Diabetic Nephropathy: Where Hemodynamics Meets Metabolism

Abstract

Diabetic nephropathy (DN), the most common cause of end stage renal disease in developed nations, is thought to result from interactions between metabolic and haemodynamic factors. Specific metabolically driven, glucose dependent pathways are activated within diabetic renal tissues. These pathways induce oxidative stress, polyol pathway flux, hexosamine flux and accumulation of advanced glycated end-products (AGEs). Haemodynamic factors are also implicated in the pathogenesis of DN and include elevations of systemic and intraglomerular pressure and activation of various vasoactive hormone pathways including the renin-angiotensin aldosterone system (RAAS), endothelin and urotensin. These altered hemodynamics act independently and in concert with metabolic pathways, to activate intracellular second messengers such as protein kinase C (PKC) and MAP kinase (MAPK), nuclear transcription factors such as nuclear factor-κB (NF-κB) and various growth factors such as the prosclerotic cytokines, transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF) and the angiogenic, permeability enhancing growth factor, vascular endothelial growth factor, VEGF. Ultimately these molecular mechanisms lead to increased renal albumin permeability, and extracellular matrix accumulation, which results in increasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis.In the past, the treatment of diabetic nephropathy has focused on control of hyperglycemia and the interruption of the RAAS with certain anti-hypertensive agents. Newer novel targets, some of which are linked to glucose dependent pathways, appear to be a major focus of new therapies directed against the development and progression of renal damage as a result of diabetes. It is likely that resolution of diabetic nephropathy will require synergistic therapies to target multiple mediators of this disease.

Key words

diabetes - nephropathy - hemodynamics - advanced glycated end products - Angiotensin

References

• 1 UK Prospective Diabetes Study (UKPDS) Group . Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).  Lancet. 1998;  352 854-865
• 2 Abreu JG, Ketpura NI, Reversade B, De Robertis EM. Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta.  Nat Cell Biol. 2002;  4 599-604
• 3 Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study.  BMJ. 2000;  321 412-419
• 4 Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE. et al . Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders.  N Engl J Med. 1994;  331 1480-1487
• 5 Aiello LP, Bursell SE, Clermont A, Duh E, Ishii H, Takagi C, Mori F, Ciulla TA, Ways K, Jirousek M, Smith LEH, King GL. Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase c in vivo and suppressed by an orally effective beta-isoform-selective inhibitor.  Diabetes. 1997;  46 1473-1480
• 6 Allen TJ, Cao Z, Youssef S, Hulthen UL, Cooper ME. The role of angiotensin II and bradykinin in experimental diabetic nephropathy: functional and structural studies.  Diabetes. 1997;  46 1612-1618
• 7 Andersen S, Tarnow L, Rossing P, Hansen BV, Parving HH. Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy.  Kidney International. 2000;  57 601-606
• 8 Anderson S, Jung FF, Ingelfinger JR. Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations.  Am J Physiol. 1993;  265 F477-F486
• 9 Anderson S, Rennke HG, Garcia DL, Brenner BM. Short and long term effects of antihypertensive therapy in the diabetic rat.  Kidney Inter. 1989;  36 526-536
• 10 Appel G, Bolton K, Freedman B, Wuerth JKC. Pimagedine (PG) lowers total urinary toal protein (tUP) and slows progression of overt diabetes in patients with type 1 diabetes mellitus (DM).  J Am Soc Nephrol. 1999;  10 153A
• 11 Araki N, Higashi T, Mori T, Shibayama R, Kawabe Y, Kodama T, Takahashi K, Shichiri M, Horiuchi S. Macrophage scavenger receptor mediates the endocytic uptake and degradation of advanced glycation end products of the maillard reaction.  European Journal of Biochemistry. 1995;  230 408-415
• 12 Arendshorst WJ, Brannstrom K, Ruan XP. Actions of angiotensin II on the renal microvasculature.  Journal of the American Society of Nephrology. 1999;  10 S149-S161
• 13 Asaba K, Tojo A, Onozato ML, Goto A, Quinn MT, Fujita T, Wilcox CS. Effects of NADPH oxidase inhibitor in diabetic nephropathy.  Kidney Int. 2005;  67 1890-1898
• 14 Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine.  Diabetes. 2003;  52 2110-2120
• 15 Bank N, Mower P, Aynedjian H, Wilkes B, Silverman S. Sorbinil prevents glomerular hyperperfusion in diabetic rats.  Am J Physiol. 1989;  256 F1000-F1006
• 16 Barnes PJ, Larin M. Mechanisms of disease-nuclear factor-kappa-b-a pivotal transcription factor in chronic inflammatory diseases [review].  New England Journal of Medicine. 1997;  336 1066-1071
• 17 Basta G, Lazzerini G, Massaro M, Simoncini T, Tanganelli P, Fu C, Kislinger T, Stern DM, Schmidt AM, De Caterina R. Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses.  Circulation. 2002;  105 816-822
• 18 Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm.  Diabetes. 1999;  48 1-9
• 19 Beisswenger P, Ruggiero-Lopez D. Metformin inhibition of glycation processes.  Diabetes Metab. 2003;  29 6S95-6103
• 20 Benigni A, Colosio W, Brena C, Bruzzi I, Bertani T, Remuzzi G. Unselective Inhibition of Endothelin Receptors Reduces Renal Dysfunction in Experimental Diabetes.  Diabetes. 1998;  47 450-456
• 21 Benigni A, Remuzzi G. Endothelin antagonists.  Lancet. 1999;  353 133-138
• 22 Benigni A, Zoja C, Corna D, Orisio S, Facchinetti D, Benatti L, Remuzzi G. Blocking both type a and B endothelin receptors in the kidney attenuates renal injury and prolongs survival in rats with remnant kidney.  American Journal of Kidney Diseases. 1996;  27 416-423
• 23 Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP. Understanding RAGE, the receptor for advanced glycation end products.  J Mol Med. 2005;  83 876-886
• 24 Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Kloting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt AM, Stern DM, Haring HU, Schleicher E, Nawroth PP. Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB.  Diabetes. 2001;  50 2792-2808
