Nossos resultados nos permitem concluir que:
1) As células RAEC possuem a via Keap1/Nrf2 responsivas aos ativadores clássicos, como tBHQ, e principalmente à alta concentração de glicose e sulforafano;
2) A exposição ao soro urêmico induz uma ativação transiente da via de Keap1/Nrf2, sendo ela ativa nas primeiras horas de exposição mas inativada depois de 24h de exposição, em relação ao soro não urêmico e aos controles. 3) A expressão dos genes da heme oxigenase 1 (HO1) e cisteína ligase (GCLC) foi
maior nas primeiras horas de exposição ao soro urêmico, sendo ela reduzida a níveis basais após 24h de exposição ao soro urêmico, em relação ao soro não urêmico e aos controles;
4) A toxina isolada, indoxil sulfato, parece ter um papel ativador da via nas primeiras horas, sendo significativo para o gene HO1 e não significativo pra GCLC, porém depois de 24h essa via encontra-se inativada. Mas todos os resultados obtidos para indoxil sulfato foram inferiores aos obtidos para o soro urêmico total.
REFERÊNCIAS
AMINZADEH, Mohammad A. et al. The synthetic triterpenoid RTA dh404 (CDDO-dhT- FEA) restores Nrf2 activity and attenuates oxidative stress, inflammation, and fibrosis in rats with chronic kidney disease. Xenobiotica, v. 44, n. 6, p. 570-578, 2013.
ANGELONI, Cristina et al. Modulation of phase II enzymes by sulforaphane: implications for its cardioprotective potential. Journal of agricultural and food chemistry, v. 57, n. 12, p. 5615-5622, 2009.
AVELES, Paulo R. et al. Association between biomarkers of carbonyl stress with in- creased systemic inflammatory response in different stages of chronic kidney disease and after renal transplantation. Nephron. Clinical practice, v. 116, n. 4, p. c294-9, 2009.
AZNAR-SALATTI, J. et al. Uraemic medium causes endothelial cell dysfunction charac- terized by an alteration of the properties of its subendothelial matrix. Nephrology Dialy- sis Transplantation, v. 10, n. 12, p. 2199-2204, 1995.
BALIGA, Radhakrishna et al. Oxidant mechanisms in toxic acute renal failure. American
journal of kidney diseases, v. 29, n. 3, p. 465-477, 1997.
BARRETO, Fellype C. et al. Serum indoxyl sulfate is associated with vascular disease
and mortality in chronic kidney disease patients. Clinical Journal of the American So-
ciety of Nephrology, v. 4, n. 10, p. 1551-1558, 2009.
BOLATI, Dilinaer et al. Indoxyl sulfate, a uremic toxin, downregulates renal expression of
Nrf2 through activation of NF-κB. BMC nephrology, v. 14, n. 1, p. 56, 2013.
Brenner BM. Brenner and Rector´s.The Kidney. 8ª ed. Philadelphia: Saunders, an im-
print of Elsevier Inc., 2008.
BRYAN, Holly K. et al. The Nrf2 cell defence pathway: Keap1-dependent and-independ-
ent mechanisms of regulation. Biochemical pharmacology, v. 85, n. 6, p. 705-717,
2013.
CARBÓ, Carla et al. Differential expression of proteins from cultured endothelial cells
exposed to uremic versus normal serum. American Journal of Kidney Diseases, v.
51, n. 4, p. 603-612, 2008.
CARRERO, Juan J.; STENVINKEL, Peter. Inflammation in End‐Stage Renal Disease—
What Have We Learned in 10 Years?. In: Seminars in dialysis. Blackwell Publishing
Ltd, 2010. p. 498-509.
CECIL, R. L.; ANDREOLI, T.; CECIL, E. Medicina interna básica. 4ª edição. Rio de Ja-
neiro: Guanabara, 1998.
CHARTOUMPEKIS, Dionysios V.; KENSLER, Thomas W. New player on an old field; the keap1/Nrf2 pathway as a target for treatment of type 2 diabetes and metabolic syn- drome. Current diabetes reviews, v. 9, n. 2, p. 137, 2013.
