Summary of Research Project Results Under the JSPS FY2000
"Research for the future Program"



1.Research Institution Tokai University
 
2.Research Area Life Science
 
3.Research Field Cellular Signaling
 
4.Term of Project FY1996〜FY2000
 
5.Project Number 96L00303
 
6.Title of Project Elucidation of carbonyl stress pathway and the mechanism of redox regulation to carbonyl atress.

7.Projetct Leader
Name Institution,Department Title of Position
Toshio Miyata Tokai University School of Medicine, Department of Internal Medicine Associate Professor

8.Core Members

Names Institution,Department Title of Position
Kiyoshi Kurokawa Tokai University School of Medicine Department of Internal Medicine Professor
Izumi Nakasima Nagoya University School of Medicine, Department of Medical Internal of Medicine Professor
Charles van Ypersele de Strihou Universite Catholique de Louvain Service de Nephrologie Professor

9.Cooperating Researchers

10.Summary of Research Results

Research on the role of advanced glycation end products (AGEs) has brought new insights to non-enzymatic biochemistry. It revealed increased progressive, irreversible protein modifications with reactive carbonyl compounds (RCOs), derived from oxidative and non-oxidative chemistry ("carbonyl stress"). Under carbonyl stress, not only AGEs derived from carbohydrates but also advanced lipoxidation end products (ALEs) derived from lipids modify matrix as well as cellular proteins. Carbonyl stress is augmented by either oxidative stress or impaired detoxification of RCOs. Nitric oxide is also implicated in the atherogenic and inflammatory effects of carbonyl stress. We demonstrated the pathological significance of carbonyl stress in uremia complications (amyloidosis and peritoneal sclerosis), diabetic complications, atherosclerosis, rheumatoid arthritis, age-related macular degeneration, and ling fibrosis.
Carbonyl stress mediates intracellular signalings by multiple pathways directly and indirectly, leading to cellular activation or cell death. The indirect pathway involves reaction between RCOs and proteins to produce AGEs, which then bind with RAGE and induce generation of oxygen. In contrast, the direct pathway involves induction of cross-linking or clustering of cell surface receptors by different RCOs to activate receptor (EGFR, Ret etc.) and non-receptor (c-Src, Lck etc.) protein tyrosine kinases (PTKs), and to produce free radicals. The generated free radicals may further accelerate activation of PTKs potentially through a redox reaction-mediated structural modification of the kinase proteins on one hand, and activate ASK1-SEK1-JNK pathway leading to activation of caspases for cell death on the other. The RCOs-mediated activation of PTKs leads to activation of Ras-MAPK pathway.
The manipulation of carbonyl stress should provide new therapeutic insights. Among them, these appear promising: thiol repletion, development of novel inhibitors of carbonyl amine chemistry, and acceleration of the glyoxalase detoxification pathway. These therapeutic approaches indeed inhibit the carbonyl modification of proteins with carbohydrates and lipids, prevent the intracellular signaling and cellular responses, and effectively retard the development of tissue damage in vivo in animal models.

11.Key Words

(1)carbonyl stress、(2)carbonyl stress inhibitor、(3)oxidative stress
(4)reactive carbonyl copound、(5)advanced glycation/lipoxidation end product、(6)diabetes mellitus
(7)chronic renal failure、(8)atherosclerosi、(9)aging

12.References

[Reference Articles]
Author Title of Article
Miyata T et. al New aspects in the pathogenesis of dialysis-related amyloidosis: Role of β2-microglobulin modified with advanced glycation end products in bone and joint destruction.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 11 [suppl 2] 1996 140-143

Author Title of Article
Miyata T et. al Monocyte/macrophage response toβ2-microglobulin modified with advanced glycation end products.
Journal Volume Year Pages Concerned
Kidney Int 49 1996 538-550

Author Title of Article
Miyata T et. al Identification of pentosidine as a native structure for advanced glycation end products in β2-microglobulin forming amyloid fibrils in patients with dialysis-related amyloidosis.
Journal Volume Year Pages Concerned
Proc Natl Acad Sci USA 93 1996 2353-2358

