Introduction

Abstract

The Fifth Hyonam Kidney Laboratory International Diabetes Symposium entitled ‘Vascular Complications of Diabetes: New Insights into Mechanisms and Novel Therapeutics’ was held in Seoul, Korea, February 2–3, 2007 on the occasion of Professor Hi Bahl Lee's retirement from the university. Professor Lee has organized four previous International Diabetes Symposia focusing on the mechanisms involved in the renal injury in diabetes. At the fifth symposium, he expanded the scope and invited topics on vascular complications of diabetes in general and added informations on novel therapeutics. Given the increasing recognition that reactive oxygen species (ROS) play a major role in the development and progression of diabetic vascular complications, Rhee et al. gave an overview on the basic ROS biology with emphasis on sulfiredoxin-dependent peroxidation of 2-Cys peroxiredoxins (Prxs), which contain two conserved Cys residues. Prxs are the main component removing extracellular signal-induced cytosolic H2O2 due to its cytosolic localization and high affinity toward H2O2 and thus serve as the main component in H2O2signaling cascade. Prx hyperoxidized lose their peroxidase function and concomitantly gain chaperone function. The sole function of sulfiredoxin appears to support reversible sulfinic modification of 2-Cys Prx. They proposed that Prx play a pivotal role in cellular response to external stimuli based on Prx's dual function in modulating H2O2concentration and in preventing protein aggregation. The role of Prx in the pathogenesis of diabetic vascular complications remains to be elucidated. Eberhardt and Pfeilschifter reviewed the mechanisms underlying both antiatherogenic and proatherogenic properties of nitric oxide in perivascular extracellular matrix remodeling. Antiatherogenic/antifibrotic effect of nitric oxide depends on functional antagonism to angiotensin II, inhibition of angiotensin-converting enzyme (ACE) activity and angiotensin type I receptor expression, rapid decay of cytokine-induced MMP-9 mRNA as a result of inhibiting the mRNA-stabilizing factor HuR and upregulation of an intrinsic MMP-9 inhibitor TIMP-1. Nitric oxide, at the same time, activates a major profibrotic mediator transforming growth factor-β1. Understanding the precise molecular mechanisms will provide new targets in treatment of diabetic nephropathy as well as atherosclerosis resulting from chronic inflammation. Advanced glycation end products (AGEs) are known to have a wide range of chemical, cellular, and tissue effects implicated in the development and progression of diabetic vascular complications. AGE generate ROS directly or through binding receptors for AGE, whereas ROS, in turn, promote formation of AGE. Schleicher and Friess focused on molecular mechanisms of accelerated atherosclerosis in diabetic patients and developed a hypothesis unifying the wealth of data that indicate apparently diverse pathways. Activation of endothelial cells, an early event in atherosclerosis, is proposed to occur only if the stress including hemodynamic factors, metabolic factors, and periodically increased repair/inflammatory cytokines were qualitatively and/or quantitatively increased. Prolonged ‘stress’ leads to sustained production of ROS via activation of NADPH oxidase and/or mitochondria and inflammatory cytokines/growth factors leading to endothelial dysfunction. Kang et al. reviewed recent data supporting that podocytes play an important role in mediating diabetic renal injury. Major factors suggested to mediate diabetic renal injury including high glucose, angiotensin, transforming growth factor-β1, and mechanical stretch are shown to induce glomerular hypertrophy, podocytopenia, glomerulosclerosis, and foot process effacement all of which contribute to diabetic renal injury. Na+/glucose cotransporters in renal proximal tubules have an important role in regulating plasma glucose and are proposed as potential targets for the treatment of diabetes. Han et al. utilized primary rabbit kidney epithelial cells that have been characterized to keep transporter phenotype to study the regulatory mechanisms of Na+/glucose cotransporters. High glucose inhibits Na+/glucose cotransporters through ROS-NF-κB pathway and angiotensin II through tyrosine kinase-protein kinase C (PKC)-mitogen-activated protein kinase-cytosolic phospholipase A2, whereas enhanced Na+/glucose cotransporter activity has cytoprotection against hypoxia in renal proximal tubules. Genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy and type II diabetes. Recent advance in technology for genetic studies allowed genome-wide association study using sufficient