review article chronic kidney disease effect of oxidative...

Review ArticleChronic Kidney DiseasemdashEffect of Oxidative Stress

Subha Palaneeswari Meenakshi Sundaram1

Sivakumar Nagarajan2 and Arcot Jagdeeshwaran Manjula Devi1

1 Department of Biochemistry Sree Balaji Medical College and Hospital Bharath UniversityCLC Works Road Chrompet Chennai 600 044 India

2Department of Nephrology Sree Balaji Medical College and Hospital Bharath UniversityCLC Works Road Chrompet Chennai 600 044 India

Correspondence should be addressed to Subha Palaneeswari Meenakshi Sundaram msubhavishgmailcom

Received 27 September 2013 Accepted 30 October 2013 Published 21 January 2014

Academic Editors A Castaneyra-Perdomo W Ding and R Malli

Copyright copy 2014 Subha Palaneeswari Meenakshi Sundaram et al This is an open access article distributed under the CreativeCommons Attribution License which permits unrestricted use distribution and reproduction in any medium provided theoriginal work is properly cited

Chronic kidney disease (CKD) is a growing health problem with increasing incidence The annual mortality of end-stage renaldisease patients is about 9 which is 10ndash20 fold higher than the general population approximately 50 of these deaths are dueto cardiovascular (CV) disease CV risk factors such as diabetes hypertension and hyperlipidemia are strongly associated withpoor outcome Many other nontraditional risk factors such as inflammation infection oxidative stress anemia and malnutritionare also present In this review we will focus on the role of oxidative stress in chronic kidney disease

1 Introduction

Chronic kidney disease (CKD) is a growing health problemwith increasing incidence In the United States approxi-mately 8 million adults have stage 3 CKD and about 400 000have end-stage renal disease (ESRD) with over 300 000 ofthem on maintenance dialysis (MHD) The annual mortalityof ESRDpatients is about 9 which is 10ndash20-fold higher thanthe general population approximately 50 of these deathsare due to cardiovascular (CV) disease [1] CKD is associatedwith high cardiovascular risk which is not fully due totraditional CV risk factors CV risk factors such as diabeteshypertension and hyperlipidemia are strongly associatedwith poor outcome other nontraditional risk factors arealso present such as renal-specific risk factors uraemia ordialysis and extrarenal risk factors proteinuria chronic vol-ume overload increased renin-angiotensin system activityinflammation infection oxidative stress altered calciumand phosphorus metabolism anemia malnutrition elevatedlevels of homocysteine uraemic toxins and thrombogenicfactors [1] Changes in serum cytokines begin at an earlyphase of renal dysfunction High levels of cytokines lead to

changes in the levels of many acute phase proteins like c-reactive protein (CRP) albumin brain natriuretic peptide(BNP) adiponectin fetuin and asymmetric dimethylargai-nine Changes in these proteins can predict intima-mediathickness of carotid artery and left ventricular hypertro-phy leading to accelerated cardiovascular mortality Chronicinflammation is a possible mediator between microvascularand macrovascular disease Oxidative stress may accelerateatherogenesis and hence make a significant contribution tothe increased CV disease burden in CKD patients Oxidativestress may actually represent a new target for therapeuticintervention In this review first we will discuss the role andthe biochemical burden of diabetes and dyslipidemia in CKDand then focus on the role of oxidative stress in CKD

2 Dyslipidemia and CKD

Dyslipidemia is related to the incidence and prognosisof CKD through mechanisms such as inflammation andincreased oxidative stress which could cause endothelialdamage and atherosclerosis [2] Studies have reported that

Hindawi Publishing CorporationChinese Journal of BiologyVolume 2014 Article ID 216210 6 pageshttpdxdoiorg1011552014216210