• 25 Bonnet F, Cao Z, Cooper M. Apoptosis and angiotensin II; yet another renal regulatory system.  Exp Nephrol. 2001;  , in press
• 26 Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis [Review].  New England Journal of Medicine. 1994;  331 1286-1292
• 27 Brenner BM, Cooper ME, de Zeeuw D, Grunfeld J-P, Keane WF, Kurokawa K, McGill JB, Mitch WE, Parving HH, Remuzzi G, Ribeiro AB, Schluchter MD, Snavely D, Zhang Z, Simpson R, Ramjit D, Shahinfar S. for the RENAAL study investigators . The losartan renal protection study - rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan).  JRAAS. 2000;  1 328-335
• 28 Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.  N Engl J Med. 2001;  345 861-869
• 29 Brownlee M. Lilly Lecture 1993. Glycation and diabetic complications.  Diabetes. 1994;  43 836-841
• 30 Brownlee M. Biochemistry and molecular cell biology of diabetic complications.  Nature. 2001;  414 813-820
• 31 Burns KD. Angiotensin II and its receptors in the diabetic kidney.  Am J Kidney Dis. 2000a;  36 449-467
• 32 Burns KD. Angiotensin II and its receptors in the diabetic kidney [Review].  American Journal of Kidney Diseases. 2000b;  36 449-467
• 33 Burrell LM, Risvanis J, Johnston CI, Naitoh M, Balding LC. Vasopressin receptor antagonism-a therapeutic option in heart failure and hypertension.  Experimental Physiology. 2000;  85 259S-265S
• 34 Cameron NE, Cotter MA. Effects of antioxidants on nerve and vascular dysfunction in experimental diabetes.  Diabetes Res Clin Pract. 1999;  45 137-146
• 35 Campbell DJ, Kelly DJ, Wilkinson-Berka JL, Cooper ME, Skinner SL. Increased bradykinin and ‘normal’ angiotensin peptide levels in streptozotocin-diabetic Sprague Dawley and TGR(mRen-2) rats.  Kidney Inter. 1999;  56 211-221
• 36 Cao Z, Bonnet F, Davis B, Cox AJ, Allen T, Cooper ME. Additive hypotensive and antialbuminuric effects of angiotensin converting enzyme inhibition and angiotensin receptor antagonism in diabetic spontaneously hypertensive rat.  Clinical Science. 2001a;  , in press
• 37 Cao Z, Burrell LM, Tikkanen I, Bonnet F, Cooper ME, Gilbert R. Vasopeptidase inhibition attenuates the progression of renal injury in subtotal nephrectomised rats.  Kidney Int. 2001b;  , in press
• 38 Cao ZM, Cooper ME, Wu LL, Cox AJ, Jandeleit-Dahm K, Kelly DJ, Gilbert RE. Blockade of the reninangiotensin and endothelin systems on progressive renal injury.  Hypertension. 2000a;  36 561-568
• 39 Cao ZM, Kelly DJ, Cox A, Casley D, Forbes JM, Martinello P, Dean R, Gilbert RE, Cooper ME. Angiotensin type 2 receptor is expressed in the adult rat kidney and promotes cellular proliferation and apoptosis.  Kidney International. 2000b;  58 2437-2451
• 40 Carey RM, Siragy HM. The intrarenal renin-angiotensin system and diabetic nephropathy.  Trends Endocrinol Metab. 2003a;  14 274-281
• 41 Carey RM, Siragy HM. Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation.  Endocr Rev. 2003b;  24 261-271
• 42 Cellek S, Qu W, Schmidt AM, Moncada S. Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes.  Diabetologia. 2003; 
• 43 Cha DR, Kim NH, Yoon JW, Jo SK, Cho WC, Kim HK, Won NH. Role of vascular endothelial growth factor in diabetic nephropathy.  Kidney International. 2000;  58 S104-S112
• 44 Chang WP, Dimitriadis E, Allen T, Dunlop ME, Cooper M, Larkins RG. The effect of aldose reductase inhibitors on glomerular prostaglandin production and urinary albumin excretion in experimental diabetes mellitus.  Diabetologia. 1991;  34 225-231
• 45 Chen S, Cohen MP, Lautenslager GT, Shearman CW, Ziyadeh FN. Glycated albumin stimulates TGF-beta 1 production and protein kinase C activity in glomerular endothelial cells.  Kidney International. 2001;  59 673-681
• 46 Choi ME. Mechanism of transforming growth factor-beta 1 signaling: Role of the mitogen-activated protein kinase.  Kidney International. 2000;  58 S53-S58
• 47 Christ M, Bauersachs J, Liebetrau C, Heck M, Gunther A, Wehling M. Glucose increases endothelial dependent superoxide formation in coronary arteries by NAD(P)H oxidase activation: attenuation by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin.  Diabetes. 2002;  51 2648-2652
• 48 Cohen RM, Holmes YR, Chenier TC, Joiner CH. Discordance between HbA1c and fructosamine: evidence for a glycosylation gap and its relation to diabetic nephropathy.  Diabetes Care. 2003;  26 163-167
• 49 Cooper ME. Pathogenesis, prevention and treatment of diabetic nephropathy.  Lancet. 1998;  352 213-219
• 50 Cooper ME. Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy.  Diabetologia. 2001;  44 1957-1972
• 51 Cooper ME, Allen TJ, O'Brien R, Clarke B, Jerums G, Doyle AE. Effects of genetic hypertension on diabetic nephropathy in the rat-functional and structural characteristics.  J Hypertension. 1988;  6 1009-1016
• 52 Cooper ME, Vranes D, Youssef S, Stacker SA, Cox AJ, Rizkalla B, Casley DJ, Bach LA, Kelly DJ, Gilbert RE. Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes.  Diabetes. 1999;  48 2229-2239
• 53 Corbett JA, Tilton RG, Chang K, Hasan KS, Ido Y, Wang JL, Sweetland MA, Lancaster Jr JR, Williamson JR, McDaniel ML. Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction.  Diabetes. 1992;  41 552-556
• 54 Cotter MA, Cameron NE. Effect of the NAD(P)H oxidase inhibitor, apocynin, on peripheral nerve perfusion and function in diabetic rats.  Life Sci. 2003;  73 1813-1824
• 55 Courderot-Masuyer C, Dalloz F, Maupoil V, Rochette L. Antioxidant properties of aminoguanidine.  Fundam Clin Pharmacol. 1999;  13 535-540
• 56 Davis BJ, Forbes JM, Thomas MC, Jerums G, Burns WC, Kawachi H, Allen TJ, Cooper ME. Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat.  Diabetologia. 2003a; 
• 57 Davis BJ, Johnston CI, Burrell LM, Burns WC, Kubota E, Cao Z, Cooper ME, Allen TJ. Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy.  Diabetologia. 2003b;  46 961-971
• 58 De Vriese AS, Tilton RG, Stephan CC, Lameire NH. Vascular endothelial growth factor is essential for hyperglycemia-induced structural and functional alterations of the peritoneal membrane.  J Am Soc Nephrol. 2001;  12 1734-1741
• 59 De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM. Endothelial dysfunction in diabetes.  Br J Pharmacol. 2000;  130 963-974
