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Nitric oxide in the normal kidney and in patients with diabetic nephropathy

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Abstract

Nitric oxide (NO) is a gas with biological and regulatory properties, produced from arginine by the way of nitric oxide synthases (NOS), and with a very short half-life (few seconds). A “coupled” NOS activity leads to NO generation, whereas its uncoupling produces the reactive oxygen species peroxynitrite (ONOO−). Uncoupling is usually due to inflammation, oxidative stress, decreased cofactor availability, or excessive NO production. Competitive inhibitors of NO production are post-translationally methylated arginine residues in proteins, which are constantly released into the circulation. NO availability is altered in many clinical conditions associated with vascular dysfunction, such as diabetes mellitus. The kidney plays an important role in body NO homeostasis. This article provides an overview of current literature, on NO production/availability, with a focus on diabetic nephropathy. In diabetes, NO availability is usually decreased (with exception of the early, hyper filtration phase of nephropathy in Type 1 diabetes), and it could constitute a factor of the generalized vasculopathy present in diabetic nephropathy. NO generation in Type 2 diabetes with nephropathy is inversely associated with the dimethyl-arginine concentrations, which are therefore important modulators of NO synthesis independently from the classic stimulatory pathways (such as the insulin effect). A disturbed NO metabolism is present in diabetes associated with nephropathy. Although modulation of NO production is not yet a common therapeutical strategy, a number of yet experimental compounds need to be tested as potential interventions to treat the vascular dysfunction and nephropathy in diabetes, as well as in other diseased states. Finally, in diabetic nephropathy NO deficiency may be associated to that of hydrogen sulfide, another interesting gaseous mediator which is increasingly investigated.

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References

  1. Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Engl J Med 329(27):2002–2012

    CAS  PubMed  Google Scholar 

  2. Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288(5789):373–376

    CAS  PubMed  Google Scholar 

  3. Förstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33(7):829–837

    PubMed Central  PubMed  Google Scholar 

  4. Boudko DY (2007) Bioanalytical profile of the L-arginine/nitric oxide pathway and its evaluation by capillary electrophoresis. J Chromatogr B Analyt Technol Biomed Life Sci 851(1–2):186–210

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Dejam A, Hunter CJ, Pelletier MM et al (2005) Erythrocytes are the major intravascular storage sites of nitrite in human blood. Blood 106(2):734–739

    PubMed Central  CAS  PubMed  Google Scholar 

  6. Recchia FA, Vogel TR, Hintze TH (2000) NO metabolites accumulate in erythrocytes in proportion to carbon dioxide and bicarbonate concentration. Am J Physiol Heart Circ Physiol 279(2):H852–H856

    CAS  PubMed  Google Scholar 

  7. Nathan C, Xie QW (1994) Regulation of biosynthesis of nitric oxide. J Biol Chem 269(19):13725–13728

    CAS  PubMed  Google Scholar 

  8. Chen K, Popel AS (2007) Vascular and perivascular nitric oxide release and transport: biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3). Free Radic Biol Med 42(6):811–822

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Haque MM, Panda K, Tejero J et al (2007) A connecting hinge represses the activity of endothelial nitric oxide synthase. Proc Natl Acad Sci USA 104(22):9254–9259

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Mann GE, Yudilevich DL, Sobrevia L (2003) Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells. Physiol Rev 83(1):183–252

    CAS  PubMed  Google Scholar 

  11. Montezano AC, Touyz RM (2012) Reactive oxygen species and endothelial function—role of NOS uncoupling and Nox family NADPH oxidases. Basic Clin Pharmacol Toxicol 110(1):87–94

    CAS  PubMed  Google Scholar 

  12. Leiper J, Nandi M (2011) The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis. Nat Rev Drug Discov 10(4):277–291

    CAS  PubMed  Google Scholar 

  13. Davids M, Swieringa E, Palm F et al (2012) Simultaneous determination of asymmetric and symmetric dimethylarginine, L-monomethylarginine, L-arginine, and L-homoarginine in biological samples using stable isotope dilution liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 900:38–47