Author Title of Article
Miyata T Advanced glycation end products and β2-microglobulin in the pathogenesis of bone lesions in dialysis-associated amyloidosis.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 11 1996 86-90

Author Title of Article
Cai T et. al β2-Microglobulin modified with advanced glycation end products induces monocyte chemotaxis in vivo.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 11 1996 1181-1191

Author Title of Article
Miyata T et. al New aspects in the pathogenesis of dialysis-related amyloidosis: Pathophysiology of advancesglycation end products in renal failure.
Journal Volume Year Pages Concerned
Jpn J Nephrol 38 1996 191-197

Author Title of Article
Miyata T et. al Alternate repetition of short fore- and backfiltrations reduces convective albumin loss.
Journal Volume Year Pages Concerned
Kidney Int 50 1996 432-435

Author Title of Article
Miyata T et. al Accmulation of alubumin-linked and free-form pentosidine in the circulation of uremic patients with end-stage renal failure: Renal implications in the pathophysiology of pentosidine.
Journal Volume Year Pages Concerned
J Am Soc Nephrol 7 1996 1198-1206

Author Title of Article
Miyata T et. al The receptor for advanced glycation end-products(RAGE) is a central mediator of the interaction of AGE-β2microglobulin with human mononuclearphagocytes via an oxidant-sensitive pathway: implications for the pathogenesis of dialysis-related amyloidosis.
Journal Volume Year Pages Concerned
J Clin Invest 98 1996 2353-2358

Author Title of Article
Miyata T et. al Advanced glycation end products and β2-microglobulin in the pathogenesis of bone lesions in dialysis-associated amyloidosis
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 11 1996 86-90

Author Title of Article
Miyata T et. al Pathophysiology of advanced glycation end products in renal failure.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 11 [suppl 5] 1996 27-30

Author Title of Article
Sugiyama S et. al Advanced glycation end products in diabetic nephropathy.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 11 [suppl 5] 1996 91-94

Author Title of Article
Miyata T et. al Possible involvement of advanced glycation end products in bone resorption.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 11 [suppl 5] 1996 54-57

Author Title of Article
Kimura T et. al, Identification of advanced glycation end-products of the maillard reaction in pick's disease.
Journal Volume Year Pages Concerned
Neuroscience Letters 219 1996 95-98

Author Title of Article
Takeda A et. al Immunohistochemical study of advanced glycation end products in aging and alzheimer's disease brain.
Journal Volume Year Pages Concerned
Neuroscience Letters 221 1996 17-20

Author Title of Article
Miyata T et. al Advanced glycation end products enhance osteoclast-induced bone resorpion in cultured mouse unfractionated bone cells and in rats implanted with devitalized bone particles.
Journal Volume Year Pages Concerned
J Am Soc Nephrol 8 1997 260-270

Author Title of Article
Miyata T et. al Oxidation conspires with glycation to create noxious advanced glycation end products in renal failure.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 12 1997 255-258

Author Title of Article
Miyata T et. al Clearance of pentosidine, an advanced glycation end product, by different modalities of renal replacement therapy.
Journal Volume Year Pages Concerned
Kidney Int 51 1997 880-887

Author Title of Article
Miyata T et. al Implication of an increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure
Journal Volume Year Pages Concerned
Kidney Int 51 1997 1170-1181

Author Title of Article
Horie K et. al Immunohistochemical localization of advanced glycation end products, pentosidine and carboxymetyllysine, inlipofuscin pigments of alzheimer's disease and aged neurons.
Journal Volume Year Pages Concerned
Biochem Biophys Res Commun 236 1997 327-332

Author Title of Article
Uchida K et al Protein modification by a maillard reaction intermediate methylglyoxal immunochemical detection of fluorescent 5-methylimidazolone derivatives in vivo.
Journal Volume Year Pages Concerned
FEBS Letter 410 1997 313-318