• 60 Degenhardt TP, Alderson NL, Arrington DD, Beattie RJ, Basgen JM, Steffes MW, Thorpe SR, Baynes JW. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat.  Kidney Int. 2002;  61 939-950
• 61 Diabetes Control and Complications Trial Research Group . The effect of intensive treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus.  N Engl J Med. 1993;  329 977-986
• 62 Dieterle W, Mann J, Kutz K. Multiple-dose pharmacokinetics, pharmacodynamics and tolerability of the oral ET(A) endothelin-receptor antagonist SPP301 in man.  Int J Clin Pharmacol Ther. 2005;  43 178-186
• 63 Dunlop M. Aldose reductase and the role of the polyol pathway in diabetic nephropathy.  Kidney International. 2000;  58 S3-S12
• 64 Dunlop ME, Muggli EE. Small heat shock protein alteration provides a mechanism to reduce mesangial cell contractility in diabetes and oxidative stress.  Kidney International. 2000;  57 464-475
• 65 Figarola JL, Scott S, Loera S, Tessler C, Chu P, Weiss L, Hardy J, Rahbar S. LR-90 a new advanced glycation endproduct inhibitor prevents progression of diabetic nephropathy in streptozotocin-diabetic rats.  Diabetologia. 2003;  46 1140-1152
• 66 Flyvbjerg A. Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease [Review].  Diabetologia. 2000;  43 1205-1223
• 67 Flyvbjerg A, Dagnaes-Hansen F, De Vriese AS, Schrijvers BF, Tilton RG, Rasch R. Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody.  Diabetes. 2002;  51 3090-3094
• 68 Flyvbjerg A, Denner L, Schrijvers BF, Tilton RG, Mogensen TH, Paludan SR, Rasch R. Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice.  Diabetes. 2004;  53 166-172
• 69 Forbes JM, Cooper ME, Thallas V, Burns WC, Thomas MC, Brammar GC, Lee F, Grant SL, Burrell LA, Jerums G, Osicka TM. Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy.  Diabetes. 2002;  51 3274-3282
• 70 Forbes JM, Soulis T, Thallas V, Panagiotopoulos S, Long DM, Vasan S, Wagle D, Jerums G, Cooper ME. Renoprotective effects of a novel inhibitor of advanced glycation.  Diabetologia. 2001;  44 108-114
• 71 Forbes JM, Thallas V, Thomas MC, Founds HW, Burns WC, Jerums G, Cooper ME. The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes.  Faseb J. 2003;  17 1762-1764
• 72 Forbes JM, Thorpe SR, Thallas-Bonke V, Pete J, Thomas MC, Deemer ER, Bassal S, El-Osta A, Long DM, Panagiotopoulos S, Jerums G, Osicka TM, Cooper ME. Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy.  J Am Soc Nephrol. 2005;  16 2363-2372
• 73 Forster A, Kuhne Y, Henle T. Studies on absorption and elimination of dietary maillard reaction products.  Ann N Y Acad Sci. 2005;  1043 474-481
• 74 Fu MX, Wells-Knecht KJ, Blackledge JA, Lyons TJ, Thorpe SR, Baynes JW. Glycation, glycoxidation, and cross-linking of collagen by glucose. Kinetics, mechanisms, and inhibition of late stages of the Maillard reaction.  Diabetes. 1994;  43 676-683
• 75 Fujii J, Myint T, Okado A, Kaneto H, Taniguchi N. Oxidative stress caused by glycation of Cu,Znsuperoxide dismutase and its effects on intracellular components.  Nephrol Dial Transplant. 1996;  11 34-40
• 76 Fukui M, Nakamura T, Ebihara I, Osada S, Tomino Y, Masaki T, Goto K, Furuichi Y, Koide H. Gene Expression for Endothelins and Their Receptors in Glomeruli of Diabetic Rats.  Journal of Laboratory & Clinical Medicine. 1993;  122 149-156
• 77 Gilbert RE, Kelly DJ, Cox AJ, Wilkinson-Berka JL, Rumble JR, Osicka T, Panagiotopoulos S, Lee V, Hendrich EC, Jerums G, Cooper ME. Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes.  Diabetologia. 2000;  43 1360-1367
• 78 Greene DA, Lattimer SA, Sima AAF. Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications.  N Engl J Med. 1987;  316 599-606
• 79 Gruden G, Thomas S, Burt D, Lane S, Chusney G, Sacks S, Viberti G. Mechanical Stretch Induces Vascular Permeability Factor in Human Mesangial Cells - Mechanisms of Signal Transduction.  Proceedings of the National Academy of Sciences of the United States of America. 1997;  94 12112-12116
• 80 Gruden G, Thomas S, Burt D, Zhou WD, Chusney G, Gnudi L, Viberti G. Interaction of angiotensin II and mechanical stretch on vascular endothelial growth factor production by human mesangial cells.  Journal of the American Society of Nephrology. 1999;  10 730-737
• 81 Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.  Nat Med. 2003;  9 294-299
• 82 Haneda M, Araki S, Togawa M, Sugimoto T, Isono M, Kikkawa R. Mitogen-Activated Protein Kinase Cascade Is Activated in Glomeruli of Diabetic Rats and Glomerular Mesangial Cells Cultured under High Glucose Conditions.  Diabetes. 1997;  46 847-853
• 83 Hargrove GM, Dufresne J, Whiteside C, Muruve DA, Wong NCW. Diabetes mellitus increases endothelin-1 gene transcription in rat kidney.  Kidney International. 2000;  58 1534-1545
• 84 Harrison DG, Cai H, Landmesser U, Griendling KK. Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease.  J Renin Angiotensin Aldosterone Syst. 2003;  4 51-61
• 85 He CJ, Zheng F, Stitt S, Striker L, Hattori M, Vlassara H. Differential expression of renal AGE-receptor genes in NOD mice: possible role in nonobese diabetic renal disease.  Kidney International. 2000;  58 1931-1940
• 86 Heilig CW, Concepcion LA, Riser BL, Freytag SO, Zhu M, Cortes P. Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype.  J Clin Invest. 1995;  96 1802-1814
• 87 Heilig CW, Kreisberg JI, Freytag S, Murakami T, Ebina Y, Guo L, Heilig K, Loberg R, Qu X, Jin Y, Henry D, Brosius 3rd FC. Antisense GLUT-1 protects mesangial cells from glucose induction of GLUT-1 and fibronectin expression.  Am J Physiol Renal Physiol. 2001;  280 F657-666
• 88 Heilig CW, Liu Y, England RL, Freytag SO, Gilbert JD, Heilig KO, Zhu M, Concepcion LA, Brosius 3rd FC. D-glucose stimulates mesangial cell GLUT1 expression and basal and IGF- I-sensitive glucose uptake in rat mesangial cells: implications for diabetic nephropathy.  Diabetes. 1997;  46 1030-1039
• 89 Henry DN, Busik JV, Brosius 3rd FC, Heilig CW. Glucose transporters control gene expression of aldose reductase, PKCalpha, and GLUT1 in mesangial cells in vitro.  Am J Physiol. 1999;  277 F97-104