    CAS  PubMed  Google Scholar 

  14. López-Jaramillo P, Arenas WD, García RG et al (2008) The role of the L-arginine-nitric oxide pathway in preeclampsia. Ther Adv Cardiovasc Dis 2(4):261–275

    PubMed  Google Scholar 

  15. Leighton F, Urquiaga I (2007) Endothelial nitric oxide synthase as a mediator of the positive health effects of Mediterranean diets and wine against metabolic syndrome. World Rev Nutr Diet 97:33–51

    CAS  PubMed  Google Scholar 

  16. Shpektor A (2010) Cardiogenic shock: the role of inflammation. Acute Card Care 12(4):115–118

    PubMed  Google Scholar 

  17. Kayali Z, Herring J, Baron P et al (2009) Increased plasma nitric oxide, L-arginine, and arginase-1 in cirrhotic patients with progressive renal dysfunction. J Gastroenterol Hepatol 24(6):1030–1037

    CAS  PubMed  Google Scholar 

  18. Böger RH, Diemert A, Schwedhelm E et al (2010) The role of nitric oxide synthase inhibition by asymmetric dimethylarginine in the pathophysiology of preeclampsia. Gynecol Obstet Invest 69(1):1–13

    PubMed  Google Scholar 

  19. Münzel T, Daiber A, Gori T (2011) Nitrate therapy: new aspects concerning molecular action and tolerance. Circulation 123(19):2132–2144 Review

    PubMed  Google Scholar 

  20. Mount PF, Power DA (2006) Nitric oxide in the kidney: functions and regulation of synthesis. Acta Physiol (Oxf) 187(4):433–446

    CAS  Google Scholar 

  21. Rippin JD, Patel A, Belyaev ND et al (2003) Nitric oxide synthase gene polymorphisms and diabetic nephropathy. Diabetologia 46(3):426–428

    CAS  PubMed  Google Scholar 

  22. Welch WJ, Wilcox CS (1997) Macula densa arginine delivery and uptake in the rat regulates glomerular capillary pressure. Effects of salt intake. J Clin Invest 100(9):2235–2242

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Hall CN, Garthwaite J (2009) What is the real physiological NO concentration in vivo? Nitric Oxide 21(2):92–103

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Brosnan ME, Brosnan JT (2004) Renal arginine metabolism. J Nutrition 134:2791S–2797S

    CAS  Google Scholar 

  25. Kakoki M, Kim HS, Edgell CJS et al (2006) Amino acids as modulators of endothelium-derived nitric oxide. Am J Physiol Renal Physiol 291(2):F297–F304

    CAS  PubMed  Google Scholar 

  26. Wu F, Cholewa B, Mattson DL (2000) Characterization of L-arginine transporters in rat renal inner medullary collecting duct. Am J Physiol Regul Integr Comp Physiol 278(6):R1506–R1512

    CAS  PubMed  Google Scholar 

  27. Zoccali C (2007) The endothelium as a target in renal diseases. J Nephrol 20(Suppl 12):S39–S44

    CAS  PubMed  Google Scholar 

  28. Lahera V, Salom MG, Miranda-Guardiola F et al (1991) Effects of NG-nitro-L-arginine methyl ester on renal function and blood pressure. Am J Physiol 261(6 Pt 2):F1033–F1037

    CAS  PubMed  Google Scholar 

  29. Aulak KS, Liu J, Wu J et al (1996) Molecular sites of regulation of expression of the rat cationic amino acid transporter gene. J Biol Chem 271:29799–29806

    CAS  PubMed  Google Scholar 

  30. Kakoki M, Kim H-S, Arendshorst W et al (2004) L-Arginine uptake affects nitric oxide production and blood flow in the renal medulla. Am J Physiol Regul Integr Comp Physiol 287(6):R1478–R1485