47
CHITALIA, Vipul C. et al. Uremic Serum and Solutes Increase Post–Vascular Interven- tional Thrombotic Risk Through Altered Stability of Smooth Muscle Cell Tissue Factor. Circulation, v. 127, n. 3, p. 365-376, 2013.
CUI, Wenpeng et al. Prevention of diabetic nephropathy by sulforaphane: possible role
of Nrf2 upregulation and activation. Oxidative medicine and cellular longevity, v.
2012, 2012.
CULLINAN, Sara B. et al. The Keap1-BTB protein is an adaptor that bridges Nrf2 to a
Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Molecular and
cellular biology, v. 24, n. 19, p. 8477-8486, 2004.
DE ZEEUW, Dick et al. Rationale and Trial Design of B ardoxolone Methyl E va luation in Patients with C hronic Kidney Disease and Type 2 Diabetes: The O ccurrence of Re-
nal Eve n ts (BEACON). Am J Nephrol, v. 37, p. 212-222, 2013.
DESCAMPS‐LATSCHA, Béatrice; DRÜEKE, Tilman; WITKO‐SARSAT, Véronique. Dial- ysis‐induced oxidative stress: biological aspects, clinical consequences, and therapy. In: Seminars in dialysis. Blackwell Science Inc, 2001. p. 193-199.
DI MARCO, Giovana Seno et al. Increased inorganic phosphate induces human endo-
thelial cell apoptosis in vitro. American Journal of Physiology-Renal Physiology, v.
294, n. 6, p. F1381-F1387, 2008.
DINKOVA-KOSTOVA, Albena T. et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcino-
gens and oxidants. Proceedings of the National Academy of Sciences, v. 99, n. 18,
p. 11908-11913, 2002.
DOU, L. et al. The uremic solute indoxyl sulfate induces oxidative stress in endothelial
cells. Journal of Thrombosis and Haemostasis, v. 5, n. 6, p. 1302-1308, 2007.
DOU, Laetitia et al. The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid. Journal of the American Society of Nephrology: JASN, 2014.
DOU, Laetitia et al. The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair. Kidney international, v. 65, n. 2, p. 442-451, 2004. DRAGER, Luciano F. et al. Renal effects of N-acetylcysteine in patients at risk for con-
trast nephropathy: decrease in oxidant stress-mediated renal tubular injury. Nephrology
Dialysis Transplantation, v. 19, n. 7, p. 1803-1807, 2004.
DUFFY, Steven; SO, Austin; MURPHY, Timothy H. Activation of Endogenous Antioxi-
dant Defenses in Neuronal Cells Prevents Free Radical‐Mediated Damage. Journal of
neurochemistry, v. 71, n. 1, p. 69-77, 1998.
EGGLER, A. et al. Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1. Biochem. J, v. 422, p. 171-180, 2009.
GALLI, Francesco et al. Mononuclear leukocyte apoptosis in haemodialysis patients: the role of cell thiols and vitamin E. Nephrology Dialysis Transplantation, v. 18, n. 8, p. 1592-1600, 2003.
GALLI, Francesco. Protein damage and inflammation in uraemia and dialysis patients. Nephrology Dialysis Transplantation, v. 22, n. suppl 5, p. v20-v36, 2007.
GELASCO, Andrew K.; RAYMOND, John R. Indoxyl sulfate induces complex redox al-
terations in mesangial cells. American Journal of Physiology-Renal Physiology, v.
290, n. 6, p. F1551-F1558, 2006.
GOLBIDI, Saeid; BADRAN, Mohammad; LAHER, Ismail. Diabetes and alpha lipoic acid. Frontiers in pharmacology, v. 2, 2011.
GÜNTHNER, Thomas et al. PROGRESS IN UREMIC TOXIN RESEARCH: Endothelium
and Vascular Smooth Muscle Cells in the Context of Uremia. In: Seminars in dialysis.
Blackwell Publishing Ltd, 2009. p. 428-432.
Guyton, AC, Hall, JE. Fisiologia Humana e Mecanismos das Doenças. 6a Edição, Gua-
nabara Koogan, 1998.