• 90 Herman WH, Emancipator SN, Rhoten RLP, Simonson MS. Vascular and Glomerular Expression of Endothelin-1 in Normal Human Kidney.  American Journal of Physiology - Renal Fluid & Electrolyte Physiology. 1998;  44 F8-F17
• 91 Hill C, Flyvbjerg A, Gronbaek H, Petrik J, Hill DJ, Thomas CR, Sheppard MC, Logan A. The renal expression of transforming growth factor-beta isoforms and their receptors in acute and chronic experimental diabetes in rats.  Endocrinology. 2000;  141 1196-1208
• 92 Hocher B, Schwarz A, Reinbacher D, Jacobi J, Lun A, Priem F, Bauer C, Neumayer HH, Raschack M. Effects of endothelin receptor antagonists on the progression of diabetic nephropathy.  Nephron. 2001;  87 161-169
• 93 Hodgkinson AD, Bartlett T, Oates PJ, Millward BA, Demaine AG. The response of antioxidant genes to hyperglycemia is abnormal in patients with type 1 diabetes and diabetic nephropathy.  Diabetes. 2003;  52 846-851
• 94 Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides.  Cell. 1999;  97 889-901
• 95 Hopfner RL, Misurski D, Wilson TW, McNeill JR, Gopalakrishnan V. Insulin and vanadate restore decreased plasma endothelin concentrations and exaggerated vascular responses to normal in the streptozotocin diabetic rat.  Diabetologia. 1998;  41 1233-1240
• 96 Hostetter T, Rennke H, Brenner B. The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies.  Am J Med. 1982;  72 375-380
• 97 Igarashi M, Wakasaki H, Takahara N, Ishii H, Jiang ZY, Yamauchi T, Kuboki K, Meier M, Rhodes CJ, King GL. Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways.  Journal of Clinical Investigation. 1999;  103 185-195
• 98 Inoguchi T, Battan R, Handler E, Sportsman JR, Heath W, King GL. Preferential elevation of protein kinase C isoform beta II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation.  Proc Natl Acad Sci USA. 1992;  89 11059-11063
• 99 Inoki K, Haneda M, Ishida T, Mori H, Maeda S, Koya D, Sugimoto T, Kikkawa R. Role of mitogenactivated protein kinases as downstream effectors of transforming growth factor-beta in mesangial cells.  Kidney International. 2000;  58 S76-S80
• 100 Isaka Y, Fujiwara Y, Ueda N, Kaneda Y, Kamada T, Imai E. Glomerulosclerosis induced by in vivo transfection of transforming growth factor-beta or platelet-derived growth factor gene into the rat kidney.  J Clin Invest. 1993;  92 2597-2601
• 101 Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL. Amelioration of Vascular Dysfunctions in Diabetic Rats by an Oral Pkc Beta Inhibitor.  Science. 1996;  272 728-731
• 102 Ishii H, Tada H, Isogai S. An Aldose Reductase Inhibitor Prevents Glucose-Induced Increase in Transforming Growth Factor-Beta and Protein Kinase C Activity in Cultured Human Mesangial Cells.  Diabetologia. 1998;  41 362-364
• 103 Ito Y, Aten J, Bende RJ, Oemar BS, Rabelink TJ, Weening JJ, Goldschmeding R. Expression of connective tissue growth factor in human renal fibrosis.  Kidney Int. 1998;  53 853-861
• 104 James LR, Fantus IG, Goldberg H, Ly H, Scholey JW. Overexpression of GFAT activates PAI-1 promoter in mesangial cells.  American Journal of Physiology - Renal Fluid & Electrolyte Physiology. 2000;  279 F718-F727
• 105 Jandeleit-Dahm K, Allen TJ, Youssef S, Gilbert RE, Cooper ME. Is there a role for endothelin antagonists in diabetic renal disease?.  Diabetes, Obesity and Metabolism. 2000;  2 15-24
• 106 Jandeleit-Dahm K, Cao ZM, Cox AJ, Kelly DJ, Gilbert RE, Cooper ME. Role of hyperlipidemia in progressive renal disease: Focus on diabetic nephropathy.  Kidney International. 1999;  56 S31-S36
• 107 Jang YY, Song JH, Shin YK, Han ES, Lee CS. Protective effect of boldine on oxidative mitochondrial damage in streptozotocin-induced diabetic rats.  Pharmacological Research. 2000;  42 361-371
• 108 Jauslin ML, Meier T, Smith RA, Murphy MP. Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants.  Faseb J. 2003;  17 1972-1974
• 109 Johnston CI. Angiotensin receptor antagonists: focus on losartan.  Lancet. 1995;  346 1403-1407
• 110 Johnston CI, Naitoh M, Risvanis J, Farina N, Burrell LM. New Hormonal Blockade Strategies in Cardiovascular Disease.  Scandinavian Cardiovascular Journal. 1998a;  32 61-66
• 111 Johnston CI, Risvanis J, Naitoh M, Tikkanen I. Mechanism of Progression of Renal Disease - Current Hemodynamic Concepts.  Journal of Hypertension. 1998b;  16 S3-S7
• 112 Kagami S, Border WA, Miller DE, Noble NA. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells.  J Clin Invest. 1994;  93 2431-2437
• 113 Kalinyak JE, Sechi LA, Griffin CA, Don BR, Tavangar K, Kraemer FB, Hoffman AR, Schambelan M. The renin-angiotensin system in streptozotocin-induced diabetes mellitus in the rat.  J Am Soc Nephrol. 1993;  4 1337-1345
• 114 Kang MJ, Wu XY, Ly H, Thai K, Scholey JW. Effect of glucose on stress-activated protein kinase activity in mesangial cells and diabetic glomeruli.  Kidney International. 1999;  55 2203-2214
• 115 Kato S, Horiuchi S, Liu J, Cleveland DW, Shibata N, Nakashima K, Nagai R, Hirano A, Takikawa M, Kato M, Nakano I, Ohama E. Advanced glycation endproduct-modified superoxide dismutase-1 (SOD1)- positive inclusions are common to familial amyotrophic lateral sclerosis patients with SOD1 gene mutations and transgenic mice expressing human SOD1 with a G85R mutation.  Acta Neuropathol (Berl). 2000;  100 490-505
• 116 Kelly DJ, Gilbert RE, Cox AJ, Soulis T, Jerums G, Cooper ME. Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy.  J Am Soc Nephrol. 2001a;  12 2098-2107
• 117 Kelly DJ, Gilbert RE, Cox AJ, Soulis T, Jerums G, Cooper ME. Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy.  JASN. 2001b;  , in press
• 118 Kelly DJ, Skinner SL, Gilbert RE, Cox AJ, Cooper ME, Wilkinson-Berka JL. Effects of endothelin or angiotensin II receptor blockade on diabetes in the transgenic (mRen-2)27 rat.  Kidney International. 2000;  57 1882-1894
• 119 Kelly DJ, Zhang Y, Hepper C, Gow RM, Jaworski K, Kemp BE, Wilkinson-Berka JL, Gilbert RE. Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension.  Diabetes. 2003;  52 512-518
• 120 Kennefick TM, Oyama TT, Thompson MM, Vora JP, Anderson S. Enhanced renal sensitivity to angiotensin actions in diabetes mellitus in the rat.  Am J Physiol. 1996;  271 F595-F602
• 121 Kim NH, Jung HH, Cha DR, Choi DS. Expression of vascular endothelial growth factor in response to high glucose in rat mesangial cells.  Journal of Endocrinology. 2000a;  165 617-624
