Radical approach to diabetic nephropathy

http://www.kidney-international.org & 2007 International Society of Nephrology

Radical approach to diabetic nephropathy HB Lee1, JY Seo1,2, MR Yu1, S-T Uh1 and H Ha2,3 1

Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea and 2College of Pharmacy, Ewha Woman’s University, Seoul, Korea and 3Center for Cell Signaling and Drug Discovery Research, Ewha Woman’s University, Seoul, Korea

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-b1 (TGF-b1) and angiotensin II (Ang II) in renal cells and high glucose, TGF-b1, and Ang II all generate and signal through ROS. ROS mediate high glucose-induced activation of protein kinase C and nuclear factor-jB 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 be effective in preventing the development and progression of CKD in diabetes. Kidney International (2007) 72, S67–S70; doi:10.1038/sj.ki.5002389 KEYWORDS: antioxidant; chronic kidney disease; diabetes; oxidative stress; protein kinase C; reactive oxygen species

Correspondence: H Ha, Ewha Woman’s University College of Pharmacy, 11-1 Daehyun Dong, Seodaemun Ku, Seoul 120-750, Korea. E-mail: [email protected] Kidney International (2007) 72, S67–S70

Diabetes mellitus (DM) is the leading cause of end-stage renal disease (ESRD), non-traumatic lower extremity amputations, and adult blindness.1 DM increases the risk of cardiac, cerebral, and peripheral vascular disease two- to sevenfold.2 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 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 Large, randomized clinical trials of individuals with type I4 or type II DM5 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 There is much evidence from experimental studies that the formation of ROS is a direct consequence of hyperglycemia.6 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 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.7,8 ROS mediate hyperglycemia-induced activation of signaltransduction cascades and transcription factors leading to transcriptional activation of profibrotic genes.8 Furthermore, activated signaling molecules generate and signal through ROS, thus ROS act as a signal amplifier.8 In this review, we will present evidence that oxidative stress plays an important pathogenic role in the development S67

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of diabetic complications and that antioxidants may be helpful in the treatment of patients with diabetes and CKD. DIABETES AND CKD ARE INCREASING MEDICAL AND SOCIOECONOMIC BURDEN

DM is the leading cause of ESRD and a known risk for CKD.3 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 Mortality due to cardiovascular disease is 10–30 times higher in ESRD patients than in the general population.10 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 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 Prevalence of CKD before dialysis is estimated at 10–11% of adult population in Norway and USA.11 OXIDATIVE STRESS IS INCREASED IN DIABETES AND CKD

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 F2a, and oxidized low-density lipoprotein in type I and type II DM when compared to healthy age-matched subjects. Dandona et al.12 showed an approximately fourfold higher median concentration of 8-hydroxydeoxyguanosine in mononuclear cells of diabetic patients compared to corresponding controls. Nourooz-Zadeh et al.13–15 demonstrated an approximately twofold increase in the plasma 8-epiprostaglandin F2a and hydroperoxides and three- to sixfold imbalance between increased levels of oxidative stress and the depletion of RRR-a-tocopherol in plasma of diabetic patients. Increased low-density lipoprotein oxidation16 and imbalance between elevated oxidized low-density lipoprotein levels and decreased RRR-a-tocopherol levels (cholesterol standardized) were observed in the low-density lipoprotein particle in diabetic patients when compared to healthy control.17 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 13-Hydroxyoctadecadienoic acid, protein carbonyls, 8-hydroxydeoxyguanosine, asymmetric dimethylarginine, and GSSG/GSH were all increased in CKD patients on hemodialysis.19 S68

HIGH GLUCOSE, TGF-b1, AND ANGIOTENSIN II INDUCE GENERATION OF ROS IN VASCULAR CELLS

Nishikawa et al.20 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 hyperglycemiainduced cellular damage20–22 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 and that high glucose-induced ROS is dependent on activation of PKC,23 nicotinamide adenine dinucleotide phosphate oxidase,8 and mitochondrial electron gradient.8 We and others have shown that TGF-b18 and angiotensin II (Ang II)24 can induce nicotinamide adenine dinucleotide phosphate oxidase-dependent ROS in renal cells. Onozato et al.25 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. ROS MEDIATE HIGH GLUCOSE-INDUCED ACTIVATION OF PKC AND NUCLEAR FACTOR-jB IN RENAL CELLS

We demonstrated that activation of PKC-d and PKC-e was significantly increased in diabetic glomeruli and that this was effectively prevented by antioxidant taurine.26 We also demonstrated that high glucose activates PKC in mesangial cells.23 Studer et al.27 showed that structurally different antioxidants significantly inhibit high glucose-induced activation of PKC in mesangial cells. Haneda et al.28 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-kB is mediated by ROS and PKC and that high glucose-induced monocyte chemoattractant protein-1 expression is nuclear factor-kB-dependent and is also mediated by ROS and PKC.23 ROS MEDIATE HIGH GLUCOSE-INDUCED TGF-b1 AND PLASMINOGEN ACTIVATOR INHIBITOR-1 IN RENAL CELLS

We had earlier demonstrated that high glucose stimulates TGF-b1 and fibronectin in mesangial cells29 and that Kidney International (2007) 72, S67–S70

HB Lee et al.: Treatment of diabetic nephropathy

antioxidants inhibit glomerular TGF-b1 and fibronectin mRNA expression in diabetic rats.30 We found that high glucose- and TGF-b1-induced upregulation of plasminogen activator inhibitor (PAI)-1 is mediated by ROS.31,32 On the other hand, TGF-b1 was found to mediate PAI-1-induced fibronectin and collagen I expression in PAI-1-deficient mesangial cells cultured under high glucose.33 PAI-1 was shown to stimulate TGF-b1 promoter activity comparable to TGF-b1 in mesangial cells,33 suggesting that TGF-b1 and PAI-1 together constitute a positive feed back loop in tissue fibrosis. We also observed that TGF-b1-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 ROS mediate high glucose, TGF-b1, and Ang II signals in renal cells and thus play a major role in renal fibrosis in hyperglycemic conditions. TREATMENT OF DIABETIC NEPHROPATHY: RADICAL APPROACH

Intensive glycemic control in patients with type I4 and type II5 DM significantly prevented the onset and progression of diabetic nephropathy. Lewis et al.35,36 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 Overexpression of catalytic antioxidants copper/zinc superoxide dismutase and manganese superoxide dismutase were shown to protect against diabetic injury. Craven et al.37 demonstrated that diabetic copper/zinc superoxide dismutase transgenic mice had significantly lower urinary albumin excretion, glomerular hypertrophy, and glomerular expression of TGF-b1 and collagen IV protein compared to nontransgenic mice. Du et al.38 showed that overexpression of manganese superoxide dismutase in bovine aortic endothelial cells prevented high glucose-induced activation of PKC, NKkB, hexosamine, and advanced glycation end product pathways. Transketolase activator benfotiamine39 and poly (ADP-ribose) polymerase inhibitor PJ3438 were also shown to block biochemical pathways of hyperglycemic damage.

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. DISCLOSURE

The authors have stated they have nothing to disclose. ACKNOWLEDGMENTS

This work was supported, in part, by a grant from Korea Research Foundation E00013. REFERENCES 1.

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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 Kidney International (2007) 72, S67–S70

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