    CAS  PubMed  Google Scholar 

  31. Dallinger S, Sieder A, Strametz J et al (2003) Vasodilator effects of L-arginine are stereospecific and augmented by insulin in humans. Am J Physiol Endocrinol Metab 284(6):E1106–E1106

    CAS  PubMed  Google Scholar 

  32. Ruiz M, Singh P, Thomson SC et al (2008) L-arginine-induced glomerular hyperfiltration response: the roles of insulin and ANG-II. Am J Physiol Regul Integr Comp Physiol 294(5):R1744–R1751

    CAS  PubMed  Google Scholar 

  33. Rajapakse NW, Mattson DL (2009) Role of L-arginine in nitric oxide production in health and hypertension. Clin Exp Pharm Physiol 36:249–255

    CAS  Google Scholar 

  34. Gruden G, Viberti G (2005) Pathogenesis of diabetic nephropathy. In: Kahn CR (ed) Joslin’s diabetes mellitus, 14th edn. PA. Lippincott Williams and Wilkins, Philadelphia, pp 853–866

    Google Scholar 

  35. Verzola D, Gandolfo MT, Ferrario F et al (2007) Apoptosis in the kidneys of patients with type II diabetic nephropathy. Kidney Int 72(10):1262–1272

    CAS  PubMed  Google Scholar 

  36. Verzola D, Cappuccino L, D’Amato E, et al. (2014) Enhanced glomerular Toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria. Kidney Int [Epub ahead of print]

  37. Williams ME, Stanton RC (2005) Management of Diabetic Kidney Disease. In: Kahn CR (ed) Joslin’s Diabetes Mellitus, 14th edn. Lippincot Williams & Wilkins, Philadelphia

  38. Zelmanovitz T, Gerchman F, Balthazar APS et al (2009) Diabetic nephropathy. Diabetol Metab Syndr 1(1):10

    PubMed Central  PubMed  Google Scholar 

  39. Rossing P (2005) The changing epidemiology of diabetic microangiopathy in type 1 diabetes. Diabetologia 48:1439–1444

    CAS  PubMed  Google Scholar 

  40. Valmadrid CT, Klein R, Moss SE, Klein BE (2000) The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch Intern Med 160:1093–1100

    CAS  PubMed  Google Scholar 

  41. Amanda Adler I, Richard Stevens J, on behalf of the UKPDS Group et al (2003) Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 63:225–232

    PubMed  Google Scholar 

  42. American Diabetes Association (2004) Nephropathy in diabetes. Position statement. Diabetes Care 27:s79–s83

    Google Scholar 

  43. Reutens AT (2013) Epidemiology of diabetic kidney disease. Med Clin North Am 97(1):1–18

    PubMed  Google Scholar 

  44. Eschwège E (2003) The dysmetabolic syndrome, insulin resistance and increased cardiovascular (CV) morbidity and mortality in type 2 diabetes: aetiological factors in the development of CV complications. Diabetes Metab 29(4 Pt 2):6S19–6S27 (Review)

    PubMed  Google Scholar 

  45. Nakagawa T, Segal M, Croker B, Johnson RJ (2007) A breakthrough in diabetic nephropathy: the role of endothelial dysfunction. Nephrol Dial Transplant 22(10):2775–2777

    CAS  PubMed  Google Scholar 

  46. Tufro A, Veron D (2012) VEGF and podocytes in diabetic nephropathy. Semin Nephrol 32(4):385–393

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Valiatti FB, Crispim D, Benfica C et al (2011) The role of vascular endothelial growth factor in angiogenesis and diabetic retinopathy. Arq Bras Endocrinol Metab 55(2):106–113

    Google Scholar 

  48. Hargrove GM, Dufresne J, Whiteside C et al (2000) Diabetes mellitus increases endothelin-1 gene transcription in rat kidney. Kidney Int 58(4):1534–1545

    CAS  PubMed  Google Scholar 

  49. Muniyappa R, Quon MJ (2007) Insulin action and insulin resistance in vascular endothelium. Curr Opin Clin Nutr Metab Care 10(4):523–530