2 Chinese Journal of Biology

obesity and metabolic syndrome adversely affects renal func-tion and may be associated with morbidity and mortality inpatients with CKD [3ndash5] The expression of inflammatorygenes and genes implicated in insulin resistance is increasedin the glomeruli of patients with obesity-related nephropathyAdipose tissue is the source of active substances known asadipokines Many adipokines including IL-6 TNF-120572 andplasminogen activator inhibitor-1 (PAI-1) may cause tissuedamage by a direct proinflammatory mechanism or insulinresistance and can lead to inflammatory changes in thekidney The pattern of dyslipidemia in CKD differs fromthe non-CKD [6] and is similar to those found in dys-lipidemia associated with diabetes [7] The most importantabnormalities are an increase in serum triglyceride (TGL)predominantly very low-density lipoprotein (VLDL) andintermediate-density lipoprotein (IDL) mainly due to abnor-mal lipase function [6] causing hypertriglyceridemia andlow high-density lipoprotein (HDL) Even though the totalcholesterol level may be within normal range the lipid profilepatternmay be abnormalwith predominantly the small denseLDL particles which are atherogenic Lipoprotein-a (Lp-a)component is also elevated The Chronic Renal Impairemntin Birmingham (CRIB) study has confirmed the presenceof dyslipidemia in early CKD The components of TGL-richlipoproteins such as apolipoprotein B apolipoprotein C-IIIand apolipoprotein E are elevated in ESRD [7] In patientswith hypertriglyceridemia diabetic nephropathy and ESRDon hemodialysis (HD) small dense LDL preferentially accu-mulate thus leading to increased risk of peripheral vasculardisease coronary artery disease and myocardial infarction[8]

3 Diabetes and CKD

Hyperglycemia leads to vascular damage via several mecha-nismsThe four mainmechanisms are increased flux throughthe hexosamine path increased flux through polyol pathwayactivation of protein kinase C (PKC) and increased for-mation of advanced glycation end-products (AGE) Hyper-glycemia leads to activation of hexosamine pathway whichinturn leads to changes in gene expression protein functionand transcription of PAI-1 thus leading to the pathogen-esis of diabetic complications [7] The polyol pathway isimplicated in diabetic neuropathy and diabetic retinopathyCellular hyperglycemia leads to PKC activation which inturnaffects the expression and function of endothelial nitricoxide synthase endothelin-1 vascular endothelial growthfactor transforming growth factor-beta nuclear factor-120581Band nicotine adenine diphosphate oxidase [9]

The effects of AGEs can be classified as receptor-independent or receptor-dependent and can act intracellu-larly or on cell surface receptors such as the receptor forAGEs (RAGEs) Advanced glycation occurs over a prolongedperiod of time and mainly affects the long-lived proteinssuch as connective tissue matrix in particular basementmembrane components such as type-IV collagen are primetargets including other long-lived proteins such as myelintubulin plasminogen activator 1 and fibrinogen [10 11]

Glycation leads to structural alterations increased stiffnessand resistance to proteolytic digestion AGEs may promoteatherosclerosis by their interaction with AGE receptors onthe endothelial cells causing the expression of adhesionmolecules and attraction of monocytes into the vessel wallAGEs also alter the plasmaproteins thus inducing the expres-sion of proinflammatory and procoagulatory molecules bythe endothelial cells for example thrombomodulin expres-sion of cytokines and growth factors by macrophages andmesangial cells for example IL-1 IL-2 IL-6 and tumornecrosis factor-120572 These changes result in inflammationoxidative stress and coagulopathy and promote atheroscle-rosis [9] In CKD there is an accumulation of AGEs whichmay be due to increased concentration of reactive dicarbonylsin uremia and decreased renal clearance of AGEs Elevatedserum levels of neopterin (monocyte activation marker) andpentosidine correlate with the rate of progression of diabeticnephropathy [11]

The receptor-dependent effects of AGE are mediatedthrough its interactions with various proteins like the RAGEprotein AGE receptors and the ezrin radixin and moesin(ERM) family RAGE is a member of the immunoglobulinsuperfamily of receptors AGEs through their interactionwith RAGE activate secondary messenger pathways suchas protein kinase C The key target of RAGE signaling isnuclear factor-120581B (NF-kB) which increases transcription ofmany proteins including intercellular adhesion molecule-1 The strongest evidence for AGEs in the development ofdiabetic nephropathy has come from studies targeting theAGE-RAGE pathway [11 12]

