Radical approach to diabetic nephropathy
2007; Elsevier BV; Volume: 72; Linguagem: Inglês
10.1038/sj.ki.5002389
ISSN1523-1755
AutoresH.B. Lee, Ji Yeon Seo, Mi Ra Yu, Soo Tack Uh, Hunjoo Ha,
Tópico(s)Biochemical Acid Research Studies
ResumoThere is increasing evidence that reactive oxygen species (ROS) play a major role in the development of diabetic complications. Oxidative stress is increased in diabetes and in chronic kidney disease (CKD). High glucose upregulates transforming growth factor-β1 (TGF-β1) and angiotensin II (Ang II) in renal cells and high glucose, TGF-β1, and Ang II all generate and signal through ROS. ROS mediate high glucose-induced activation of protein kinase C and nuclear factor-κB in renal cells. Intensive glycemic control and inhibition of Ang II delay the onset and progression of diabetic nephropathy, in part, through antioxidant activity. Conventional and catalytic antioxidants were shown to prevent or delay the onset of diabetic nephropathy. Transketolase activators and poly (ADP-ribose) polymerase inhibitors were shown to block major biochemical pathways of hyperglycemic damage. Combination of strategies to prevent overproduction of ROS, to increase the removal of preformed ROS, and to block ROS-induced activation of biochemical pathways leading to cellular damage may prove to the effective in preventing the development and progression of CKD in diabetes. There is increasing evidence that reactive oxygen species (ROS) play a major role in the development of diabetic complications. Oxidative stress is increased in diabetes and in chronic kidney disease (CKD). High glucose upregulates transforming growth factor-β1 (TGF-β1) and angiotensin II (Ang II) in renal cells and high glucose, TGF-β1, and Ang II all generate and signal through ROS. ROS mediate high glucose-induced activation of protein kinase C and nuclear factor-κB in renal cells. Intensive glycemic control and inhibition of Ang II delay the onset and progression of diabetic nephropathy, in part, through antioxidant activity. Conventional and catalytic antioxidants were shown to prevent or delay the onset of diabetic nephropathy. Transketolase activators and poly (ADP-ribose) polymerase inhibitors were shown to block major biochemical pathways of hyperglycemic damage. Combination of strategies to prevent overproduction of ROS, to increase the removal of preformed ROS, and to block ROS-induced activation of biochemical pathways leading to cellular damage may prove to the effective in preventing the development and progression of CKD in diabetes. Diabetes mellitus (DM) is the leading cause of end-stage renal disease (ESRD), non-traumatic lower extremity amputations, and adult blindness.1.Powers C. Diabetes mellitus.in: Kasper D.L. Braunwald E. Fauci A. Hauser S.L. Longo D.L. Jameson J.L. Harrison's Principles of Internal Mediciney. 16th edn. Vol. 2. McGraw Hills, New York2005: 2152-2180Google Scholar DM increases the risk of cardiac, cerebral, and peripheral vascular disease two- to sevenfold.2.Serwin R.S. Diabetes mellitus.in: Glodman L. Ausiello D. Cecil Textbook of Medicine. 22nd edn. Vol. 2. Elsevier, Philadelphia2004: 1424-1452Google Scholar In the United States, recognized chronic kidney disease (CKD) and ESRD patients accounted for 5.7 and 1.1%, respectively, of the Medicare population 65 years of age or older in 2003.3.US Renal Data System Excerpts from the USRDS 2006 annual data report.Am J Kidney Dis. 2007; 49: S1-S296PubMed Google Scholar Twenty-one percent had diabetes and 56.4% carried a diagnosis of hypertension. CKD increases the morbidity and costs associated with diabetes and hypertension, themselves known risks for CKD. Patients with CKD and ESRD accounted for 16.5 and 7.2%, respectively, of Medicare costs in 2003.3.US Renal Data System Excerpts from the USRDS 2006 annual data report.Am J Kidney Dis. 2007; 49: S1-S296PubMed Google Scholar Large, randomized clinical trials of individuals with type I4.