    CAS  PubMed  Google Scholar 

  50. Tessari P, Inchiostro S, Biolo G et al (1991) Effects of acute systemic hyperinsulinemia on forearm muscle proteolysis in healthy man. J Clin Invest 88(1):27–33

    PubMed Central  CAS  PubMed  Google Scholar 

  51. Tessari P, Biolo G, Inchiostro S et al (1990) Effects of insulin on whole body and forearm leucine and KIC metabolism in type 1 diabetes. Am J Physiol 259(1 Pt 1):E96–E103

    CAS  PubMed  Google Scholar 

  52. Zanetti M, Barazzoni R, Kiwanuka E, Tessari P (1999) Effects of branched-chain-enriched amino acids and insulin on forearm leucine kinetics. Clin Sci (Lond) 97(4):437–448

    CAS  Google Scholar 

  53. Reikerås O, Gunnes P (1986) Effects of high doses of insulin on systemic haemodynamics and regional blood flows in dogs. Clin Physiol 6(2):129–138

    PubMed  Google Scholar 

  54. Brownlee M (1992) Glycation products and the pathogenesis of diabetic complications. Diabetes Care 15(12):1835–1843 (Review)

    CAS  PubMed  Google Scholar 

  55. Selemidis S, Sobey CG, Wingler K et al (2008) NADPH oxidases in the vasculature: molecular features, roles in disease and pharmacological inhibition. Pharmacol Ther 120(3):254–291 (Review)

    CAS  PubMed  Google Scholar 

  56. Tian XY, Wang WT, Xu A et al (2012) Uncoupling protein-2 protects endothelial function in diet-induced obese mice. Circ Res 110(9):1211–1216

    CAS  PubMed  Google Scholar 

  57. Tomita H, Sanford RB, Smithies O, Kakoki M (2012) The kallikrein-kinin system in diabetic nephropathy. Kidney Int 81(8):733–744

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Conway BR, Maxwell AP (2009) Genetics of diabetic nephropathy: are there clues to the understanding of common kidney diseases? Nephron Clin Pract 112(4):c213–c221

    CAS  PubMed  Google Scholar 

  59. Dellamea BS, Pinto LC, Leitão CB et al (2014) Endothelial nitric oxide synthase gene polymorphisms and risk of diabetic nephropathy: a systematic review and meta-analysis. BMC Med Genet 15:9

    PubMed Central  PubMed  Google Scholar 

  60. Kagawa Y, Cha SH, Hasegawa K et al (1999) Regulation of energy metabolism in human cells in aging and diabetes: FoF(1), mtDNA, UCP, and ROS. Biochem Biophys Res Commun 266(3):662–676

    CAS  PubMed  Google Scholar 

  61. Lim SC, Goh SK, Lai YR et al (2006) Relationship between common functional polymorphisms of the p22phox gene (−930 A > G and +242 C > T) and nephropathy as a result of type 2 diabetes in a Chinese population. Diabet Med 23(9):1037–1041

    CAS  PubMed  Google Scholar 

  62. Vozarova B, Fernández-Real JM et al (2003) The interleukin-6 (−174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians. Hum Genet 112(4):409–413

    CAS  PubMed  Google Scholar 

  63. Kang P, Tian C, Jia C (2012) Association of RAGE gene polymorphisms with type 2 diabetes mellitus, diabetic retinopathy and diabetic nephropathy. Gene 500(1):1–9

    CAS  PubMed  Google Scholar 

  64. Abhary S, Burdon KP, Kuot A et al (2010) Sequence variation in DDAH1 and DDAH2 genes is strongly and additively associated with serum ADMA concentrations in individuals with type 2 diabetes. PLoS One 5(3):e9462