4 Oxidative Stress and Inflammation in CKD

Oxidative stress is a state of imbalance between free radicalsproduction and its degradation by antioxidant systems withincreased accumulation of the radicals Over 90 of reactiveoxygen species (ROS) formation occurs in mitochondriaduring metabolism of oxygen when some electrons passingthe electron transport chain may leak from the main pathand can directly reduce oxygen molecules to the superoxideanion [1 11 13] ROS could also be deliberately synthesizedin phagocytic cells as well as in vascular wall and vari-ous other tissues by enzymes such as NAD[P]H oxidasemyeloperoxidase (MPO) xanthine oxidase cyclooxygenaseand lipoxygenase The release of an ROS may lead to theproduction of several through radical chain reactions Thesepotentially deleterious reactions are regulated by enzymaticand nonenzymatic antioxidants which eliminate prooxidantsand scavenge-free radicals Superoxide dismutase (SOD)glutathione peroxidase glutathione reductase and catalaseare among the main enzymatic antioxidants Glutathionethiols ascorbic acid alpha-tocopherol (vitamin E) mixedcarotenoids and bioflavonoids are the major nonenzymaticantioxidant defense processes [11]

At low concentrations ROS like superoxide anionhydrogen peroxide hydroxyl radical hypochlorite ion andhydroperoxyl radical play vital role in many physiologicfunctions For example ROS are known regulators of nitric

Chinese Journal of Biology 3

Oxidative stressConsumes nitric oxide

Free radicalsrelease

Chronicinflammation

CKD Endothelial dysfunction

Endothelial injury

Macrophage aggregatescholesterol accumulatesand become foam cells

Cytokines productionand stimulation ofinflammatory cellsAtherosclerosis

Figure 1 Role of oxidative stress in chronic inflammation andCKD

oxide synthesis intracellular signaling cascades and are alsoinvolved in the modulation of immune responses apoptosisand mutagenesis ROS produced during phagocytic burst isa key defense mechanism against environmental pathogensThey also lead to the formation of peroxynitrite which iscytotoxic and also responsible for both increased plateletaggregation and vasoconstriction When excess ROS areproduced they can react with various biomolecules thusaltering their structure and function resulting in cellulardamage and pathologic processes including atherosclerosis[13] Together with proinflammatory cytokines angiotensinII and advanced glycation end-products ROS release willaugment the ROS generation process (Figure 1)

41 Biomarkers of Oxidative Stress Free radicals have a veryshort half-life (in seconds) hence their evaluation in clinicalsetting is difficult But there aremore stablemarkermoleculeswith longer half-lives ranging from hours to weeks whichcan be used to assess oxidative stress associated with diversediseases including uremia [1] Some of these are oxidationbyproducts such as oxidized low-density lipoprotein (LDL)reactive carbonyl compounds advanced glycosylation end-product (AGE) and oxidized thiol compounds which canpotentially contribute to the pathogenesis of CV diseaseinflammation and other complications of uremia [12 14 15]

411 Circulating Biomarkers of Oxidative Stress in ChronicKidney Disease Patients [16]

Carbohydrates

Advanced glycosylation end-products (AGEs)Reactive aldehydes

Proteins

Amine oxidationAdvanced oxidation protein products (AOPPs)Carbonyl formationThiol oxidation

Amino Acids

CysteineHomocysteineIsoaspartateNitrotyrosine

Lipids

Advanced lipoxidation end-products (ALEs)Exhaled alkanesMalondialdehyde (MDA)Lipid hydroperoxidesOxidized low-density lipoprotein (ox-LDL)

Arachidonic Acid Derivatives

F2 isoprostanesIsolevuglandins

Nucleic Acids

8-Hydroxy 21015840-deoxyguanosine (8-OHdG)

42 Role of Oxidative Stress in Renal Dysfunction Many clin-ical studies have confirmed themajor role played by oxidativestress in renal dysfunction In dialysis patients AGEs havebeen associated with atherosclerosis and dialysis-associatedamyloidosis Malondialdehyde (MDA) has been suggestedas one of the best predictors of cardiovascular disease inhemodialysis patients [16 17] 8-Hydroxydeoxyguanosine(8-OHdG) concentrations were highest in long-term HDpatients Witko-Sarsat et al identified the presence ofadvanced oxidation protein products (AOPPs) in the plasmaof uremic patients and the AOPP levels increased as renalfunction declined [18] Drueke et al found that levels ofAOPP strongly correlated with carotid artery intima-medialthickness (IMT) in patients with ESRD [19] A similar findingwas reported by Yang et al in CKD [20] Additionallysignificant positive correlation between carotid artery IMTand thiobarbituric acid reactive substances (TBARS) andMPO and negative correlation between carotid artery IMTand reduced SOD and plasma sulfhydryl were reported inpatients with ESRD Shoji et al [21] observed a statisti-cal trend in correlation between carotid artery IMT andautoantibodies against oxidatively modified LDL (oxLDL)A stronger correlation was observed between femoral arteryIMT and autoantibodies against oxLDL in ESRD [15 22] InCKD patients not on maintenance dialysis autoantibodiesagainst oxLDL correlated with carotid atherosclerosis andstrongly predicted cardiovascular mortality during 4 years offollow-up study in hemodialysis patients [15]