Author Title of Article
Satoh H et. al Advanced glycation endproducts stimulate mitogen-activated protein kinase and proliferation in rabbit vascular smooth muscle cells.
Journal Volume Year Pages Concerned
Biochem Biophys Res Commun 239 1997 111-115

Author Title of Article
Horie K et. al Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions.
Journal Volume Year Pages Concerned
J Clin Invest 100 1997 2995-3004

Author Title of Article
Yasuda Y et. al Funcional quantiative analysis of the genome in cultured human mesangial cells.
Journal Volume Year Pages Concerned
Kidney Int 53 1998 154-158

Author Title of Article
Yasuda Y et. al Funcional quantiative analysis of the genome in cultured human mesangial cells.
Journal Volume Year Pages Concerned
Kidney Int 53 1998 154-158

Author Title of Article
Miyata T et. al Renal catabolism of advanced glycation end products: the fate of pentosidne.
Journal Volume Year Pages Concerned
Biochem Biophys Res Commun 244 1998 45-49

Author Title of Article
Uchida K et. al Protein-bound acrolein: potential markers for oxidative stress.
Journal Volume Year Pages Concerned
Proc Natl Acad Sci USA 95 1998 4882-4887

Author Title of Article
Ehlerding G et. al Alteraitions of synovial tissue and their potential role in the deposition of β2-microglobulin-associated amyloid.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 13 1998 1465-1475

Author Title of Article
Miyata T et. al β2-Microgloburin in renal disease.
Journal Volume Year Pages Concerned
J Am Soc Nephrol 9 1998 1723-1735

Author Title of Article
Sugiyama S et. al Implication of the glycoxidation and lipoxidation rections in the pathogenesis of dialysis-related amyloidosis.
Journal Volume Year Pages Concerned
Int J Mol Med 2 1998 561-565

Author Title of Article
Uchida K et. al Implication of the glycoxidation and lipoxidation rections in the pathogenesis of dialysis-related amyloidosis.
Journal Volume Year Pages Concerned
Int J Mol Med 2 1998 4882-4887

Author Title of Article
Ueda Y et. al Implication of altered redox regulation by antioxidant enzymes in the increased plasma pentosidine, an advanced glycation end product, in uremia.
Journal Volume Year Pages Concerned
Biochem Biophys Res Commun 245 1998 785-790

Author Title of Article
Miyata T et. al Autoxidation products of both carbohydrates and lipids are increased in uremic plasma: Is there oxidative stress in uremia?
Journal Volume Year Pages Concerned
Kidney Int 54 1998 1290-1295

Author Title of Article
Miyata T et. al A mesangium-predominant gene, megsin, is a new serpin up-regulated in IgA nephropathy.
Journal Volume Year Pages Concerned
J Clin Invest 102 1998 828-836

Author Title of Article
Niwa H et. al Accelerated formation of carboxymethyllysine, an advanced glycation end product, by glyoxal and 3-deoxyglucosone in cultured rat sensory neurons.
Journal Volume Year Pages Concerned
Biochem Biophys Res Commun 248 1998 93-97

Author Title of Article
Takeda A et. al Advanced glycation end products co-localization with astoricytes and microglial cells in Alzheimer's disease brain.
Journal Volume Year Pages Concerned
Acta Neuropathol 98 1998 555-558

Author Title of Article
Miyata T et. al Generation of protein carbonyls by glycation and lipoxidation reactions with autoxidation products of ascorbic acid and polyunsaturated fatty acids.
Journal Volume Year Pages Concerned
FEBS letter 437 1998 24-28

Author Title of Article
Kimura T et. al ocalization of identified advanced glycation end product structure, N-carboxymethyllysine and pentosidine, in age-related inclusions in human brains.
Journal Volume Year Pages Concerned
Pathology International 48 1998 575-579

Author Title of Article
Hangaishi M et. al Increased aggregation of human platelets produced by advanced glycation end products in vitro.
Journal Volume Year Pages Concerned
Biochem Biophys Res Commun 248 1998 285-292