HALLAN, Stein I. et al. Age and association of kidney measures with mortality and end-
stage renal disease. Jama, v. 308, n. 22, p. 2349-2360, 2012.
HAYES, John D.; MCLELLAN, LESLEY I. Glutathione and glutathione-dependent en-
zymes represent a co-ordinately regulated defence against oxidative stress. Free radi-
cal research, v. 31, n. 4, p. 273-300, 1999.
HELOISA, MARIA et al. N-acetylcysteine attenuates the progression of chronic renal failure. Kidney international, v. 68, n. 5, p. 2208-2217, 2005.
HIMMELFARB, Jonathan. Innovation in the Treatment of Uremia: Proceedings from the Cleveland Clinic Workshop: Uremic Toxicity, Oxidative Stress, and Hemodialysis as Re-
nal Replacement Therapy. In: Seminars in dialysis. Blackwell Publishing Ltd, 2009. p.
636-643.
HONG, Fei; FREEMAN, Michael L.; LIEBLER, Daniel C. Identification of sensor cyste- ines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chemical research in toxicology, v. 18, n. 12, p. 1917-1926, 2005.
INNAMORATO, Nadia G. et al. The transcription factor Nrf2 is a therapeutic target
against brain inflammation. The Journal of Immunology, v. 181, n. 1, p. 680-689,
2008.
ITOH, Ken et al. Keap1 represses nuclear activation of antioxidant responsive elements
by Nrf2 through binding to the amino-terminal Neh2 domain. Genes & development, v.
13, n. 1, p. 76-86, 1999.
KARAMOUZIS, Ioannis et al. Increase in oxidative stress but not in antioxidant capacity
with advancing stages of chronic kidney disease. American journal of nephrology, v.
28, n. 3, p. 397-404, 2007.
KAY, Jay et al. Acetylcysteine for prevention of acute deterioration of renal function fol- lowing elective coronary angiography and intervention: a randomized controlled trial. Jama, v. 289, n. 5, p. 553-558, 2003.
49
KIM, Hyun Ju et al. Role of intrarenal angiotensin system activation, oxidative stress, in- flammation, and impaired nuclear factor-erythroid-2-related factor 2 activity in the pro-
gression of focal glomerulosclerosis. Journal of Pharmacology and Experimental
Therapeutics, v. 337, n. 3, p. 583-590, 2011.
KIM, Hyun Ju; VAZIRI, Nosratola D. Contribution of impaired Nrf2-Keap1 pathway to oxi-
dative stress and inflammation in chronic renal failure. American Journal of Physiol-
ogy-Renal Physiology, v. 298, n. 3, p. F662-F671, 2010.
KOLAGAL, V. et al. Determination of oxidative stress markers and their importance in early diagnosis of uremia-related complications. Indian journal of nephrology, v. 19, n. 1, p. 8, 2009.
KWAK, Mi-Kyoung et al. Modulation of gene expression by cancer chemopreventive di- thiolethiones through the Keap1-Nrf2 pathway Identification of novel gene clusters for cell survival. Journal of Biological Chemistry, v. 278, n. 10, p. 8135-8145, 2003. LAHERA, Vicente et al. Oxidative stress in uremia: the role of anemia correction. Jour- nal of the American Society of Nephrology, v. 17, n. 12 suppl 3, p. S174-S177, 2006. LEE, Jong-Min et al. Identification of the NF-E2-related factor-2-dependent genes con- ferring protection against oxidative stress in primary cortical astrocytes using oligonucle-
otide microarray analysis. Journal of Biological Chemistry, v. 278, n. 14, p. 12029-
12038, 2003.
LEVEY, Andrew S. et al. Definition and classification of chronic kidney disease: a posi-
tion statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney in-
ternational, v. 67, n. 6, p. 2089-2398, 2005.
LEVEY, Andrew S.; EKNOYAN, Garabed. Cardiovascular disease in chronic renal dis-
ease. Nephrology Dialysis Transplantation, v. 14, n. 4, p. 828-833, 1999.
LEVONEN, A. et al. Cellular mechanisms of redox cell signalling: role of cysteine modifi- cation in controlling antioxidant defences in response to electrophilic lipid oxidation prod- ucts. Biochem. J, v. 378, p. 373-382, 2004.