43 Mechanisms That Lead to Increased Oxidative Stress inCKD Different mechanisms could explain the increasedoxidative stress in CKD Basic characteristics of renal patientssuch as advanced age diabetes renal hypertension lowerlevels of antioxidant vitamin due to dietary restriction of fresh


fruits and vegetables (to avoid hyperkalaemia) and failure ofROS clearance with decline in renal function are implicatedin increased oxidative stress and progression of CKD andoxidative stress seems to happen early during the course ofrenal decline [1 16 22]The pathogenesis of oxidative stress inCKD patients is complex and includes uremia-related factorsand dialysis-related factors

431 Uremia-Related Factors Studies have shown that theresting serum levels of superoxide anion were higher inHD patients than in healthy controls Several evidence sug-gests that antioxidant enzymes are altered as renal functiondeclines and are profoundly impaired in patientswith uremiaInvestigators have also found that CKD was associated withlow concentration of serum selenium and lower plateletglutathione peroxidase (GPx) activity [16] Ceballos-Picotet al [23] demonstrated lower serum levels of glutathioneand plasma GPx activity in renal failure patients CKD isalso associated with a profound disturbance in nitric oxidesystem as it increases the concentration of endogenous NOSinhibitors

432 Dialysis-Related Factors The bioincompatibility of HDsystems plays a pivotal role in ROS production by activationof polymorphonuclear neutrophils In particular two majorcomponents of the HD system contribute to oxidative stressthe dialyzer membrane and the trace amount of endotoxin inthe dialysate There may be a concomitant loss of antioxidantvitamins by dialysis process [1 16] Plasma vitamin E andselenium are reduced there is also significant deficiencyand downregulation of glutathione peroxidase copper-zincsuperoxide dismutase and manganese superoxide dismutasein renal dysfunction [16]

433 Role of Inflammation in CKD CKD is a low gradeinflammatory process in itself Chronic inflammation canitself lead to increased oxidative stress in advanced renaldisease with malnutrition chronic volume overload andautonomic dysfunction as some factors implicated in theincreased inflammatory state seen in renal impairmentStudies have observed association between many mediatorsof inflammation such as CRP IL-6 TNF-a fibrinogen andrenal dysfunction In CKD patients the polymorphonuclearneutrophils are activated and MPO is generated triggeringROS activation [1]

44 Clinical Effect of Oxidative Stress in CKD The impor-tant consequence of oxidative stress in CKD is endothelialdysfunction and the progression of other complications likeatherosclerosis anemia and amyloidosis Several qualitativeLDL changes like increased carbamylation AGE productsformation and oxidative stress seen in dialysis patients resultin endothelial dysfunction platelet aggregation metalopro-teinase expression and thrombogenesis Studies show that inCKD the LDL is more susceptible to in vitro oxidation thanin the healthy [24]

In CKD depending on the severity the prevalence of leftventricular hypertrophy (LVH) varies between 40 to 75

The aetiology of LVH in CKD is multifactorial such as vol-ume loading conditions (as in dialysis-dependent patients)hypertension and oxidative stress In vivo studies haveshown that oxidative stress induces several cardiomyocytehypertrophy signalling kinases (GTP-binding protein Rasmitogen activated protein kinase protein kinase C tyrosinekinase Src Jun-nuclear kinase and transcription factors (120581Bactivator-protein-1 Ets) which stimulate matrix metallopro-teinases expression [25] ROS also activate apoptosis sig-nalling kinase-1 and nuclear factor 120581B which are implicatedin cardiomyocyte hypertrophy

441 Amyloidosis In the presence of oxidative stress ROScan directly modify the function of proteins through the for-mation of oxidized amino acids Miyata et al demonstratedthat AGEs occur in beta2-microglobulin deposits of long-term HD patients suggesting that oxidative stress promotesamyloidosis due to protein denaturation [16 26]