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.New Engl J Med. 1993; 329: 977-986Crossref PubMed Scopus (22702) Google Scholar or type II DM5.UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar have conclusively demonstrated that a reduction in chronic hyperglycemia prevents or delays retinopathy, neuropathy, and nephropathy. These observations indicate that hyperglycemia is the major risk factor for vascular complications of DM. Achieving normal or near normal blood glucose levels is, however, often difficult and carries risk of hypoglycemia and its consequences. There is emerging evidence that the generation of reactive oxygen species (ROS) is one major factor in the development of diabetes and its complications.6.Rösen P. Nawroth P.P. King G. et al.The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a congress series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society.Diabetes Metab Res Rev. 2001; 17: 189-212Crossref PubMed Scopus (810) Google Scholar There is much evidence from experimental studies that the formation of ROS is a direct consequence of hyperglycemia.6.Rösen P. Nawroth P.P. King G. et al.The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a congress series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society.Diabetes Metab Res Rev. 2001; 17: 189-212Crossref PubMed Scopus (810) Google Scholar Various types of vascular cells including endothelial and renal cells are able to produce ROS under hyperglycemic conditions. Because of their ability to directly oxidize and damage DNAs, proteins, and lipids, ROS are believed to play a key direct role in the pathogenesis of late diabetic complications.6.Rösen P. Nawroth P.P. King G. et al.The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a congress series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society.Diabetes Metab Res Rev. 2001; 17: 189-212Crossref PubMed Scopus (810) Google Scholar In addition to their ability to directly inflict macromolecular damage, ROS can function as signaling molecules to activate a number of cellular stress-sensitive pathways that cause cellular damage and are ultimately responsible for the late complications of diabetes.7.Evans J.L. Goldfine I.D. Maddux B.A. et al.Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction?.Diabetes. 2003; 52: 1-8Crossref PubMed Scopus (1191) Google Scholar,8.Lee H.B. Yu M.R. Yang Y. et al.Reactive oxygen species-regulated signaling pathways in diabetic nephropathy.J Am Soc Nephrol. 2003; 14: S241-S245Crossref PubMed Google Scholar ROS mediate hyperglycemia-induced activation of signal-transduction cascades and transcription factors leading to transcriptional activation of profibrotic genes.8.Lee H.B. Yu M.R. Yang Y. et al.Reactive oxygen species-regulated signaling pathways in diabetic nephropathy.J Am Soc Nephrol. 2003; 14: S241-S245Crossref PubMed Google Scholar Furthermore, activated signaling molecules generate and signal through ROS, thus ROS act as a signal amplifier.8.Lee H.B. Yu M.R. Yang Y. et al.Reactive oxygen species-regulated signaling pathways in diabetic nephropathy.J Am Soc Nephrol. 2003; 14: S241-S245Crossref PubMed Google Scholar In this review, we will present evidence that oxidative stress plays an important pathogenic role in the development of diabetic complications and that antioxidants may be helpful in the treatment of patients with diabetes and CKD. DM is the leading cause of ESRD and a known risk for CKD.3.US Renal Data System Excerpts from the USRDS 2006 annual data report.Am J Kidney Dis. 2007; 49: S1-S296PubMed Google Scholar CKD increases the morbidity and costs associated with diabetes and in itself is a risk factor for cardiovascular disease. Individuals with CKD are more likely to die of cardiovascular disease than to develop ESRD.9.Shulman N.B. Ford C.E. Hall W.D. et al.Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the Hypertension Detection and Follow-up Program. The Hypertension Detection and Follow-up Program Cooperative Group.Hypertension. 