LI, Jiang et al. Stabilization of Nrf2 by tBHQ confers protection against oxidative stress- induced cell death in human neural stem cells. Toxicological Sciences, v. 83, n. 2, p. 313-328, 2005.
LI, Jiang; JOHNSON, Jeffrey A. Time-dependent changes in ARE-driven gene expres- sion by use of a noise-filtering process for microarray data. Physiological genomics, v. 9, n. 3, p. 137-144, 2002.
LI, Lixin et al. Vascular oxidative stress and inflammation increase with age: ameliorating
effects of α‐lipoic acid supplementation. Annals of the New York Academy of Sci-
ences, v. 1203, n. 1, p. 151-159, 2010.
LI, Wenge; KONG, Ah‐Ng. Molecular mechanisms of Nrf2‐mediated antioxidant re-
LOCATELLI, Francesco et al. Oxidative stress in end‐stage renal disease: an emerging
threat to patient outcome. Nephrology Dialysis Transplantation, v. 18, n. 7, p. 1272-
1280, 2003.
LONDON, Roger et al. Examination of resource use and clinical interventions associated
with chronic kidney disease in a managed care population. Journal of managed care
pharmacy: JMCP, v. 9, n. 3, p. 248-255, 2002.
MARTINES, AEMSSMGE; RIELLA, LS Nakao MC; PECOITS-FILHO, CA Aita R. In- creased plasma and endothelial cell expression of chemokines and adhesion molecules
in chronic kidney disease. Nephron Clin Pract, v. 111, p. c117-c126, 2009.
MATSUYAMA, Yukie et al. Albumin thiol oxidation and serum protein carbonyl formation
are progressively enhanced with advancing stages of chronic kidney disease. Clinical
and experimental nephrology, v. 13, n. 4, p. 308-315, 2009.
MISHRA, Manish; ZHONG, Qing; KOWLURU, Renu A. Epigenetic modifications of Keap1 regulate its interaction with the protective factor Nrf2 in the development of dia- betic retinopathy. Investigative ophthalmology & visual science, v. 55, n. 11, p. 7256- 7265, 2014.
MITSUISHI, Yoichiro; MOTOHASHI, Hozumi; YAMAMOTO, Masayuki. The Keap1–Nrf2
system in cancers: stress response and anabolic metabolism. Frontiers in oncology, v.
2, 2012.
MURPHY, Timothy H.; LONG, Mary J.; COYLE, Joseph T. Enhanced NAD (P) H: qui- none reductase activity prevents glutamate toxicity produced by oxidative stress. Jour- nal of neurochemistry, v. 56, n. 3, p. 990-995, 1991.
MUTELIEFU, Gulinuer et al. Indoxyl sulfate promotes vascular smooth muscle cell se-
nescence with upregulation of p53, p21, and prelamin A through oxidative stress. Amer-
ican Journal of Physiology-Cell Physiology, v. 303, n. 2, p. C126-C134, 2012. NITURE, Suryakant K.; JAIN, Abhinav K.; JAISWAL, Anil K. Antioxidant-induced modifi- cation of INrf2 cysteine 151 and PKC-δ-mediated phosphorylation of Nrf2 serine 40 are both required for stabilization and nuclear translocation of Nrf2 and increased drug re- sistance. Journal of cell science, v. 122, n. 24, p. 4452-4464, 2009.
Niwa T. Indoxyl sulfate is a nephro-vascular toxin. J RenNutr;20(5 Suppl):S2-6, 2010.
PATIDAR, Ashish et al. Human uraemic serum displays calcific potential in vitro that in-
creases with advancing chronic kidney disease. Clinical Science, v. 125, n. 5, p. 237-
245, 2013.
PECOITS-FILHO, Roberto. Increased calcification and protein nitration in arteries of chronic kidney disease patients. Blood Purif, v. 330327, p. 2, 2011.
PECOITS-FILHO, Roberto. Increased calcification and protein nitration in arteries of chronic kidney disease patients. Blood Purif, v. 330327, p. 2, 2011.