442 Anemia Previous studies indicated that the serum ofHD patients has higher levels of MDA in erythrocytes anda severe deficiency in vitamin content which may shortenthe lifespan of erythrocytes in CKD Antioxidant therapyimproved anemia in CKD and reduced the requirement forerythropoiesis-stimulating agents (ESAs) in them [1 27]

5 Role of Antioxidant

Many studies have examined the effect of antioxidant inter-ventions on oxidative stress markers in CKD The SPACE(Secondary Prevention with Antioxidants of Cardiovascu-lar Disease in End-Stage Renal Disease) study observeda reduction in the primary composite outcome consist-ing of myocardial infarction ischemic stroke peripheralvascular disease and unstable angina in ESRD patientsreceiving vitamin E [28] Statins also reduce inflammatorymarkers A decrease in cumulative incidence for stroketotal coronary events total cardiovascular events and all-cause mortality was observed in the Anglo-ScandinavianCardiac Outcomes TrialmdashLipid Lowering Arm (ASCOT-LLA) [15 29] study which also included a subgroup ofCKD patients Wassmann et al have described a relationshipbetween atorvastatin-induced improvement of endothelialdysfunction and reduced free-radical release in the vas-culature associated with a statin-induced downregulationof angionten-I-receptor expression [7 30] Statins can alsoinhibit the activation and proliferation of lymphocytes andsmooth-muscle cells as well as chemotaxis and oxidative-burst of macrophages platelet adhesion and aggregationare also blocked The Study of Heart and Renal Protection(SHARP) tells the cardiovascular benefits of statin use inCKD patients [15 31]

Antioxidant-based dialysis membranes such as vita-min E-modified cellulose membranes have been shown toimprove endothelial dysfunction and increase oxidised LDLRecently there have been promising reports of haemolipo-dialysis using vitamin C and vitamin E-containing liposomesin the dialysate to reduce dialysis-induced oxidative stress


the liposomes get oxidised and killed because of their highdegree of unsaturation and thus act as the ldquoradical sinkrdquo[1 32]

Angiotensin-converting enzyme inhibitors and angiot-ensin receptor blockers are highly effective inhibitors ofangiotensin II-dependent NADPH oxidase activation andhave been used successfully in the clinical setting especiallyin patients with CKDESRD

6 Conclusion

CKD patients are affected by multiple concomitant condi-tions like diabetes dyslipidemia and hypertension which areall associated with oxidative stress The presence of CKDappears to further enhance the oxidative stress independentlyfrom the underlying conditions Hemodialysis has also beendemonstrated to contribute to the oxidative stress Increasingevidence suggests that oxidative stress is a plausible inde-pendent cardiovascular risk factor in CKD Cardiovasculardisease is an important cause of morbidity and mortalityin patients with impaired kidney function Furthermoreidentification of biochemical andor functional biomarkersthat could be used in clinical practice to monitor oxidativeimbalance in CKDmay allow the development of an optimalintervention strategy to reduce oxidative stress in CKD

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] M P Kao D S Ang A Pall and A D Struthers ldquoOxidativestress in renal dysfunction mechanisms clinical sequelae andtherapeutic optionsrdquo Journal of human hypertension vol 24 no1 pp 1ndash8 2010

[2] W H Sheu and Y Sheen ldquoMetabolic syndrome and renalinjuryrdquo Cardiology Research and Practice vol 1 no 1 ArticleID 567389 2011

[3] P Iglesias and J J Dıez ldquoAdipose tissue in renal disease clinicalsignificance and prognostic implicationsrdquo Nephrology DialysisTransplantation vol 25 no 7 pp 2066ndash2077 2010

[4] I Lee C Huang W Lee H Lee and W H-H Sheu ldquoAggrava-tion of albuminuria by metabolic syndrome in type 2 diabeticAsian subjectsrdquo Diabetes Research and Clinical Practice vol 81no 3 pp 345ndash350 2008

[5] J Lucove S Vupputuri G Heiss K North and M RussellldquoMetabolic syndrome and the development of CKD in Ameri-can Indians the StrongHeart StudyrdquoAmerican Journal of KidneyDiseases vol 51 no 1 pp 21ndash28 2008