1989; 13: I80-I93Crossref PubMed Google Scholar Mortality due to cardiovascular disease is 10–30 times higher in ESRD patients than in the general population.10.Sarnak M.J. Levey A.S. Schoolwerth A.C. et al.Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology and prevention.Circulation. 2003; 108: 2154-2169Crossref PubMed Scopus (2874) Google Scholar In the United States, recognized CKD and ESRD patients together accounted for 6.8% of Medicare population in 2003 but accounted for 23.7% of Medicare costs in the same year.3.US Renal Data System Excerpts from the USRDS 2006 annual data report.Am J Kidney Dis. 2007; 49: S1-S296PubMed Google Scholar Prevalence and incidence of ESRD are increasing worldwide. Percent of incident ESRD patients with diabetes is also increasing. In 2004, diabetes accounted for 45.6% of incident ESRD patients in USA, 43.4% in Korea, 41.0% in Japan, 34.2% in Germany, and for 30.1% in Australia.3.US Renal Data System Excerpts from the USRDS 2006 annual data report.Am J Kidney Dis. 2007; 49: S1-S296PubMed Google Scholar Prevalence of CKD before dialysis is estimated at 10–11% of adult population in Norway and USA.11.Hallan S.I. Coresh J. Astor B.C. et al.International comparison of the relationship of chronic kidney disease prevalence and ESRD risk.J Am Soc Nephrol. 2006; 17: 2275-2284Crossref PubMed Scopus (537) Google Scholar There appears to be a general agreement that the production of free radicals is increased in diabetic patients. Several clinical studies show increases in levels of oxidative stress markers, for instance 8-hydroxydeoxyguanosine, hydroperoxides, 8-epi-prostaglandin F2α, and oxidized low-density lipoprotein in type I and type II DM when compared to healthy age-matched subjects. Dandona et al.12.Dandona P. Thusu K. Cook S. et al.Oxidative damage to DNA in diabetes mellitus.Lancet. 1996; 347: 444-445Abstract PubMed Scopus (683) Google Scholar showed an approximately fourfold higher median concentration of 8-hydroxydeoxyguanosine in mononuclear cells of diabetic patients compared to corresponding controls. Nourooz-Zadeh et al.13.Gopaul N.K. Änggård E.E. Mallet A.I. et al.Plasma 8-epi-PGF2α levels are elevated in individuals with non-insulin dependent diabetes mellitus.FEBS Lett. 1995; 368: 225-229Abstract Full Text PDF PubMed Scopus (370) Google Scholar, 14.Nourooz-Zadeh J. Tajaddini-Sarmadi J. McCarthy S. et al.Elevated levels of authentic plasma hydroperoxides in NIDDM.Diabetes. 1995; 44: 1054-1058Crossref PubMed Scopus (258) Google Scholar, 15.Nourooz-Zadeh J. Rahimi A. Tajaddini-Sarmadi J. et al.Relationships between plasma measures of oxidative stress and metabolic control in NIDDM.Diabetologia. 1997; 40: 647-653Crossref PubMed Scopus (271) Google Scholar demonstrated an approximately twofold increase in the plasma 8-epi-prostaglandin F2α and hydroperoxides and three- to sixfold imbalance between increased levels of oxidative stress and the depletion of RRR-α-tocopherol in plasma of diabetic patients. Increased low-density lipoprotein oxidation16.Bellomo G. Maggi E. Poli M. et al.Autoantibodies against oxidatively modified low-density lipoproteins in NIDDM.Diabetes. 1995; 44: 60-66Crossref PubMed Scopus (175) Google Scholar and imbalance between elevated oxidized low-density lipoprotein levels and decreased RRR-α-tocopherol levels (cholesterol standardized) were observed in the low-density lipoprotein particle in diabetic patients when compared to healthy control.17.Leonhardt W. Hanefeld M. Lattke P. et al.Vitamin E-Mangel und oxidierbarkeit der Low-Density-Lipoproteine bei Typ-I und Typ-II-diabetes: Einfluβ, der Qualität der Stoffwechselkontrolle.Diabetes und Stoffwechsel. 1997; 6: 24-28Google Scholar Oxidative stress is also increased in CKD and ESRD patients. Diene conjugates, lipid hydroperoxide, and oxidized glutathione (GSSG) were increased, whereas reduced glutathione (GSH) was decreased resulting in increased ratio of GSSG/GSH in CKD patients before dialysis.18.Annuk M. Zilmer M. Lind L. et al.Oxidative stress and endothelial function in chronic renal failure.J Am Soc Nephrol. 