• 122 Kim SI, Han DC, Lee HB. Lovastatin inhibits transforming growth factor-beta 1 expression in diabetic rat glomeruli and cultured rat mesangial cells.  Journal of the American Society of Nephrology. 2000b;  11 80-87
• 123 Koga K, Yamagishi S, Takeuchi M, Inagaki Y, Amano S, Okamoto T, Saga T, Makita Z, Yoshizuka M. CS-886, a new angiotensin II type 1 receptor antagonist, ameliorates glomerular anionic site loss and prevents progression of diabetic nephropathy in Otsuka Long-Evans Tokushima fatty rats.  Mol Med. 2002;  8 591-599
• 124 Komers R, Allen TJ, Cooper ME. Role of endothelium-derived nitric oxide in the pathogenesis of the renal hemodynamic changes of experimental diabetes.  Diabetes. 1994;  43 1190-1197
• 125 Koo JR, Ni Z, Oviesi F, Vaziri ND. Antioxidant therapy potentiates antihypertensive action of insulin in diabetic rats.  Clin Exp Hypertens. 2002;  24 333-344
• 126 Koschinsky T, He CJ, Mitsuhashi T, Bucala R, Liu C, Buenting C, Heitmann K, Vlassara H. Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy.  Proc Natl Acad Sci USA. 1997;  94 6474-6479
• 127 Koya D, Haneda M, Nakagawa H, Isshiki K, Sato H, Maeda S, Sugimoto T, Yasuda H, Kashiwagi A, Ways DK, King GL, Kikkawa R. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes.  FASEB Journal. 2000;  14 439-447
• 128 Koya D, Jirousek MR, Lin YW, Ishii H, Kuboki K, King GL. Characterization of Protein Kinase C Beta Isoform Activation on the Gene Expression of Transforming Growth Factor-Beta, Extracellular Matrix Components, and Prostanoids in the Glomeruli of Diabetic Rats.  Journal of Clinical Investigation. 1997;  100 115-126
• 129 Lacourciere Y, Belanger A, Godin C, Halle JP, Ross S, Wright N, Marion J. Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy.  Kidney Int. 2000;  58 762-769
• 130 Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM. Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress.  J Biol Chem. 1997;  272 17810-17814
• 131 Langham RG, Kelly DJ, Gow RM, Zhang Y, Dowling JK, Thomson NM, Gilbert RE. Increased expression of urotensin II and urotensin II receptor in human diabetic nephropathy.  Am J Kidney Dis. 2004;  44 826-831
• 132 Lee FT, Cao Z, Long DM, Panagiotopoulos S, Jerums G, Cooper ME, Forbes JM. Interactions between Angiotensin II and NF-{kappa}B-Dependent Pathways in Modulating Macrop.  J Am Soc Nephrol. 2004;  15 2139-2151
• 133 Leehey DJ, Singh AK, Alavi N, Singh R. Role of angiotensin II in diabetic nephropathy.  Kidney International. 2000;  58 S93-S98
• 134 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy.  N Engl J Med. 1993a;  329 1456-1462
• 135 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.  N Engl J Med. 1993b;  329 1456-1462
• 136 Li JF, Schmidt AM. Characterization and functional analysis of the promoter of rage, the receptor for advanced glycation end products.  J Biol Chem. 1997;  272 16498-16506
• 137 Li JH, Huang XR, Zhu HJ, Oldfield M, Cooper M, Truong LD, Johnson RJ, Lan HY. Advanced glycation end products activate Smad signaling via TGF-beta-dependent and -independent mechanisms: implications for diabetic renal and vascular disease.  Faseb J. 2003; 
• 138 Li Y, Mitsuhashi T, Wojciechowicz D, Shimizu N, Li J, Stitt A, He C, Banerjee D, Vlassara H. Molecular identity and distribution of advanced glycation endproducts receptors: Relationship of p60 to OST-48 and p90 to 80K-H membrane proteins.  Proc Natl Acad Sci USA. 1996;  93 11047-11052
• 139 Li YM, Tan AX, Vlassara H. Antibacterial activity of lysozyme and lactoferrin is inhibited by binding of advanced glycation-modified proteins to a conserved motif.  Nature Medicine. 1995;  1 1057-1061
• 140 Lu C, He JC, Cai W, Liu H, Zhu L, Vlassara H. Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells.  Proc Natl Acad Sci USA. 2004;  101 11767-11772
• 141 Lu M, Kuroki M, Amano S, Tolentino M, Keough K, Kim I, Bucala R, Adamis AP. Advanced Glycation End Products Increase Retinal Vascular Endothelial Growth Factor Expression.  Journal of Clinical Investigation. 1998;  101 1219-1224
• 142 Maisonneuve P, Agodoa L, Gellert R, Stewart JH, Buccianti G, Lowenfels AB, Wolfe RA, Jones E, Disney AP, Briggs D, McCredie M, Boyle P. Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study.  Am J Kidney Dis. 2000;  35 157-165
• 143 Malherbe P, Richards JG, Gaillard H, Thompson A, Diener C, Schuler A, Huber G. cDNA cloning of a novel secreted isoform of the human receptor for advanced glycation end products and characterization of cells co-expressing cell-surface scavenger receptors and Swedish mutant amyloid precursor protein.  Brain Res Mol Brain Res. 1999;  71 159-170
• 144 Marx N, Walcher D, Ivanova N, Rautzenberg K, Jung A, Friedl R, Hombach V, de Caterina R, Basta G, Wautier MP, Wautiers JL. Thiazolidinediones reduce endothelial expression of receptors for advanced glycation end products.  Diabetes. 2004;  53 2662-2668
• 145 Massague J. TGF-beta signal transduction [review].  Annual Review of Biochemistry. 1998;  67 753-791
• 146 Mauer SM, Steffes MW, Azar S, Brown DM. Effects of sorbinil on glomerular structure and function in long-term- diabetic rats.  Diabetes. 1989;  38 839-846
• 147 McAuliffe AV, Brooks BA, Fisher EJ, Molyneaux LM, Yue DK. Administration of Ascorbic Acid and an Aldose Reductase Inhibitor (Tolrestat) in Diabetes - Effect on Urinary Albumin Excretion.  Nephron. 1998;  80 277-284
• 148 McCaleb ML, McKean ML, Hohman TC, Laver N, Robison Jr WG. Intervention with the aldose reductase inhibitor, tolrestat, in renal and retinal lesions of streptozotocin-diabetic rats.  Diabetologia. 1991;  34 695-701
• 149 McRobert EA, Gallicchio M, Jerums G, Cooper ME, Bach LA. The amino-terminal domains of the ezrin, radixin, and moesin (ERM) proteins bind advanced glycation end products, an interaction that may play a role in the development of diabetic complications.  J Biol Chem. 2003;  278 25783-25789
• 150 Meier M, Park JK, Boehn M, Elger M, Leitges M, Haller H, Menne J. Knockout of protein kinase C alpha protect against the development of albuminuria but not renal hypertrophy.  Diabetes. 2003;  , In Press, Accepted 10th December, 2003.
