Oxidative Stress and Disease
Ph.D. in Clinical Medicine - Semmelweis University of Budapest, December, 2004 (summa cum laude honors).
Master of Sciences in Bioengineering - Faculty of Chemical Engineering, Technical University of Budapest, Hungary, 1999
Our NIH-funded laboratory has a general interest in the in vivo role of free radicals - reactive oxygen and nitrogen species - with emphasis on diabetes, insulin resistance and diabetic nephropathy. Our research focuses on the exact free radical mechanisms that can play a role in the pathogenesis of these conditions, ultimately contributing to insulin resistance or leading to tissue damage and to complications.
Currently we are interested in:
- Understanding how the accumulation of toxic lipid metabolites interferes with the insulin receptor signaling pathway and participates in the development of insulin resistance;
- Developing new, targeted strategies against reactive lipid-induced insulin resistance;
- Understanding the specific role of redox signaling in an important complication of diabetes: diabetic nephropathy. For this project we use high fat diet models, diabetic models with significant renal pathology, transgenic and pharmacological approaches and kidney cell lines studying proximal tubular cells and conditionally immortalized podocytes. Loss of podocytes - which are important cells in the integrity of the filtration barrier in the kidney - is characteristic to obesity and diabetes related nephropathy. Loss of podocytes will result in proteinuria and renal complications. Little is known about redox signaling mechanisms and their role in controlling podocyte survival and death. Identifying these mechanisms has high clinical significance as it may help designing targeted therapies to prevent diabetic nephropathy or similar proteinuric diseases.
Through the use of in vivo electron spin resonance (EPR) methodologies and spin trapping we are able to directly and specifically detect increased free radical production in tissues, body fluids or cells. Low temperature EPR from frozen samples can be used to evaluate the integrity of various protein complexes, for example the different components of the electron transport chain. In addition, with the combination of EPR and immunological techniques (e.g. confocal microscopy, immunohistochemistry) a detailed search for the sources and the localization of reactive intermediates and their targets (lipids or proteins) can be achieved. The uniqueness of EPR spectroscopy combined with in vivo spin trapping allows us to identify free radical metabolites and the participating primary reactive species unambiguously, while the sensitivity of a novel immunospin-trapping approach makes the identification of the targets and their localization within the cell possible.
Research in this laboratory is funded by the Pennington Foundation, through grant support by NIDDK 4R00DK083615 (PI: Krisztian Stadler), and by an NIDDK/DiaComp Pilot and Feasibility grant 14GHSU1393 (through P30-DK076169) (PI: Krisztian Stadler).
Ruggiero C, Elks CM, Kruger C, Cleland E, Addison K, Noland RC, Stadler K. Albumin-bound fatty acids but not albumin itself alter redox balance in tubular epithelial cells and induce a peroxide-mediated redox-sensitive apoptosis. Am J Physiol Renal Physiol. 2014 Apr 15;306(8):F896-906
Kadiiska MB, Bonini MG, Ruggiero C, Cleland E, Wicks S, Stadler K. Thiazolidinedione treatment decreases oxidative stress in spontaneously hypertensive heart failure rats through attenuation of iNOS-mediated lipid radical formation. Diabetes 2012 Mar;61(3):586-96.
Ansenberger-Fricano K, Ganini D, Mao M, Chatterjee S, Dallas S, Mason RP, Stadler K, Santos JH, Bonini MG.The peroxidase activity of mitochondrial superoxide dismutase.Free Radic Biol Med. 2013 Jan;54:116-24.
Stadler K.Oxidative stress in diabetes. Adv Exp Med Biol. 2012;771:272-87.
Kadiiska MB, Bonini MG, Ruggiero C, Cleland E, Wicks S, Stadler K. Thiazolidinedione treatment decreases oxidative stress in spontaneously hypertensive heart failure rats through attenuation of inducible nitric oxide synthase-mediated lipid radical formation.Diabetes. 2012 Mar;61(3):586-96.
Mao M, Varadarajan S, Ansenberger-Fricano K, Fernandes DC, Tanaka LY, Fukai T, Laurindo FR, Mason RP, Vasquez-Vivar J, Minshall RD, Stadler K, Bonini MG. Nitroglycerin drives endothelial nitric oxide synthase activation via the phosphatidylinositol 3-kinase/protein kinase B pathway.
Free Radic Biol Med. 2011 Oct 7. epub ahead of print.
Ruggiero C, Ehrenshaft M, Cleland E, Stadler K. (2011) High fat diet induces an initial adaptation of mitochondrial bioenergetics in the kidney despite evident oxidative stress and mitochondrial ROS production. Am J Physiol Endocrinol Metab 300: E1047-58.
Levesque S, Taetzsch T, Lull ME, Kodavanti U, Stadler K, Wagner A, Johnson JA, Duke L, Kodavanti P, Surace MJ, Block ML.(2011) Diesel exhaust activates & primes microglia: Air pollution, neuroinflammation & regulation of dopaminerg neurotoxicity. Environ Health Perspect 119(8):1149-55.
Vandanmagsar B, Youm YH, Ravussin A, Galgani J, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD. (2011) The Cryopyrin/NALP3/NLRP3 Inflammasome Instigates Obesity-Induced Autoinflammation and Insulin Resistance. Nat Med. 17:179-88.
Stadler K. (2011) Peroxynitrite-driven mechanisms in diabetes and insulin resistance – the latest advances. Curr Med Chem 18:280-90.
Chatterjee S, Lardinois O, Bonini MG, Bhattacharjee S, Stadler K, Corbett J, Deterding LJ, Tomer KB, Kadiiska M, Mason RP. (2009) Site-specific carboxypeptidase B1 tyrosine nitration and pathophysiological implications following its physical association with nitric oxide synthase-3 in experimental sepsis. J Immunol. 183(6):4055-66.
Stadler K, Bonini MG, Dallas S, Jiang JJ, Mason RP, Kadiiska MB (2008) Involvement of inducible nitric oxide synthase in hydroxyl radical-mediated lipid peroxidation in streptozotocin-induced diabetes. Free Radic Biol Med 45: 866-74.
Stadler K, Bonini MG, Dallas S, Mason RP, Kadiiska MB (2008) Direct evidence of iNOS-mediated in vivo free radical production and protein oxidation in acetone-induced ketosis. Am J Physiol Endocrinol Metab 295: E456-E462.
Stadler K, Bonini MG, Lautenschlager S, Corbett J, et al. (2008) Constitutive nitric oxide synthase activation is a significant route for nitroglycerin-mediated vasodilation. Proc Natl Acad Sci U S A. 105: 85699-74.
Nakai K, Kadiiska MB, Jiang JJ, Stadler K, Mason RP. (2006) Free radical production requires both inducible nitric oxide synthase and xanthine oxidase in LPS-treated skin. Proc Natl Acad Sci U S A.103: 4616-21.
Stadler K, Jenei V, Somogyi A, Jakus J. (2005) Beneficial effects of aminoguanidine on the cardiovascular system of diabetic rats. Diabetes Metab. Res. Rev. 21: 189-96.
Stadler K, Jenei V, Somogyi A, von Bölcsházy G, Jakus J. (2003) Increased nitric oxide levels as an early sign of premature aging in diabetes. Free Radic. Biol. Med. 35: 1240-51.