2001; 12: 2747-2752Crossref PubMed Google Scholar 13-Hydroxyoctadecadienoic acid, protein carbonyls, 8-hydroxydeoxyguanosine, asymmetric dimethylarginine, and GSSG/GSH were all increased in CKD patients on hemodialysis.19.Aslam S. Santha T. Leone A. et al.Effects of amlodipine and valsartan on oxidative stress and plasma methylarginines in end-stage renal disease patients on hemodialysis.Kidney Int. 2006; 70: 2109-2115Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Nishikawa et al.20.Nishikawa T. Edelstein D. Du X.L. et al.Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage.Nature. 2000; 404: 787-790Crossref PubMed Scopus (3658) Google Scholar demonstrated that high glucose induced a threefold increase in ROS production by bovine aortic endothelial cells as compared to normal glucose and that overexpression of uncoupling protein-1 or manganese superoxide dismutase effectively prevented increased ROS production by high glucose, suggesting that the mitochondrial electron transport chain is the source of high glucose-induced superoxide generation. They went on and proposed a unifying mechanism of hyperglycemia-induced cellular damage20.Nishikawa T. Edelstein D. Du X.L. et al.Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage.Nature. 2000; 404: 787-790Crossref PubMed Scopus (3658) Google Scholar, 21.Brownlee M. Biochemistry and molecular cell biology of diabetic complications.Nature. 2001; 414: 813-820Crossref PubMed Scopus (7030) Google Scholar, 22.Brownlee M. The pathobiology of diabetic complications.Diabetes. 2005; 54: 1615-1625Crossref PubMed Scopus (3972) Google Scholar in which hyperglycemia-induced mitochondrial superoxide overproduction activated four biochemical pathways of cellular damage: polyol pathway, hexosamine pathway, protein kinase C (PKC) pathway, and advanced glycation end products pathway. By normalizing mitochondrial superoxide overproduction, they were able to block all pathways of hyperglycemic damage. We showed that high glucose increases dichlorofluorescein-sensitive ROS in rat mesangial cells in a time-dependent manner23.Ha H. Yu M.R. Choi Y.J. et al.Role of high glucose-induced nuclear factor-kappa B activation in monocyte chemoattractant protein-1 expression by mesangial cells.J Am Soc Nephrol. 2002; 13: 894-902PubMed Google Scholar and that high glucose-induced ROS is dependent on activation of PKC,23.Ha H. Yu M.R. Choi Y.J. et al.Role of high glucose-induced nuclear factor-kappa B activation in monocyte chemoattractant protein-1 expression by mesangial cells.J Am Soc Nephrol. 2002; 13: 894-902PubMed Google Scholar nicotinamide adenine dinucleotide phosphate oxidase,8.Lee H.B. Yu M.R. Yang Y. et al.Reactive oxygen species-regulated signaling pathways in diabetic nephropathy.J Am Soc Nephrol. 2003; 14: S241-S245Crossref PubMed Google Scholar and mitochondrial electron gradient.8.Lee H.B. Yu M.R. Yang Y. et al.Reactive oxygen species-regulated signaling pathways in diabetic nephropathy.J Am Soc Nephrol. 2003; 14: S241-S245Crossref PubMed Google Scholar We and others have shown that TGF-β18.Lee H.B. Yu M.R. Yang Y. et al.Reactive oxygen species-regulated signaling pathways in diabetic nephropathy.J Am Soc Nephrol. 2003; 14: S241-S245Crossref PubMed Google Scholar and angiotensin II (Ang II)24.Leehey D.J. Isreb M.A. Marcic S. et al.Effect of high glucose on superoxide in human mesangial cells: role of angiotensin II.Nephron Exp Nephrol. 2005; 100: e46-e53Crossref PubMed Scopus (23) Google Scholar can induce nicotinamide adenine dinucleotide phosphate oxidase-dependent ROS in renal cells. Onozato et al.25.Onozato M.L. Tojo A. Goto A. et al.Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB.Kidney Int. 2002; 61: 186-194Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar showed that angiotensin-converting enzyme inhibitor and Ang II receptor blocker inhibit p47phox and nitrotyrosine expression in diabetic kidney, suggesting that inhibition of Ang II may confer renoprotection in diabetes, in part, through antioxidant activity. We demonstrated that activation of PKC-δ and PKC-ε was significantly increased in diabetic glomeruli and that this was effectively prevented by antioxidant taurine.26.Ha H. Yu M.R. Choi Y.J. et al.Activation of protein kinase C-δ and -ε by oxidative stress in early diabetic kidney.Am J Kidney Dis. 2001; 38: S204-S207Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar We also demonstrated that high glucose activates PKC in mesangial cells.23.Ha H. Yu M.R. Choi Y.J. et al.Role of high glucose-induced nuclear factor-kappa B activation in monocyte chemoattractant protein-1 expression by mesangial cells.J Am Soc Nephrol. 2002; 13: 894-902PubMed Google Scholar Studer et al.27.Studer R.K. Craven P.A. DeRubertis F.R. Antioxidant inhibition of protein kinase C-signaled increases in transforming growth factor-beta in mesangial cells.Metabolism. 1997; 46: 918-925Abstract Full Text PDF PubMed Scopus (129) Google Scholar showed that structurally different antioxidants significantly inhibit high glucose-induced activation of PKC in mesangial cells. Haneda et al.28.Haneda M. Araki S. Togawa M. et al.Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells cultured under high glucose conditions.Diabetes. 1997; 46: 847-853Crossref PubMed Scopus (224) Google Scholar had demonstrated that high glucose activates mitogen-activated protein kinase and upstream mitogen-activated protein kinase kinase in rat mesangial cells in a PKC-dependent manner. We observed that high glucose-induced activation of nuclear factor-κB is mediated by ROS and PKC and that high glucose-induced monocyte chemoattractant protein-1 expression is nuclear factor-κB-dependent and is also mediated by ROS and PKC.23.Ha H. Yu M.R. Choi Y.J. et al.Role of high glucose-induced nuclear factor-kappa B activation in monocyte chemoattractant protein-1 expression by mesangial cells.J Am Soc Nephrol. 2002; 13: 894-902PubMed Google Scholar We had earlier demonstrated that high glucose stimulates TGF-β1 and fibronectin in mesangial cells29.Oh J.H. Ha H. Yu M.R. et al.Sequential effects of high glucose on mesangial cell TGF-β1 and fibronectin synthesis.Kidney Int. 1998; 54: 1872-1878Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar and that antioxidants inhibit glomerular TGF-β1 and fibronectin mRNA expression in diabetic rats.30.Ha H. Yu M.R. Kim K.H. Melatonin and taurine reduce early glomerulopathy in diabetic rats.Free Radic Biol Med. 1999; 26: 944-950Crossref PubMed Scopus (136) Google Scholar We found that high glucose- and TGF-β1-induced upregulation of plasminogen activator inhibitor (PAI)-1 is mediated by ROS.31.Lee E.A. Seo J.Y. Jiang Z. et al.Reactive oxygen species mediate high glucose-induced plasminogen activator inhibitor-1 upregulation in mesangial cells and in diabetic kidney.Kidney Int. 2005; 67: 1762-1771Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar,32.Jiang Z. Seo J.Y. Ha H. et al.Reactive oxygen species mediate TGF-β1-induced plasminogen activator inhibitor-1 upregulation in mesangial cells.Biochem Biophys Res Commun. 2003; 309: 961-966Crossref PubMed Scopus (100) Google Scholar On the other hand, TGF-β1 was found to mediate PAI-1-induced fibronectin and collagen I expression in PAI-1-deficient mesangial cells cultured under high glucose.33.Seo J.Y. Ha H. Lee H.B. Role of PAI-1 in ECM remodeling in diabetic kidney.Nephrol Dial Transplant. 2006; 21 (abstract): iv33Google Scholar PAI-1 was shown to stimulate TGF-β1 promoter activity comparable to TGF-β1 in mesangial cells,33.Seo J.Y. Ha H. Lee H.B. Role of PAI-1 in ECM remodeling in diabetic kidney.Nephrol Dial Transplant. 