    PubMed Central  PubMed  Google Scholar 

  65. Tanhäuserová V, Tomand J, Pácal L et al (2012) ADMA, SDMA and L-arginine/ADMA ratio but not DDAH genetic polymorphisms are reliable predictors of diabetic nephropathy progression as identified by competing risk analysis. Kidney Blood Press Res 36(1):200–208

    PubMed  Google Scholar 

  66. Pieper GM (1999) Enhanced, unaltered and impaired nitric oxide-mediated endothelium-dependent relaxation in experimental diabetes mellitus: importance of disease duration. Diabetologia 42(2):204–213

    CAS  PubMed  Google Scholar 

  67. Ishii N, Patel KP, Lane PH et al (2001) Nitric oxide synthesis and oxidative stress in the renal cortex of rats with diabetes mellitus. J Am Soc Nephrol 12(8):1630–1639

    CAS  PubMed  Google Scholar 

  68. Komers R, Anderson S (2003) Paradoxes of nitric oxide in the diabetic kidney. Am J Physiol Renal Physiol 284(6):F1121–F1137

    CAS  PubMed  Google Scholar 

  69. Prabhakar SS (2004) Role of nitric oxide in diabetic nephropathy. Semin Nephrol 24(4):333–344

    CAS  PubMed  Google Scholar 

  70. Goligorsky, Chen J, Brodsky S (2001) Workshop: endothelial cell dysfunction leading to diabetic nephropathy: focus on nitric oxide. Hypertension 37(2 Part 2):744–748

    CAS  PubMed  Google Scholar 

  71. Prabhakar S, Starnes J, Shi S et al (2007) Diabetic nephropathy is associated with oxidative stress and decreased renal nitric oxide production. J Am Soc Nephrol 18(11):2452–2945

    Google Scholar 

  72. Stehouver CD, Henry RM, Dekker JM et al (2004) Microalbuminuria is associated with impaired endothelium dependent, 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 92:S42–S44

    Google Scholar 

  73. Chu S, Bohlen HG (2004) High concentration of glucose inhibits glomerular endothelial eNOS through a PKC mechanism. Am J Physiol Renal Physiol 287(3):F384–F392

    CAS  PubMed  Google Scholar 

  74. Tessari P, Cecchet D, Cosma A et al (2010) Nitric oxide synthesis is reduced in subjects with type 2 diabetes and nephropathy. Diabetes 59(9):2152–2159

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Avogaro A, Toffolo G, Kiwanuka E et al (2003) L-arginine-nitric oxide kinetics in normal and type 2 diabetic subjects: a stable-labelled 15N arginine approach. Diabetes 52(3):795–802

    CAS  PubMed  Google Scholar 

  76. Kashyap SR, Roman LJ, Lamont J et al (2005) Insulin resistance is associated with impaired nitric oxide synthase activity in skeletal muscle of type 2 diabetic subjects. J Clin Endocrinol Metab 90(2):1100–1105

    CAS  PubMed  Google Scholar 

  77. Tessari P, Cecchet D, Artusi C et al (2013) Roles of insulin, age, and asymmetric dimethylarginine on nitric oxide synthesis in vivo. Diabetes 62(8):2699–2708

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Badal SS, Danesh FR (2012) Strategies to reverse endothelial dysfunction in diabetic nephropathy. Kidney Int 82(11):1151–1154

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Noori N, Tabibi H, Hosseinpanah F et al (2013) Effects of combined lipoic acid and pyridoxine on albuminuria, advanced glycation end-products, and blood pressure in diabetic nephropathy. Int J Vitam Nutr Res 83(2):77–85

    CAS  PubMed  Google Scholar 

  80. Imanishi M, Okada N, Konishi Y et al (2013) Angiotensin II receptor blockade reduces salt sensitivity of blood pressure through restoration of renal nitric oxide synthesis in patients with diabetic nephropathy. J Renin Angiotensin Aldosterone Syst 14(1):67–73

    CAS  PubMed  Google Scholar 

  81. Arima S, Kohagura K, Takeuchi K et al (2002) Biphasic vasodilator action of troglitazone on the renal microcirculation. J Am Soc Nephrol 13:342e9