Author Title of Article
Anwarul AA et. al Level of HgC12-meditated phosphorylation of intracellular proteins determines death of thymic T-lymphocytes with or without DNA fragmentation.
Journal Volume Year Pages Concerned
J Cellular Biochemistry 71 1998 243-253

Author Title of Article
Miyata T et. al Carbonyl stress in uremia: Accumulation of carbonyls accelerate the formation of pentosidine, an advanced glycation end product.
Journal Volume Year Pages Concerned
J Am Soc Nephrol 9 1998 2349-2356

Author Title of Article
Anwarul AA et. al Carbonyl compounds cross-link cellular proteins and activate protein-tyrosine kinase p60c-src
Journal Volume Year Pages Concerned
J Cellular Biochemistry 72 1999 1-7

Author Title of Article
Miyata T et. al Alterations in non-enzymatic biochemistry in uremia. Origin and significance of carbonyl stress in long-term uremic complications.
Journal Volume Year Pages Concerned
Kidney Int 55 1999 389-399

Author Title of Article
Miyata T et. al Diagnosis, pathogenesis, and treatment of dialysis-related amyloidosis.
Journal Volume Year Pages Concerned
Miner Electrolyte Metab 25 1999 114-117

Author Title of Article
Wada T et. al Implication of Carbonyl stress in long-term uremic complications.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 14[Supple 1] 1999 79-81

Author Title of Article
Miyata T et. al 2-Isopropylidenehydrazono-4-oxo-thiazolidin-5ylacetanilide (OPB-9195) treatment inhibits the development of initial thickening after balloon injury of rat carotid artry proliferation of rat carotid artery following balloon injury: role of glycoxidation and lipoxidation reactions in vascular tissue damage.
Journal Volume Year Pages Concerned
FEBS Letter 445 1999 202-206

Author Title of Article
Miyata T et. al Carbonyl stress: Increased carbonyl modification of tissue and cellular proteins in uremia.
Journal Volume Year Pages Concerned
Perit Dial Int 19 [Supple 2] 1999 58-61

Author Title of Article
Wada T et. al β2-microglobulin and renal bone disease.
Journal Volume Year Pages Concerned
Perit Dial Int 10 [Supple 2] 1999 413-416

Author Title of Article
Izuhara Y et. al A sensitive and specific ELISA for plasma pentosidine.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 14 1999 576-580

Author Title of Article
Suzuki D et. al Immunohistochemical evidence for an increased oxidative stress and carbonyl modification of proteins in diabetic glomerular lesions.
Journal Volume Year Pages Concerned
J Am Soc Nephrol 10 1999 822-832

Author Title of Article
Jadoul M et. al Influence of hemodialysis membrane type on pentosidine plasma level, a marker of carbonyl stress
Journal Volume Year Pages Concerned
Kidney Int 55 1999 2487-2492

Author Title of Article
Miyata T et. al Carbonyl stress: increased carbonyl modification of proteins by autoxidation products of carbohydrates and lipids in uremia.
Journal Volume Year Pages Concerned
Int J Art Org 22 1999 195-198

Author Title of Article
Miyata T et. al Increased carbonyl modification by lipids and carbohydrates in diabetic nephropathy.
Journal Volume Year Pages Concerned
Kidney Int 56(Supple71) 1999 54-56

Author Title of Article
Miyata T et. al Apolipoprotein E2/E5 variants in lipoprotein glomerulopathy recurred in transplanted kidney.
Journal Volume Year Pages Concerned
J Am Soc Nephrol 10 1999 1590-1595

Author Title of Article
Stein G et. al Decrease in serum pentosidine levels of ESRD patients during polysulfone hemodialysis.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 14 1999 1606-1608

Author Title of Article
Kikuchi S et. al Neurotoxicity of methylglyoxal and 3-Deoxyglycose on cultured cortical neurons: Synergism between glycation and oxidative stress, possibly involved in neurodegnerative diseases.
Journal Volume Year Pages Concerned
J Neurosci Res 57 1999 280-289

Author Title of Article
Handa JT et. al Increase in the advanced glycation end product pentosidine in Bruch's membrane with age.
Journal Volume Year Pages Concerned
Investigative Ophthalmology Vis Sci. 40 1999 775-779