[6] M P Delaney C P Price and D J Newman ldquoEdmund lambKidney disaserdquo in Tietz Texstbook of Clinical Biochemistry pp1670ndash1745 Saunders 4th edition 2006

[7] V Krane andCWanner ldquoThemetabolic burden of diabetes anddyslipidaemia in chronic kidney diseaserdquo Nephrology DialysisTransplantation vol 17 no 11 pp 23ndash27 2002

[8] T Quaschning V Krane T Metzger and C Wanner ldquoAbnor-malities in uremic lipoprotein metabolism and its impact on

cardiovascular diseaserdquo American Journal of Kidney Diseasesvol 38 supplement 1 pp S14ndashS19 2001

[9] H J Goldberg J Scholey and I G Fantus ldquoGlucosamineactivates the plasminogen activator inhibitor 1 gene promoterthrough Sp1 DNA binding sites in glomerular mesangial cellsrdquoDiabetes vol 49 no 5 pp 863ndash871 2000

[10] M Brownlee ldquoBiochemistry and molecular cell biology ofdiabetic complicationsrdquo Nature vol 414 no 6865 pp 813ndash8202001

[11] S Goh and M E Cooper ldquoThe role of advanced glycation endproducts in progression and complications of diabetesrdquo Journalof Clinical Endocrinology and Metabolism vol 93 no 4 pp1143ndash1152 2008

[12] A Flyvbjerg L Denner B F Schrijvers et al ldquoLong-term renaleffects of a neutralizing RAGE antibody in obese type 2 diabeticmicerdquo Diabetes vol 53 no 1 pp 166ndash172 2004

[13] J M Forbes T Soulis V Thallas et al ldquoRenoprotective effectsof a novel inhibitor of advanced glycationrdquoDiabetologia vol 44no 1 pp 108ndash114 2001

[14] H Honda M Ueda S Kojima et al ldquoAssessment of myeloper-oxidase and oxidative 120572-antitrypsin in patients on hemodialy-sisrdquo Clinical Journal of the American Society of Nephrology vol4 no 1 pp 142ndash151 2009

[15] N Le and E O Gosmanova ldquoCardiovascular complications inCKD patients role of oxidative stressrdquo Cardiology Research andPractice vol 1 no 1 Article ID 156326 2011

[16] K-L Kuo and D-C Tarng ldquoOxidative stress in chronic kidneydiseaserdquo Adaptive Medicine vol 2 no 2 pp 87ndash94 2010

[17] W Droge ldquoFree radicals in the physiological control of cellfunctionrdquo Physiological Reviews vol 82 no 1 pp 47ndash95 2002

[18] V Witko-Sarsat M Friedlander T N Khoa et al ldquoAdvancedoxidation protein products as novel mediators of inflammationand monocyte activation in chronic renal failurerdquo Journal ofImmunology vol 161 no 5 pp 2524ndash2532 1998

[19] T Drueke V Witko-Sarsat Z Massy et al ldquoIron ther-apy advanced oxidation protein products and carotid arteryintima-media thickness in end-stage renal diseaserdquo Circulationvol 106 no 17 pp 2212ndash2217 2002

[20] X Yang F Hou Q Wu et al ldquoIncreased levels of advancedoxidation protein products are associated with atherosclerosisin chronic kidney diseaserdquo Zhonghua Nei Ke Za Zhi vol 44 no5 pp 342ndash346 2005

[21] T Shoji E Kimoto K Shinohara et al ldquoThe associationof antibodies againstoxidized low-density lipoprotein withatherosclerosis in hemodialysis patientsrdquo Kidney InternationalSupplement vol 63 no 84 pp S128ndashS130 2003

[22] F Locatelli B Canaud K Eckardt P Stenvinkel C Wannerand C Zoccali ldquoOxidative stress in end-stage renal diseasean emerging treat to patient outcomerdquo Nephrology DialysisTransplantation vol 18 no 7 pp 1272ndash1280 2003

[23] I Ceballos-Picot V Witko-Sarsat M Merad-Boudia et alldquoGlutathione antioxidant system as a marker of oxidative stressin chronic renal failurerdquo Free Radical Biology and Medicine vol21 no 6 pp 845ndash853 1996

[24] R J Esper R A Nordaby J O Vilarino A Paragano J LCacharron and R A Machado ldquoEndothelial dysfunction acomprehensive appraisalrdquo Cardiovascular Diabetology vol 5article 4 2006