    Google Scholar 

  82. Bolignano D, Zoccali C (2012) Glitazones in chronic kidney disease: potential and concerns. Nutr Metab Cardiovasc Dis 22(3):167–175

    CAS  PubMed  Google Scholar 

  83. Pistrosch F, Passauer J, Herbrig K et al (2012) Effect of thiazolidinedione treatment on proteinuria and renal hemodynamic in type 2 diabetic patients with overt nephropathy. Horm Metab Res 44(12):914–918

    CAS  PubMed  Google Scholar 

  84. Nakamura T, Ushiyama C, Shimada N et al (2000) Comparative effects of pioglitazone, glibenclamide, and voglibose on urinary endothelin-1 and albumin excretion. In diabetes patients. J Diabetes Complicat 14:250e4

    Google Scholar 

  85. Hanefeld M, Brunetti P, Schernthaner GH, QUARTET study group et al (2004) One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes. Diabetes Care 27:141e7

    Google Scholar 

  86. Sironi AM, Vichi S, Gastaldelli A et al (1997) Effects of troglitazone on insulin action and cardiovascular risk factors in patients with non-insulin-dependent diabetes. Clin Pharmacol Ther 62:194–202

    CAS  PubMed  Google Scholar 

  87. Agarwal R, Saha C, Battiwala M et al (2005) A pilot randomized controlled trial of renal protection with pioglitazone in diabetic nephropathy. Kidney Int 68:285–292

    CAS  PubMed  Google Scholar 

  88. Cherney DZ, Perkins BA, Soleymanlou N et al (2014) Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129(5):587–597

    CAS  PubMed  Google Scholar 

  89. Hills CE, Brunskill NJ, Squires PE (2010) C-peptide as a therapeutic tool in diabetic nephropathy. Am J Nephrol 31(5):389–397

    CAS  PubMed  Google Scholar 

  90. Turgut F, Bolton WK (2010) Potential new therapeutic agents for diabetic kidney disease. Am J Kidney Dis 55(5):928–940

    CAS  PubMed  Google Scholar 

  91. Coronel I, Arellano-Mendoza MG, del Valle-Mondragon L et al (2010) L-arginine and antioxidant diet supplementation partially restores nitric oxide-dependent regulation of phenylephrine renal vasoconstriction in diabetics rats. J Ren Nutr 20(3):158–168

    CAS  PubMed  Google Scholar 

  92. Klahr S, Morrissey J (2004) L-arginine as a therapeutic tool in kidney disease. Semin Nephrol 24(4):389–394 (Review)

    CAS  PubMed  Google Scholar 

  93. Verzola D, Bertolotto MB, Villaggio B et al (2002) Taurine prevents apoptosis induced by high ambient glucose in human tubule renal cells. J Investig Med 50(6):443–451

    CAS  PubMed  Google Scholar 

  94. Pandya KG, Budhram R, Clark G, Lau-Cam CA (2013) Comparative evaluation of taurine and thiotaurine as protectants against diabetes-induced nephropathy in a rat model. Adv Exp Med Biol 775:371–394

    CAS  PubMed  Google Scholar 

  95. Xiao L, Zhu X, Yang S et al (2014) Rap1 ameliorates renal tubular injury in diabetic nephropathy. Diabetes 63(4):1366–1380

    PubMed Central  CAS  PubMed  Google Scholar 

  96. Yuan F, Liu YH, Liu FY et al (2014) Intraperitoneal administration of the globular adiponectin gene ameliorates diabetic nephropathy in Wistar rats. Mol Med Rep 9(6):2293–2300

    CAS  PubMed  Google Scholar 

  97. Matavelli LC, Siragy HM (2013) Reduction of aldosterone production improves renal oxidative stress and fibrosis in diabetic rats. J Cardiovasc Pharmacol 61(1):17–22