Author Title of Article
Liu W et. al Hydroxynonenal triggers an epidermal growth factor receptor-linked signal pathway for growth inhibition.
Journal Volume Year Pages Concerned
J Cell Sci 112 1999 2409-2417

Author Title of Article
Farboud B et. al Development of a polyclonal antibody with broad epitope specificity for advanced glycation end products and localization of these epitpes in Bruch's membrane of the aging eye.
Journal Volume Year Pages Concerned
Molecular Vision 5 1999 11

Author Title of Article
Akhand AA et. al Nitric oxide controles src kinase activity through a sulfhydryl group modification-mediated Tyr-527-independent and Try-416-linked mechanism.
Journal Volume Year Pages Concerned
J Biol Chem 274 1999 25821-25826

Author Title of Article
Inagi R et. al oxdative protein damage with carbohydrates and lipids in uremia: carbonyl stress
Journal Volume Year Pages Concerned
Blood Purification 17 1999 95-98

Author Title of Article
Kawada N et. al Increased oxidative stress in mouse kidneys with unilateral ureteral obstruction.
Journal Volume Year Pages Concerned
Kidney Int 56 1999 1004-1013

Author Title of Article
Nangaku M et. al Possible involvement of carbonyl stress in the pathogenesis of dialysis-related amyloidosis.
Journal Volume Year Pages Concerned
Am J Med Sci 317 1999 410-415

Author Title of Article
Suzuki D et. al Carbonyl stress and diabetic nephropathy.
Journal Volume Year Pages Concerned
Internal Medicine 38 1999 309-314

Author Title of Article
Suzuki D et. al Expression of megsin mRNA, a novel mesangium-predominant gene, in the renal tissues of various glomerular diseases.
Journal Volume Year Pages Concerned
J Am Soc Nephrol 10 1999 2606-2613

Author Title of Article
Hori Y et. al Crry, a complement regulatory protein, modulates renal interstitial disease induced by proteinuria.
Journal Volume Year Pages Concerned
Kidney Int 56 1999 2096-2106

Author Title of Article
Inagi R et. al Glucose degradation product methylglyoxal enhances the production of vascular endothelial growth factor in peritoneal cells: role in the functional and morphological alterations of peritoneal membranes in peritoneal dialysis.
Journal Volume Year Pages Concerned
FEBS Letter 463 1999 260-264

Author Title of Article
Miyata T et. al Carbonyl stress and dialysis-related amyloidosis.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant 15(Supple1) 2000 25-28

Author Title of Article
Liu W et. al 4-hydroxynonenal induces a cellular redox-related activation of the caspase cascade for apoptotic cell death.
Journal Volume Year Pages Concerned
J Cell Sci 113 2000 635-641

Author Title of Article
Combet S et. al Vascular proliferation and enhanced expression of endothelial nitric oxide synthase in human peritoneum exposed to long-term peritoneal dialysis.
Journal Volume Year Pages Concerned
J Am Soc Nephrol 11 2000 717-728

Author Title of Article
Miyata T et. al Advanced glycation and lipoxidation of the peritoneal membrane: Respective roles of serum and peritoneal fluid reactive carbonyl compounds
Journal Volume Year Pages Concerned
Kidney Int 58 2000 425-435

Author Title of Article
Miyata T et. al Role of reactive carbonyl compounds generated during carbohydrate and lipid metabolism.
Journal Volume Year Pages Concerned
J Am Soc Nephrol 11 2000 1719-1725

Author Title of Article
Miyata T et. al, Mechanism of the inhibitory effect of OPB-9195 [(±)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5ylacetanilide] on advanced lipoxidation end product formation.
Journal Volume Year Pages Concerned
J Am Soc Nephrol 11 2000 1719-1725

Author Title of Article
Miyata T et. al Relevance of oxidative and carbonyl stress to long-term uremic complications.
Journal Volume Year Pages Concerned
Kidney Int 58(Supple1) 2000 120-125