[25] E Paoletti D Bellino P Cassottana D Rolla and G CannellaldquoLeft ventricular hypertrophy in nondiabetic predialysis CKDrdquoAmerican Journal of Kidney Diseases vol 46 no 2 pp 320ndash3272005


[26] T Miyata C V de Strihou K Kurokawa and J W BaynesldquoAlterations in nonenzymatic biochemistry in uremia originand significance of ldquocarbonyl stressrdquo in long-term uremiccomplicationsrdquoKidney International vol 55 no 2 pp 389ndash3991999

[27] V Lahera M Goicoechea S G de Vinuesa et al ldquoOxidativestress in uremia the role of anemia correctionrdquo Journal of theAmerican Society of Nephrology vol 17 pp S174ndashS177 2006

[28] M Boaz S Smetana TWeinstein et al ldquoSecondary preventionwith antioxidants of cardiovascular disease in endstage renaldisease (SPACE) randomised placebo-controlled trialrdquo TheLancet vol 356 no 9237 pp 1213ndash1218 2000

[29] P S Sever B Dahlof N R Poulter et al ldquoPrevention ofcoronary and stroke events with atorvastatin in hypertensivepatients who have average or lower-than-average cholesterolconcentrations in the Anglo-Scandinavian Cardiac OutcomesTrialmdashLipid Lowering Arm (ASCOT-LLA) a multicentre ran-domised controlled trialrdquo The Lancet vol 361 no 9364 pp1149ndash1158 2003

[30] S Wassmann U Laufs A T Baumer et al ldquoHMG-CoAreductase inhibitors improve endothelial dysfunction in nor-mocholesterolemic hypertension via reduced production ofreactive oxygen speciesrdquo Hypertension vol 37 no 6 pp 1450ndash1457 2001

[31] SHARPCollaborativeGroup ldquoStudy ofHeart andRenal Protec-tion (SHARP) randomized trial to assess the effects of loweringlow-density lipoprotein cholesterol among 9 438 patients withchronic kidney diseaserdquoAmerican Heart Journal vol 160 no 5pp 785ndash794 2010

[32] M LWrattenCNavinoC Tetta andGVerzetti ldquoHaemolipo-dialysisrdquo Blood Purification vol 17 no 2-3 pp 127ndash133 1999

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


obesity and metabolic syndrome adversely affects renal func-tion and may be associated with morbidity and mortality inpatients with CKD [3ndash5] The expression of inflammatorygenes and genes implicated in insulin resistance is increasedin the glomeruli of patients with obesity-related nephropathyAdipose tissue is the source of active substances known asadipokines Many adipokines including IL-6 TNF-120572 andplasminogen activator inhibitor-1 (PAI-1) may cause tissuedamage by a direct proinflammatory mechanism or insulinresistance and can lead to inflammatory changes in thekidney The pattern of dyslipidemia in CKD differs fromthe non-CKD [6] and is similar to those found in dys-lipidemia associated with diabetes [7] The most importantabnormalities are an increase in serum triglyceride (TGL)predominantly very low-density lipoprotein (VLDL) andintermediate-density lipoprotein (IDL) mainly due to abnor-mal lipase function [6] causing hypertriglyceridemia andlow high-density lipoprotein (HDL) Even though the totalcholesterol level may be within normal range the lipid profilepatternmay be abnormalwith predominantly the small denseLDL particles which are atherogenic Lipoprotein-a (Lp-a)component is also elevated The Chronic Renal Impairemntin Birmingham (CRIB) study has confirmed the presenceof dyslipidemia in early CKD The components of TGL-richlipoproteins such as apolipoprotein B apolipoprotein C-IIIand apolipoprotein E are elevated in ESRD [7] In patientswith hypertriglyceridemia diabetic nephropathy and ESRDon hemodialysis (HD) small dense LDL preferentially accu-mulate thus leading to increased risk of peripheral vasculardisease coronary artery disease and myocardial infarction[8]