2006; 21 (abstract): iv33Google Scholar suggesting that TGF-β1 and PAI-1 together constitute a positive feed back loop in tissue fibrosis. We also observed that TGF-β1-induced phosphorylation of mitogen-activated protein kinase, Smad 2, and epithelial–mesenchymal transition in normal rat kidney epithelial cells, NRK-52E, is mediated by ROS.34.Rhyu D.Y. Yang Y. Ha H. et al.Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells.J Am Soc Nephrol. 2005; 16: 667-675Crossref PubMed Scopus (453) Google Scholar ROS mediate high glucose, TGF-β1, and Ang II signals in renal cells and thus play a major role in renal fibrosis in hyperglycemic conditions. Intensive glycemic control in patients with type I4.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.New Engl J Med. 1993; 329: 977-986Crossref PubMed Scopus (22702) Google Scholar and type II5.UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18951) Google Scholar DM significantly prevented the onset and progression of diabetic nephropathy. Lewis et al.35.Lewis E.J. Hunsicker L.G. Bain R.P. et al.The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collabrative Study Group.N Engl J Med. 1993; 329: 1456-1462Crossref PubMed Scopus (5018) Google Scholar,36.Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (5040) Google Scholar showed that angiotensin-converting enzyme inhibitor captopril and Ang II receptor blocker irbesartan significantly delayed the progression of diabetic nephropathy in patients with type I and type II DM, respectively. As hyperglycemia and Ang II induce oxidative stress, the renoprotection by glycemic control and inhibition of Ang II may be, in part, due to antioxidant activity. We demonstrated that conventional antioxidant taurine prevented glomerular hypertrophy, mesangial expansion, and proteinuria in diabetic rats.31.Lee E.A. Seo J.Y. Jiang Z. et al.Reactive oxygen species mediate high glucose-induced plasminogen activator inhibitor-1 upregulation in mesangial cells and in diabetic kidney.Kidney Int. 2005; 67: 1762-1771Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar Overexpression of catalytic antioxidants copper/zinc superoxide dismutase and manganese superoxide dismutase were shown to protect against diabetic injury. Craven et al.37.Craven P.A. Melhem M.F. Phillips S.L. et al.Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice.Diabetes. 2001; 50: 2114-2125Crossref PubMed Scopus (138) Google Scholar demonstrated that diabetic copper/zinc superoxide dismutase transgenic mice had significantly lower urinary albumin excretion, glomerular hypertrophy, and glomerular expression of TGF-β1 and collagen IV protein compared to non-transgenic mice. Du et al.38.Du X. Matsumura T. Edelstein D. et al.Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells.J Clin Invest. 2003; 112: 1049-1057Crossref PubMed Scopus (504) Google Scholar showed that overexpression of manganese superoxide dismutase in bovine aortic endothelial cells prevented high glucose-induced activation of PKC, NK-κB, hexosamine, and advanced glycation end product pathways. Transketolase activator benfotiamine39.Hammes H.P. Du X. Edelstein D. et al.Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.Nat Med. 2003; 9: 294-299Crossref PubMed Scopus (678) Google Scholar and poly (ADP-ribose) polymerase inhibitor PJ3438.Du X. Matsumura T. Edelstein D. et al.Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells.J Clin Invest. 2003; 112: 1049-1057Crossref PubMed Scopus (504) Google Scholar were also shown to block biochemical pathways of hyperglycemic damage. ROS play a major role in the development of diabetic complications including nephropathy. Combination of strategies to prevent overproduction of ROS (glycemic control and inhibition of cytokines and growth factors), to increase the removal of ROS generated (conventional or catalytic antioxidants), and to block ROS-induced activation of biochemical pathways leading to cellular damage (transketolase activators, poly (ADP-ribose) polymerase inhibitors) may prove to be effective in preventing the development and progression of CKD in diabetes.
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