diabetes Care 25, 859–864 (2002).
  Article PubMed Google Scholar
• 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. 342, 381–389 (2000).
• UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317, 703–713 (1998).
• Brenner, B. M. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001).
  Article CAS PubMed Google Scholar
• Lewis, E. J., Hunsicker, L. G., Bain, R. P. & Rohde, R. D. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N. Engl. J. Med. 329, 1456–1462 (1993).
  Article CAS PubMed Google Scholar
• Lewis, E. J. et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med. 345, 851–860 (2001).
  Article CAS PubMed Google Scholar
• Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 355, 253–259 (2000).
• Patel, A. et al. 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, 829–840 (2007).
  Article CAS PubMed Google Scholar
• Mauer, M. et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N. Engl. J. Med. 361, 40–51 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Chaturvedi, N. et al. 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, 1394–1402 (2008).
  Article CAS PubMed Google Scholar
• Sjølie, A. K. et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect. 2): a randomised placebo-controlled trial. Lancet 372, 1385–1393 (2008).
  Article CAS PubMed Google Scholar
• Bilous, R. et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann. Intern. Med. 151, 11–20 (2009).
  Article PubMed Google Scholar
• Mathiesen, E. R., Hommel, E., Giese, J. & Parving, H. H. Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. BMJ 303, 81–87 (1991).
  Article CAS PubMed PubMed Central Google Scholar
• Berlowitz, D. R. et al. Hypertension management in patients with diabetes: the need for more aggressive therapy. Diabetes Care 26, 355–359 (2003).
  Article PubMed Google Scholar
• Tomlinson, J. W., Owen, K. R. & Close, C. F. Treating hypertension in diabetic nephropathy. Diabetes Care 26, 1802–1805 (2003).
  Article CAS PubMed Google Scholar
• Sato, A., Hayashi, K., Naruse, M. & Saruta, T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 41, 64–68 (2003).
  Article CAS PubMed Google Scholar
• Schjoedt, K. J., Andersen, S., Rossing, P., Tarnow, L. & Parving, H. H. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 47, 1936–1939 (2004).
  Article CAS PubMed Google Scholar
• Mehdi, U. F., Adams-Huet, B., Raskin, P., Vega, G. L. & Toto, R. D. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J. Am. Soc. Nephrol. 20, 2641–2650 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Papaioannou, G. I. et al. Brachial artery reactivity in asymptomatic patients with type 2 diabetes mellitus and microalbuminuria (from the Detection of Ischemia in Asymptomatic Diabetics-brachial artery reactivity study). Am. J. Cardiol. 94, 294–299 (2004).
  Article PubMed Google Scholar
• Stehouwer, C. D. et al. Microalbuminuria is associated with impaired brachial artery, flow-mediated vasodilation in elderly individuals without and with diabetes: further evidence for a link between microalbuminuria and endothelial dysfunction—the Hoorn Study. Kidney Int. Suppl. S42–S44 (2004).
• Schalkwijk, C. G., Smulders, R. A., Lambert, J., Donker, A. J. & Stehouwer, C. D. ACE-inhibition modulates some endothelial functions in healthy subjects and in normotensive type 1 diabetic patients. Eur. J. Clin. Invest. 30, 853–860 (2000).
  Article CAS PubMed Google Scholar
• Perregaux, D. et al. Brachial vascular reactivity in blacks. Hypertension 36, 866–871 (2000).
  Article CAS PubMed Google Scholar
• Dries, D. L. et al. Racial differences in the outcome of left ventricular dysfunction. N. Engl. J. Med. 340, 609–616 (1999).
  Article CAS PubMed Google Scholar
• Dries, D. L., Strong, M. H., Cooper, R. S. & Drazner, M. H. Efficacy of angiotensin-converting enzyme inhibition in reducing progression from asymptomatic left ventricular dysfunction to symptomatic heart failure in black and white patients. J. Am. Coll. Cardiol. 40, 311–317 (2002).
  Article CAS PubMed Google Scholar
• Julius, S. et al. Cardiovascular risk reduction in hypertensive black patients with left ventricular hypertrophy: the LIFE study. J. Am. Coll. Cardiol. 43, 1047–1055 (2004).
  Article PubMed Google Scholar
• Jawa, A., Nachimuthu, S., Pendergrass, M., Asnani, S. & Fonseca, V. Impaired vascular reactivity in African-American patients with type 2 diabetes mellitus and microalbuminuria or proteinuria despite angiotensin-converting enzyme inhibitor therapy. J. Clin. Endocrinol. Metab. 91, 31–35 (2006).
  Article CAS PubMed Google Scholar
• Muldowney, J. A. 3rd, Davis, S. N., Vaughan, D. E. & Brown, N. J. NO synthase inhibition increases aldosterone in humans. Hypertension 44, 739–745 (2004).
  Article CAS PubMed Google Scholar
• Hanke, C. J. & Campbell, W. B. Endothelial cell nitric oxide inhibits aldosterone synthesis in zona glomerulosa cells: modulation by oxygen. Am. J. Physiol. Endocrinol. Metab. 279, E846–E854 (2000).
  Article CAS PubMed Google Scholar
• Arima, S. et al. Endothelium-derived nitric oxide modulates vascular action of aldosterone in renal arteriole. Hypertension 43, 352–357 (2004).
  Article CAS PubMed Google Scholar
• Ikeda, H. et al. Spironolactone suppresses inflammation and prevents L-NAME-induced renal injury in rats. Kidney Int. 75, 147–155 (2009).
  Article CAS PubMed Google Scholar
• Sainz, J. M. et al. Effects of nitric oxide on aldosterone synthesis and nitric oxide synthase activity in glomerulosa cells from bovine adrenal gland. Endocrine 24, 61–71 (2004).
  Article CAS PubMed Google Scholar
• Lee, S. H. et al. Activation of local aldosterone system within podocytes is involved in apoptosis under diabetic conditions. Am. J. Physiol. Renal Physiol. 297, F1381–F1390 (2009).
  Article CAS PubMed Google Scholar
• Wilkinson-Berka, J. L., Tan, G., Jaworski, K. & Miller, A. G. Identification of a retinal aldosterone system and the protective effects of mineralocorticoid receptor antagonism on retinal vascular pathology. Circ. Res. 104, 124–133 (2009).
  Article CAS PubMed Google Scholar
• Kosugi, T., Heinig, M., Nakayama, T., Matsuo, S. & Nakagawa, T. eNOS knockout mice with advanced diabetic nephropathy have less benefit from renin–angiotensin blockade than from aldosterone receptor antagonists. Am. J. Pathol. 49, 51–54 (2010).
  Google Scholar
• Wilkinson-Berka, J. L., Tan, G., Jaworski, K. & Miller, A. G. Identification of a retinal aldosterone system and the protective effects of mineralocorticoid receptor antagonism on retinal vascular pathology. Circ. Res. 104, 124–133 (2009).
  Article CAS PubMed Google Scholar
• Tousoulis, D. et al. Novel therapies targeting vascular endothelium. Endothelium 13, 411–421 (2006).
  Article CAS PubMed Google Scholar