3 Diabetes and CKD

Hyperglycemia leads to vascular damage via several mecha-nismsThe four mainmechanisms are increased flux throughthe hexosamine path increased flux through polyol pathwayactivation of protein kinase C (PKC) and increased for-mation of advanced glycation end-products (AGE) Hyper-glycemia leads to activation of hexosamine pathway whichinturn leads to changes in gene expression protein functionand transcription of PAI-1 thus leading to the pathogen-esis of diabetic complications [7] The polyol pathway isimplicated in diabetic neuropathy and diabetic retinopathyCellular hyperglycemia leads to PKC activation which inturnaffects the expression and function of endothelial nitricoxide synthase endothelin-1 vascular endothelial growthfactor transforming growth factor-beta nuclear factor-120581Band nicotine adenine diphosphate oxidase [9]

The effects of AGEs can be classified as receptor-independent or receptor-dependent and can act intracellu-larly or on cell surface receptors such as the receptor forAGEs (RAGEs) Advanced glycation occurs over a prolongedperiod of time and mainly affects the long-lived proteinssuch as connective tissue matrix in particular basementmembrane components such as type-IV collagen are primetargets including other long-lived proteins such as myelintubulin plasminogen activator 1 and fibrinogen [10 11]

Glycation leads to structural alterations increased stiffnessand resistance to proteolytic digestion AGEs may promoteatherosclerosis by their interaction with AGE receptors onthe endothelial cells causing the expression of adhesionmolecules and attraction of monocytes into the vessel wallAGEs also alter the plasmaproteins thus inducing the expres-sion of proinflammatory and procoagulatory molecules bythe endothelial cells for example thrombomodulin expres-sion of cytokines and growth factors by macrophages andmesangial cells for example IL-1 IL-2 IL-6 and tumornecrosis factor-120572 These changes result in inflammationoxidative stress and coagulopathy and promote atheroscle-rosis [9] In CKD there is an accumulation of AGEs whichmay be due to increased concentration of reactive dicarbonylsin uremia and decreased renal clearance of AGEs Elevatedserum levels of neopterin (monocyte activation marker) andpentosidine correlate with the rate of progression of diabeticnephropathy [11]

The receptor-dependent effects of AGE are mediatedthrough its interactions with various proteins like the RAGEprotein AGE receptors and the ezrin radixin and moesin(ERM) family RAGE is a member of the immunoglobulinsuperfamily of receptors AGEs through their interactionwith RAGE activate secondary messenger pathways suchas protein kinase C The key target of RAGE signaling isnuclear factor-120581B (NF-kB) which increases transcription ofmany proteins including intercellular adhesion molecule-1 The strongest evidence for AGEs in the development ofdiabetic nephropathy has come from studies targeting theAGE-RAGE pathway [11 12]

4 Oxidative Stress and Inflammation in CKD

Oxidative stress is a state of imbalance between free radicalsproduction and its degradation by antioxidant systems withincreased accumulation of the radicals Over 90 of reactiveoxygen species (ROS) formation occurs in mitochondriaduring metabolism of oxygen when some electrons passingthe electron transport chain may leak from the main pathand can directly reduce oxygen molecules to the superoxideanion [1 11 13] ROS could also be deliberately synthesizedin phagocytic cells as well as in vascular wall and vari-ous other tissues by enzymes such as NAD[P]H oxidasemyeloperoxidase (MPO) xanthine oxidase cyclooxygenaseand lipoxygenase The release of an ROS may lead to theproduction of several through radical chain reactions Thesepotentially deleterious reactions are regulated by enzymaticand nonenzymatic antioxidants which eliminate prooxidantsand scavenge-free radicals Superoxide dismutase (SOD)glutathione peroxidase glutathione reductase and catalaseare among the main enzymatic antioxidants Glutathionethiols ascorbic acid alpha-tocopherol (vitamin E) mixedcarotenoids and bioflavonoids are the major nonenzymaticantioxidant defense processes [11]

At low concentrations ROS like superoxide anionhydrogen peroxide hydroxyl radical hypochlorite ion andhydroperoxyl radical play vital role in many physiologicfunctions For example ROS are known regulators of nitric




Chronicinflammation


Endothelial injury







Carbohydrates


Proteins


Amino Acids


Lipids




Nucleic Acids




















6 Conclusion




References










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




Chronicinflammation


Endothelial injury







Carbohydrates


Proteins


Amino Acids


Lipids




Nucleic Acids




















6 Conclusion




References










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

















6 Conclusion




References










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology
















Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

review article chronic kidney disease effect of oxidative...

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