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Ishizawa K, Izawa-Ishizawa Y, Yamano N et al (2014) Nitrosonifedipine ameliorates the progression of type 2 diabetic nephropathy by exerting antioxidative effects. PLoS One 9(1):e86335

    PubMed Central  PubMed  Google Scholar 

  99. Romero MJ, Yao L, Sridhar S et al (2013) l-Citrulline Protects from Kidney Damage in Type 1 Diabetic Mice. Front Immunol 4:480

    PubMed Central  PubMed  Google Scholar 

  100. Dessapt-Baradez C, Woolf AS, White KE et al (2014) Targeted glomerular angiopoietin-1 therapy for early diabetic kidney disease. J Am Soc Nephrol 25(1):33–42

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Schildknecht S, Weber A, Gerding HR et al (2013) The NOX1/4 inhibitor GKT136901 as selective and direct scavenger of peroxynitrite. Curr Med Chem 21(3):365–376

    Google Scholar 

  102. You H, Gao T, Cooper TK et al (2013) Arginase inhibition mediates renal tissue protection in diabetic nephropathy by a nitric oxide synthase 3-dependent mechanism. Kidney Int 84(6):1189–1197

    CAS  PubMed  Google Scholar 

  103. Gu Y, Gong Y, Zhang H et al (2013) Regulation of transforming growth factor beta 1 gene expression by dihydropteridine reductase in kidney 293T cells. Biochem Cell Biol 91(3):187–193

    CAS  PubMed  Google Scholar 

  104. Kidokoro K, Satoh M, Channon KM et al (2013) Maintenance of endothelial guanosine triphosphate cyclohydrolase I ameliorates diabetic nephropathy. J Am Soc Nephrol 24(7):1139–1150

    PubMed Central  CAS  PubMed  Google Scholar 

  105. Cheng H, Wang H, Fan X et al (2012) Improvement of endothelial nitric oxide synthase activity retards the progression of diabetic nephropathy in db/db mice. Kidney Int 82(11):1176–1183

    PubMed Central  CAS  PubMed  Google Scholar 

  106. Asakura J, Hasegawa H, Takayanagi K et al (2012) Renoprotective effect of pioglitazone by the prevention of glomerular hyperfiltration through the possible restoration of altered macula densa signaling in rats with type 2 diabetic nephropathy. Nephron Exp Nephrol 122(3–4):83–94

    CAS  PubMed  Google Scholar 

  107. Lin M, Yiu WH, Li RX et al (2013) The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy. Kidney Int 83(5):887–900

    CAS  PubMed  Google Scholar 

  108. Ptilovanciv EO, Fernandes GS, Teixeira LC et al (2013) Heme oxygenase 1 improves glucoses metabolism and kidney histological alterations in diabetic rats. Diabetol Metab Syndr 5(1):3

    PubMed Central  CAS  PubMed  Google Scholar 

  109. Ojima A, Ishibashi Y, Matsui T et al (2013) Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression. Am J Pathol 182(1):132–141

    CAS  PubMed  Google Scholar 

  110. Faria AM, Papadimitriou A, Silva KC et al (2012) Uncoupling endothelial nitric oxide synthase is ameliorated by green tea in experimental diabetes by re-establishing tetrahydrobiopterin levels. Diabetes 61(7):1838–1847

    PubMed Central  CAS  PubMed  Google Scholar 

  111. Park CH, Noh JS, Tanaka T, Yokozawa T (2012) 7-O-galloyl-D-sedoheptulose ameliorates renal damage triggered by reactive oxygen species-sensitive pathway of inflammation and apoptosis. J Pharm Pharmacol 64(12):1730–1740

    CAS  PubMed  Google Scholar 

  112. Kuno Y, Iyoda M, Shibata T et al (2011) Sildenafil, a phosphodiesterase type 5 inhibitor, attenuates diabetic nephropathy in non-insulin-dependent Otsuka Long-Evans Tokushima Fatty rats. Br J Pharmacol 162(6):1389–1400