POLLMAN, Matthew J.; HALL, Jennifer L.; GIBBONS, Gary H. Determinants of vascular smooth muscle cell apoptosis after balloon angioplasty injury influence of redox state and cell phenotype. Circulation research, v. 84, n. 1, p. 113-121, 1999.
51
QUIJANO, Celia et al. Enhanced mitochondrial superoxide in hyperglycemic endothelial
cells: direct measurements and formation of hydrogen peroxide and peroxynitrite. Amer-
ican Journal of Physiology-Heart and Circulatory Physiology, v. 293, n. 6, p. H3404-H3414, 2007.
RACHAKONDA, Girish et al. Covalent modification at Cys151 dissociates the electro-
phile sensor Keap1 from the ubiquitin ligase CUL3. Chemical research in toxicology,
v. 21, n. 3, p. 705-710, 2008.
RANGASAMY, Tirumalai et al. Genetic ablation of Nrf2 enhances susceptibility to ciga-
rette smoke–induced emphysema in mice. Journal of Clinical Investigation, v. 114, n.
9, p. 1248, 2004.
RODRIGUES, Silvia D. et al. N-acetylcysteine as a potential strategy to attenuate the
oxidative stress induced by uremic serum in the vascular system. Life sciences, v. 121,
p. 110-116, 2015.
ROMÃO JUNIOR, João Egidio. Doença renal crônica: ddefinição epidemiologia e classi- ficação. J. bras. nefrol, v. 26, n. 3, supl. 1, p. 1-3, 2004.
SBN - Sociedade Brasileira de Nefrologia. Censo 2013. (2013) Disponível em:
<http://www.sbn.org.br/leigos/index.php?censo>. Acesso em: 28 Jan. 2015
SEGURO, Antonio Carlos; DE FIGUEIREDO, Luiz F. Poli; SHIMIZU, Maria Heloisa M. N-acetylcysteine (NAC) protects against acute kidney injury (AKI) following prolonged
pneumoperitoneum in the rat. Journal of Surgical Research, v. 175, n. 2, p. 312-315,
2012.
SERRADELL, Mireia et al. Uraemic medium accelerates proliferation but does not in-
duce apoptosis of endothelial cells in culture. Nephrology Dialysis Transplantation, v.
18, n. 6, p. 1079-1085, 2003.
SERRADELL, Mireia et al. Uremic medium causes expression, redistribution and shed- ding of adhesion molecules in cultured endothelial cells. haematologica, v. 87, n. 10, p. 1053-1061, 2002.
STENVINKEL, Peter et al. Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: how do new pieces fit into the uremic puzzle?. Clinical Journal of the American Society of Nephrology, v. 3, n. 2, p. 505-521, 2008.
STINGHEN, Andréa EM et al. Immune mechanisms involved in cardiovascular compli- cations of chronic kidney disease. Blood purification, v. 29, n. 2, p. 114, 2010.
TAGUCHI, Keiko et al. Keap1 degradation by autophagy for the maintenance of redox
homeostasis. Proceedings of the National Academy of Sciences, v. 109, n. 34, p.
13561-13566, 2012.
TASTEKIN, Nurettin et al. Protective effects of L-carnitine and alpha-lipoic acid in rats
with adjuvant arthritis. Pharmacological Research, v. 56, n. 4, p. 303-310, 2007.
TEPEL, Martin et al. Prevention of radiographic-contrast-agent–induced reductions in re-
nal function by acetylcysteine. New England Journal of Medicine, v. 343, n. 3, p. 180-
THIMMULAPPA, Rajesh K. et al. Identification of Nrf2-regulated genes induced by the
chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer research,
v. 62, n. 18, p. 5196-5203, 2002.
TINTUT, Yin et al. Tumor necrosis factor-α promotes in vitro calcification of vascular
cells via the cAMP pathway. Circulation, v. 102, n. 21, p. 2636-2642, 2000.
TONG, Kit I. et al. Two-site substrate recognition model for the Keap1-Nrf2 system: a
hinge and latch mechanism. Biological chemistry, v. 387, n. 10/11, p. 1311-1320,
2006.