• 151 Miyata T, Ueda Y, Horie K, Nangaku M, Tanaka S, van Ypersele de Strihou C, Kurokawa K. Renal catabolism of advanced glycation end products: the fate of pentosidine.  Kidney Int. 1998a;  53 416-422
• 152 Miyata T, Ueda Y, Yamada Y, Izuhara Y, Wada T, Jadoul M, Saito A, Kurokawa K, van Ypersele de Strihou C. Accumulation of carbonyls accelerates the formation of pentosidine, an advanced glycation end product: carbonyl stress in uremia.  J Am Soc Nephrol. 1998b;  9 2349-2356
• 153 Miyata T, Wada Y, Cai Z, Iida Y, Horie K, Yasuda Y, Maeda K, Kurokawa K, van Ypersele de Strihou C. Implication of an increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure.  Kidney Int. 1997;  51 1170-1181
• 154 Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and Lisinopril microalbuminuria (CALM) study.  British Medical Journal. 2000a;  321 1440-1444
• 155 Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study.  Bmj. 2000b;  321 1440-1444
• 156 Monnier VM, Bautista O, Kenny D, Sell DR, Fogarty J, Dahms W, Cleary PA, Lachin J, Genuth S. Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial.  Diabetes. 1999;  48 870-880
• 157 Montero A, Munger KA, Khan RZ, Valdivielso JM, Morrow JD, Guasch A, Ziyadeh FN, Badr KF. F-2-isoprostanes mediate high glucose-induced TGF-beta synthesis and glomerular proteinuria in experimental type I diabetes.  Kidney International. 2000;  58 1963-1972
• 158 Moravski CJ, Kelly DJ, Cooper ME, Gilbert RE, Bertram JF, Shahinfar S, Skinner SL, Wilkinson-Berka JL. Retinal neovascularization is prevented by blockade of the renin-angiotensin system.  Hypertension. 2000;  36 1099-1104
• 159 Muller DN, Dechend R, Mervaala EMA, Park JK, Schmidt F, Fiebeler A, Theuer J, Breu V, Ganten D, Haller H, Luft FC. NF-kappa B inhibition ameliorates angiotensin II-induced inflammatory damage in rats.  Hypertension. 2000;  35 193-201
• 160 Mullins JJ, Peters J, Ganten D. Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene.  Nature. 1990;  344 541-544
• 161 Murphy M, Godson C, Cannon S, Kato S, Mackenzie HS, Martin F, Brady HR. Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells.  Journal of Biological Chemistry. 1999;  274 5830-5834
• 162 Nagahama T, Hayashi K, Ozawa Y, Takenaka T, Saruta T. Role of protein kinase C in angiotensin IIinduced constriction of renal microvessels.  Kidney International. 2000;  57 215-223
• 163 Naicker S, Bhoola KD. Endothelins: vasoactive modulators of renal function in health and disease.  Pharmacol Ther. 2001;  90 61-88
• 164 Nakamura S, Makita Z, Ishikawa S, Yasumura K, Fujii W, Yanagisawa K, Kawata T, Koike T. Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation.  Diabetes. 1997;  46 895-899
• 165 Nakamura T, Ebihara I, Fukui M, Tomino Y, Koide H. Effect of a Specific Endothelin Receptor a Antagonist on Mrna Levels for Extracellular Matrix Components and Growth Factors in Diabetic Glomeruli.  Diabetes. 1995a;  44 895-899
• 166 Nakamura T, Ebihara I, Fukui M, Tomino Y, Koide H. Effect of a specific endothelin receptor A antagonist on mRNA levels for extracellular matrix components and growth factors in diabetic glomeruli.  Diabetes. 1995b;  44 895-899
• 167 Neeper M, Schmidt A, Brett J, Yan S, Wang F, Pan F, Elliston K, Stern D, Shaw A. Cloning and expression of a cell surface receptor for advanced glycation end products of proteins.  J Biol Chem. 1992;  267 14998-15004
• 168 Nerlich AG, Sauer U, Kolmlitty V, Wagner E, Koch M, Schleicher ED. Expression of Glutamine- Fructose-6-Phosphate Amidotransferase in Human Tissues - Evidence for High Variability and Distinct Regulation in Diabetes.  Diabetes. 1998;  47 170-178
• 169 Nicholls K, Mandel T. Advanced glycosylation end products in experimental murine diabetic nephropathy: effect of islet grafting and of aminoguanidine.  Lab Invest. 1989;  60 486-489
• 170 Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage.  Nature. 2000;  404 787-790
• 171 Odetti P, Traverso N, Cosso L, Noberasco G, Pronzato MA, Marinari UM. Good glycaemic control reduces oxidation and glycation end-products in collagen of diabetic rats.  Diabetologia. 1996;  39 1440-1447
• 172 Oldfield MD, Bach LA, Forbes JM, Nikolic-Paterson D, McRobert A, Thallas V, Atkins RC, Osicka T, Jerums G, Cooper ME. Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE).  J Clin Invest. 2001;  108 1853-1863
• 173 Onozato ML, Tojo A, Goto A, Fujita T, Wilcox CS. Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB.  Kidney Int. 2002;  61 186-194
• 174 Orth SR, Esslinger JP, Amann K, Schwarz U, Raschack M, Ritz E. Nephroprotection of an Eta-Receptor Blocker (Lu 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats.  Hypertension. 1998;  31 995-1001
• 175 Ortwerth BJ, James HL. Lens proteins block the copper-mediated formation of reactive oxygen species during glycation reactions in vitro.  Biochem Biophys Res Commun. 1999;  259 706-710
• 176 Osicka TM, Yu Y, Lee V, Panagiotopoulos S, Kemp BE, Jerums G. Aminoguanidine and ramipril prevent diabetes-induced increases in protein kinase C activity in glomeruli, retina and mesenteric artery.  Clin Sci (Colch). 2001;  100 249-257