number of subjects. Kikkawa et al. reported their recent genome-wide association study utilizing single-nucleotide polymorphism as genetic markers in a large cohort of Japanese population. SLC12A3 and ELMO1 were proposed as the new candidates for diabetic nephropathy and TGAP2B for type II diabetes. A significant combinational effect of ACE, angiotensinogen, and angiotensin type I receptor on susceptibility to diabetic nephropathy was found and TCF7L2 was confirmed as a susceptibility gene for type II diabetes in Japanese as in Caucasian. Further progress in this field will contribute to the establishment of personalized medicine in the future. With respect to novel therapeutic approach to diabetic vascular complications, Noh and King discussed strategies to target diacylglycerol–PKC pathway using isoform-specific inhibitors as one of the promising therapeutic options. The activation of diacylglycerol–PKC pathway has been associated with many vascular abnormalities in renal, retinal, and cardiovascular tissues in diabetic animals and patients. The specific effect of PKC isoforms on the renal and other vascular tissues to induce diabetic complications are just beginning to be determined using pharmacological approach and genetically altered mice. Ruboxistaurin, a selective inhibitor of PKCβ has been tested in clinical trials. Successful results in phase 3 trials for diabetic macular edema and in phase 2 trials for diabetic proteinuria in patients already treated optimally with ACE inhibitor or ARB have been reported. Well-designed large and long-term clinical trials are needed to establish its efficacy for prevention and treatment of nephropathy and other vascular complications in diabetic patients. Cooper et al. reviewed AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetes. Alagebrium has been shown to attenuate diabetic renal disease, cardiac dysfunction, and atherosclerosis and, in addition, to inhibit activation of certain PKC isoforms. Interruption of the renin-angiotensin system with either ACE inhibitors or angiotensin receptor blockers (ARB) is considered routine clinical practice in both early and late renal disease in type 1 and 2 diabetes. It is, therefore, critical to explore the renoprotective effect of alagebrium in diabetic subjects in the context of concomitant ACE inhibition or ARB for this therapeutic approach to confer superior renal benefits than seen with renin-angiotensin system blockade alone. Ha et al. proposed histone deacetylase inhibitors as a novel class of therapeutic agents in diabetic nephropathy. Histone deacetylase inhibitors at dose increasing histone acetylation effectively inhibit epithelial–mesenchymal transition and extracellular matrix accumulation in renal tubular epithelial cells and in the kidneys of diabetic rats. These findings are consistent with their suppression of myofibroblast differentiation in hepatic stellate cells, transforming growth factor-β1-induced fibrogenesis in skin fibroblasts, and cardiac hypertrophy. However, the precise mechanisms of antifibrotic effect of histone deacetylase inhibitors remain to be elucidated. Lee et al. highlighted ROS as a therapeutic target in diabetic nephropathy. Diabetes is the leading cause of end-stage renal disease and a known risk factor for chronic kidney disease, constituting an increasing medical and socio-economic burden worldwide. Mounting evidence indicates that oxidative stress is increased in both diabetes and chronic kidney disease/end-stage renal disease. They reviewed ROS-regulated signaling pathways leading to extracellular matrix deposition in diabetic kidney. ROS generated by high glucose levels activate signal transduction cascades and transcription factors and upregulate transforming growth factor-β1 and fibronectin in renal cells. They proposed that combined 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 should effectively prevent the development and progression of chronic kidney disease in diabetes. It is hoped that this symposium will stimulate scientists to generate fresh perspectives that can translate into therapeutics leading to prevention or reversal of diabetic vascular complications in the near future. The meeting was generously supported by Dr Doo Hong Choi and many other students of Professor Lee, Baxter Korea, Choogwae Pharma Corporation, FMC Korea, Gambro Korea, Hanmi Pharma, Hanwha Group, Nikiso Korea, and Soon Chun Hyang University. We are grateful to Dr Al-Awqati, Editor of Kidney International, for giving us the opportunity to bring together these contributions in one issue. We also thank all the authors and their collaborators who contributed to these Proceedings.