Author Title of Article
Kasper M et. al Induction of apoptosis by glyoxal in human embryonic lung epithelial cell line L132.
Journal Volume Year Pages Concerned
Am J Respi Cell Mol Biol 23 2000 485-491

Author Title of Article
Du J et. al Methylglyoxal induces apoptosis in jurkat leukemia T-cells by activating c-Jun N-terminal kinase.
Journal Volume Year Pages Concerned
J Cell Biochem 77 2000 333-344

Author Title of Article
Asahi K et. al Nitric oxide inhibits the formation of advanced glycation and products.
Journal Volume Year Pages Concerned
Kidney Int 58 2000 1780-1787

Author Title of Article
Ueda Y et. al Effect of dwell time on carbonyl stress using icodextrin and amino acid peritoneal dialysis fluids
Journal Volume Year Pages Concerned
Kidney Int 58 2000 2158-2524

Author Title of Article
Takeda A et. al Neuronal and glial advanced glycation end poduct[N ε -(carboxymethyl)lysine] in Alzheimer's disease brains.
Journal Volume Year Pages Concerned
Acta Neuropathol 101 2001 27-35

Author Title of Article
Yamada K et. al Clusterin is up-regulated in glomerular mesangial cells in complement-mediated injury.
Journal Volume Year Pages Concerned
Kidney Int 59 2001 2518-2524

Author Title of Article
Hou FF et. al -B2microglobulin modified with advanced glycation end products delaysmonociyte apoptosis
Journal Volume Year Pages Concerned
Kidney Int 59 2001 990-1002

Author Title of Article
Miyata T et. al Reactive carbonyl compound-related uremic toxicity (carbonyl stress).
Journal Volume Year Pages Concerned
Kidney Int in press    

Author Title of Article
Miyata T et. al Innovative approaches to more effective and biomedically more suitable peritoneal dialysis technologies.
Journal Volume Year Pages Concerned
Kidney Int in press    

Author Title of Article
Combet S et. al Chronic uremia induces permeability changes, increased nitric oxide synthase expression, and structural modifications in the peritoneum.
Journal Volume Year Pages Concerned
J Am Soc Nephrol in press    

Author Title of Article
Miyata T et. al Carbonyl Stress and long-term uremic complications. Advanced in Nephrology
Journal Volume Year Pages Concerned
Advanced in Nephrology in press    

Author Title of Article
Miyata T et. al Advanced glycation and lipoxidation end products: reactive carbonyl compounds related uremic toxicity.
Journal Volume Year Pages Concerned
Nephrol Dial Transplant in press    

Author Title of Article
Chen J et. al Delayed branching of endothelial capillary cords in glycated collagens is mediated by the early induction of PAI-1.
Journal Volume Year Pages Concerned
Am J Physiol in press    

Author Title of Article
Kurokawa K et. al Current issues and future perspectives of chronic renal failure.
Journal Volume Year Pages Concerned
J Am Soc Nephrol in press    

[Reference Books]
Author Title of Book
Miyata T et. al Stress carbonyle et complications a long terme de I ' uremie, in ACTUALITES NEPHROLOGIQUES JEAN HAMBURGER.
Publisher Year Pages
HoPITAL NECKER 1998 247-253

Author Title of Book
Miyata T et. al Oxdative stress-induced Carbonylstressin uremia.
Publisher Year Pages
Redox Regulation of Cell Signaling and Its Clinical Application. 1999 215-224

Author Title of Book
Nakashima I et. al Redox-oriented chemical events in signal transduction in cells.
Publisher Year Pages
Redox Regulation of Cell Signaling and Its Clinical Application. 1999 177-204.

Author Title of Book
Miyata T et. al Alterations in nonenzymatic biochemistry of carbohydrates and lipids in uremia.
Publisher Year Pages
Massry and Glassock's Text Book of Nephrology 2001 1275-1278

Author Title of Book
Miyata T et. al Reactive carbonyl compounds as uremic toxins.
Publisher Year Pages
Dialysis in the 21th Centur   in press


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