• 177 Osicka TM, Yu YX, Panagiotopoulos S, Clavant SP, Kiriazis Z, Pike RN, Pratt LM, Russo LM, Kemp BE, Comper WD, Jerums G. Prevention of albuminuria by aminoguanidine or ramipril in streptozotocininduced diabetic rats is associated with the normalization of glomerular protein kinase C.  Diabetes. 2000;  49 87-93
• 178 Passariello N, Sepe J, Marrazzo G, De Cicco A, Peluso A, Pisano MC, Sgambato S, Tesauro P, D’Onofrio F. Effect of aldose reductase inhibitor (tolrestat) on urinary albumin excretion rate and glomerular filtration rate in IDDM subjects with nephropathy.  Diabetes Care. 1993;  16 789-795
• 179 Pedersen MM, Christiansen JS, Mogensen CE. Reduction of glomerular hyperfiltration in normoalbuminuric IDDM patients by 6 mo of aldose reductase inhibition.  Diabetes. 1991;  40 527-531
• 180 Pieper GM. Enhanced, unaltered and impaired nitric oxide-mediated endothelium-dependent relaxation in experimental diabetes mellitus: importance of disease duration.  Diabetologia. 1999;  42 204-213
• 181 Pieper GM, Riazulhaq. Activation of Nuclear Factor-Kappa-B in Cultured Endothelial Cells by Increased Glucose Concentration - Prevention by Calphostin C.  Journal of Cardiovascular Pharmacology. 1997;  30 528-532
• 182 Pugliese G, Pricci F, Iacobini C, Leto G, Amadio L, Barsotti P, Frigeri L, Hsu DK, Vlassara H, Liu FT, Di Mario U. Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice.  Faseb J. 2001;  15 2471-2479
• 183 Rangan GK, Wang YP, Tay YC, Harris DCH. Inhibition of nuclear factor-kappa B activation reduces cortical tubulointerstitial injury in proteinuric rats.  Kidney International. 1999;  56 118-134
• 184 Remuzzi A, Perico N, Amuchastegui CS, Malanchini B, Mazerska M, Battaglia C, Bertani T, Remuzzi G. Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes.  J Am Soc Nephrol. 1993;  4 40-49
• 185 Riser BL, Denichilo M, Cortes P, Baker C, Grondin JM, Yee J, Narins RG. Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis.  Journal of the American Society of Nephrology. 2000a;  11 25-38
• 186 Riser BL, Denichilo M, Cortes P, Baker C, Grondin JM, Yee J, Narins RG. Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis.  J Am Soc Nephrol. 2000b;  11 25-38
• 187 Rocco MV, Chen Y, Goldfarb S, Ziyadeh FN. Elevated glucose stimulates TGF-beta gene expression and bioactivity in proximal tubule.  Kidney Int. 1992;  41 107-114
• 188 Rodby RA, Rohde RD, Clarke WR, Hunsicker LG, Anzalone DA, Atkins RC, Ritz E, Lewis EJ. The Irbesartan Type II Diabetic Nephropathy Trial: study design and baseline patient characteristics.  Nephrol Dial Transplant. 2000;  15 487-497
• 189 Rotig A, de Lonlay P, Chretien D, Foury F, Koenig M, Sidi D, Munnich A, Rustin P. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia.  Nat Genet. 1997;  17 215-217
• 190 Ruiz-Ortega M, Lorenzo O, Ruperez M, Konig S, Wittig B, Egido J. Angiotensin II activates nuclear transcription factor kappa B through AT(1) and AT(2) in vascular smooth muscle cells - Molecular mechanisms.  Circulation Research. 2000;  86 1266-1272
• 191 Rumble JR, Cooper ME, Soulis T, Cox A, Wu L, Youssef S, Jasik M, Jerums G, Gilbert R. Vascular hypertrophy in experimental diabetes: role of advanced glycation end products.  J Clin Invest. 1997;  99 1016-1027
• 192 Sato A, Saruta T. Aldosterone breakthrough during angiotensin-converting enzyme inhibitor therapy.  Am J Hypertens. 2003;  16 781-788
• 193 Schiffer M, Von Gersdorff G, Bitzer M, Susztak K, Bottinger EP. Smad proteins and transforming growth factor-beta signaling.  Kidney Int. 2000;  58 45-52
• 194 Schleicher ED, Weigert C. Role of the hexosamine biosynthetic pathway in diabetic nephropathy.  Kidney International. 2000;  58 S13-S18
• 195 Schneider JG, Tilly N, Hierl T, Sommer U, Hamann A, Dugi K, Leidig-Bruckner G, Kasperk C. Elevated plasma endothelin-1 levels in diabetes mellitus.  Am J Hypertens. 2002;  15 967-972
• 196 Sebekova K, Schinzel R, Munch G, Krivosikova Z, Dzurik R, Heidland A. Advanced glycation endproduct levels in subtotally nephrectomized rats: beneficial effects of angiotensin II receptor 1 antagonist losartan.  Mineral & Electrolyte Metabolism. 1999;  25 380-383
• 197 Seger R, Krebs EG. Protein Kinases. The MAPK Signaling Cascade [Review].  FASEB Journal. 1995;  9 726-735
• 198 Sell DR, Nagaraj RH, Grandhee SK, Odetti P, Lapolla A, Fogarty J, Monnier VM. Pentosidine: a molecular marker for the cumulative damage to proteins in diabetes, aging, and uremia.  Diabetes Metab Rev. 1991;  7 239-251
• 199 Shankland SJ, Wolf G. Cell cycle regulatory proteins in renal disease: role in hypertrophy, proliferation, and apoptosis [Review].  American Journal of Physiology - Renal Fluid & Electrolyte Physiology. 2000;  278 F515-F529
• 200 Sharma K, Jin Y, Guo J, Ziyadeh FN. Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice.  Diabetes. 1996;  45 522-530
• 201 Sharma K, Ziyadeh FN, Alzahabi B, McGowan TA, Kapoor S, Kurnik BR, Kurnik PB, Weisberg LS. Increased renal production of transforming growth factor-beta1 in patients with type II diabetes.  Diabetes. 1997;  46 854-859
• 202 Sheetz MJ, King GL. Molecular understanding of hyperglycemia's adverse effects for diabetic complications.  Jama. 2002;  288 2579-2588