    PubMed Central  CAS  PubMed  Google Scholar 

  113. Zhou Y, Li JS, Zhang X et al (2010) Ursolic acid inhibits early lesions of diabetic nephropathy. Int J Mol Med 26(4):565–570

    CAS  PubMed  Google Scholar 

  114. Schneider MP, Schneider A, Jumar A, et al. (2014) Effects of folic acid on renal endothelial function in patients with diabetic nephropathy: results from a randomized trial. Clin Sci (Lond) [Epub ahead of print]

  115. Mose FH, Larsen T, Jensen JM, et al. (2014) Effects of atorvastatin on systemic and renal NO dependency in patients with non-diabetic stage II-III chronic kidney disease. Br J Clin Pharmacol. doi:10.1111/bcp.12390 [Epub ahead of print]

  116. Mani S, Cao W, Wu L, et al. (2014) Hydrogen sulfide and the liver. Nitric Oxide. doi:10.1016/j.niox.2014.02.006 [Epub ahead of print] (Review)

  117. Altaany Z, Moccia F, Munaron L, et al. (2014) Hydrogen sulfide and endothelial Dysfunction: relationship with nitric oxide. Curr Med Chem [Epub ahead of print]

  118. Yuan P, Xue H, Zhou L et al (2011) Rescue of mesangial cells from high glucose-induced over-proliferation and extracellular matrix secretion by hydrogen sulfide. Nephrol Dial Transplant 26(7):2119–2126

    CAS  PubMed  Google Scholar 

  119. Kundu S, Pushpakumar SB, Tyagi A et al (2013) Hydrogen sulfide deficiency and diabetic renal remodeling: role of matrix metalloproteinase-9. Am J Physiol Endocrinol Metab 304(12):E1365–E1378

    PubMed Central  CAS  PubMed  Google Scholar 

  120. Kundu S, Pushpakumar S, Khundmiri SJ, et al. (2014) Hydrogen sulfide mitigates hyperglycemic remodeling via liver kinase B1-adenosine monophosphate-activated protein kinase signaling. Biochim Biophys Acta. pii: S0167-4889(14)00304-8. doi:10.1016/j.bbamcr.2014.08.00

  121. Xue H, Yuan P, Ni J et al (2013) H(2)S inhibits hyperglycemia-induced intrarenal renin-angiotensin system activation via attenuation of reactive oxygen species generation. PLoS One 8(9):e74366. doi:10.1371/journal.pone.0074366

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Andrésdóttir G, Bakker SJ, Hansen HP et al (2013) Urinary sulphate excretion and progression of diabetic nephropathy in Type 1 diabetes. Diabet Med 30(5):563–566

    PubMed  Google Scholar 

  123. Mizuno Y, Jacob RF, Mason RP (2010) Advances in pharmacologic modulation of nitric oxide in hypertension. Curr Cardiol Rep 12(6):472–480

    PubMed  Google Scholar 

Download references

Acknowledgment

Disclosure on financial support: the studies originally performed by the author have been supported by Grants from the Italian Minister of University and Research (“PRIN” Grants) and by Institutional Grants from the University of Padova.

Conflict of interest

Disclosure on conflict of interest: the Author doesn’t have any conflict of interest di declare.

Ethical standard

The clinical studies originally performed by the author have been approved by the local Institutional Review Board (IRB)/Ethics Committee, and have been performed according to the Declaration of Helsinki; a statement is made that informed consent was obtained by all participants.

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  1. Metabolism Division, Department of Medicine, University of Padova, via Giustiniani 2, 35128, Padua, Italy

    Paolo Tessari

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  1. Paolo Tessari
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Correspondence to Paolo Tessari.

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Tessari, P. Nitric oxide in the normal kidney and in patients with diabetic nephropathy. J Nephrol 28, 257–268 (2015). https://doi.org/10.1007/s40620-014-0136-2

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  • DOI: https://doi.org/10.1007/s40620-014-0136-2

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