UNGVARI, Zoltan et al. Adaptive induction of NF-E2-related factor-2-driven antioxidant
genes in endothelial cells in response to hyperglycemia. American Journal of Physiol-
ogy-Heart and Circulatory Physiology, v. 300, n. 4, p. H1133-H1140, 2011.
VALCARCEL-ARES, M. Noa et al. Disruption of Nrf2 signaling impairs angiogenic ca- pacity of endothelial cells: implications for microvascular aging. The Journals of Geron- tology Series A: Biological Sciences and Medical Sciences, p. glr229, 2012.
VANHOLDER, Raymond et al. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate:
a systematic review. Journal of the American Society of Nephrology, v. 25, n. 9, p.
1897-1907, 2014.
VAZIRI, Nosratola D. Roles of oxidative stress and antioxidant therapy in chronic kidney
disease and hypertension. Current opinion in nephrology and hypertension, v. 13, n.
1, p. 93-99, 2004.
WAKABAYASHI, Nobunao et al. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nature genetics, v. 35, n. 3, p. 238-245, 2003.
WAKABAYASHI, Nobunao et al. Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by in-
ducers. Proceedings of the National Academy of Sciences of the United States of
America, v. 101, n. 7, p. 2040-2045, 2004.
WILLENBERG, Torsten et al. Impact of renal insufficiency on clinical outcomes in pa- tients with critical limb ischemia undergoing endovascular revascularization. Journal of vascular surgery, v. 53, n. 6, p. 1589-1597, 2011.
XUE, Mingzhan et al. Activation of NF-E2–related factor-2 reverses biochemical dys- function of endothelial cells induced by hyperglycemia linked to vascular disease. Diabe- tes, v. 57, n. 10, p. 2809-2817, 2008.
YAN, Dong et al. Induction of the Nrf2-driven antioxidant response by tert-butylhydroqui-
none prevents ethanol-induced apoptosis in cranial neural crest cells. Biochemical
pharmacology, v. 80, n. 1, p. 144-149, 2010.
YAO, Qiang et al. Traditional and non-traditional risk factors as contributors to athero-
sclerotic cardiovascular disease in end-stage renal disease. Scandinavian journal of
urology and nephrology, v. 38, n. 5, p. 405-416, 2004.
YOON, J. W.; PAHL, M. V.; VAZIRI, N. D. Spontaneous leukocyte activation and oxy- gen-free radical generation in end-stage renal disease. Kidney international, v. 71, n. 2, p. 167-172, 2007.
53
YU, Xiaofang et al. Oxidative stress in 5/6 nephrectomized rat model: effect of alpha-li- poic acid. Renal failure, v. 34, n. 7, p. 907-914, 2012.
ZHANG, Donna D. et al. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein
for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. Journal
of Biological Chemistry, v. 280, n. 34, p. 30091-30099, 2005.
ZHANG, Donna D. Mechanistic studies of the Nrf2-Keap1 signaling pathway*. Drug me-
tabolism reviews, v. 38, n. 4, p. 769-789, 2006.
ZHANG, Donna D.; HANNINK, Mark. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreven- tive agents and oxidative stress. Molecular and cellular biology, v. 23, n. 22, p. 8137- 8151, 2003.
ZHAO, Jie et al. Mangiferin increases Nrf2 protein stability by inhibiting its ubiquitination
and degradation in human HL60 myeloid leukemia cells. International journal of mo-
lecular medicine, v. 33, n. 5, p. 1348-1354, 2014.
ZHENG, Hongting et al. Therapeutic potential of Nrf2 activators in streptozotocin-in-
duced diabetic nephropathy. Diabetes, v. 60, n. 11, p. 3055-3066, 2011.
ZIPPER, Laurie M.; MULCAHY, R. Timothy. The Keap1 BTB/POZ dimerization function
is required to sequester Nrf2 in cytoplasm. Journal of Biological Chemistry, v. 277, n.
39, p. 36544-36552, 2002.
ZOJA, Carlamaria; BENIGNI, Ariela; REMUZZI, Giuseppe. The Nrf2 pathway in the pro-