• 203 Shin SJ, Lee YJ, Lin SR, Tan MS, Lai YH, Tsai JH. Decrease of renal endothelin 1 content and gene expression in diabetic rats with moderate hyperglycemia.  Nephron. 1995;  70 486-493
• 204 Simm A, Munch G, Seif F, Schenk O, Heidland A, Richter H, Vamvakas S, Schinzel R. Advanced glycation endproducts stimulate the map-kinase pathway in tubulus cell line llc-pk1.  FEBS Letters. 1997;  410 481-484
• 205 Singh R, Alavi N, Singh AK, Leehey DJ. Role of angiotensin II in glucose-induced inhibition of mesangial matrix degradation.  Diabetes. 1999;  48 2066-2073
• 206 Soulis LT, Cooper ME, Dunlop M, Jerums G. The relative roles of advanced glycation, oxidation and aldose reductase inhibition in the development of experimental diabetic nephropathy in the Sprague- Dawley rat.  Diabetologia. 1995;  38 387-394
• 207 Soulis T, Cooper ME, Sastra S, Thallas V, Panagiotopoulos S, Bjerrum OJ, Jerums G. Relative Contributions of Advanced Glycation and Nitric Oxide Synthase Inhibition to Aminoguanidine-Mediated Renoprotection in Diabetic Rats.  Diabetologia. 1997a;  40 1141-1151
• 208 Soulis T, Cooper ME, Vranes D, Bucala R, Jerums G. The effects of aminoguanidine in preventing experimental diabetic nephropathy are related to duration of treatment.  Kidney Int. 1996;  50 627-634
• 209 Soulis T, Thallas V, Youssef S, Gilbert RE, McWilliam B, Murray-McIntosh RP, Cooper ME. Advanced glycation end products and the receptor for advanced glycated end products co-localise in organs susceptible to diabetic microvascular injury: immunohistochemical studies.  Diabetologia. 1997b;  40 619-628
• 210 Soulis-Liparota T, Cooper M, Papazoglou D, Clarke B, Jerums G. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat.  Diabetes. 1991;  40 1328-1334
• 211 Stratton IM, Adler AI, Neil HAW, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.  British Medical Journal. 2000;  321 405-412
• 212 Studer RK, Craven PA, Derubertis FR. Activation of Protein Kinase-C Reduces Thromboxane Receptors in Glomeruli and Mesangial Cells.  Kidney International. 1993;  44 58-64
• 213 Studer RK, Craven PA, Derubertis FR. Antioxidant Inhibition of Protein Kinase C Signaled Increases in Transforming Growth Factor-Beta in Mesangial Cells.  Metabolism: Clinical & Experimental. 1997;  46 918-925
• 214 Sugimoto H, Shikata K, Matsuda M, Kushiro M, Hayashi Y, Hiragushi K, Wada J, Makino H. Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy.  Diabetologia. 1998;  41 1426-1434
• 215 Suzuki D, Miyata T, Saotome N, Horie K, Inagi R, Yasuda Y, Uchida K, Izuhara Y, Yagame M, Sakai H, Kurokawa K. Immunohistochemical evidence for an increased oxidative stress and carbonyl modification of proteins in diabetic glomerular lesions.  J Am Soc Nephrol. 1999;  10 822-832
• 216 Takahashi K, Suda K, Lam HC, Ghatei MA, Bloom SR. Endothelin-like immunoreactivity in rat models of diabetes mellitus.  J Endocrinol. 1991;  130 123-127
• 217 Thallas-Bonke V, Lindschau C, Rizkalla B, Bach LA, Boner G, Meier M, Haller H, Cooper ME, Forbes JM. Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-alpha-dependent pathway.  Diabetes. 2004;  53 2921-2930
• 218 Thomas MC, Tikellis C, Burns WM, Bialkowski K, Cao Z, Coughlan MT, Jandeleit-Dahm K, Cooper ME, Forbes JM. Interactions between renin angiotensin system and advanced glycation in the kidney.  J Am Soc Nephrol. 2005;  16 2976-2984
• 219 Thornalley PJ. Glutathione-dependent detoxification of alpha-oxoaldehydes by the glyoxalase system: involvement in disease mechanisms and antiproliferative activity of glyoxalase I inhibitors.  Chem Biol Interact. 1998;  111-112 137-151
• 220 Thornalley PJ. Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts.  Arch Biochem Biophys. 2003;  419 31-40
• 221 Tikkanen T, Tikkanen I, Rockell MD, Allen TJ, Johnston CI, Cooper ME, Burrell LM. Dual inhibition of neutral endopeptidase and angiotensin-converting enzyme in rats with hypertension and diabetes mellitus.  Hypertension. 1998;  32 778-785
• 222 Tolins JP, Shultz PJ, Raij L, Brown DM, Mauer SM. Abnormal renal hemodynamic response to reduced renal perfusion pressure in diabetic rats: role of NO.  Am J Physiol. 1993;  265 F886-895
• 223 Tomlinson DR. Mitogen-activated protein kinases as glucose transducers for diabetic complications [Review].  Diabetologia. 1999;  42 1271-1281
• 224 Tsuchida K, Makita Z, Yamagishi S, Atsumi T, Miyoshi H, Obara S, Ishida M, Ishikawa S, Yasumura K, Koike T. Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195.  Diabetologia. 1999;  42 579-588
• 225 Tuttle KR, Bakris GL, Toto RD, McGill JB, Hu K, Anderson PW. The effect of ruboxistaurin on nephropathy in type 2 diabetes.  Diabetes Care. 2005;  28 2686-2690
• 226 Twigg SM, Cao Z, McLennan SV, Burns WC, Brammar G, Forbes JM, Cooper ME. Renal Connective Tissue Growth Factor Induction in Experimental Diabetes is prevented by aminoguanidine.  Endocrinology. 2002;  143 4907-4915
• 227 Twigg SM, Chen MM, Joly AH, Chakrapani SD, Tsubaki J, Kim H-S, Oh Y, Rosenfeld RG. Connective tissue growth factor/IGFBP-rP2 is up-regulated by advanced glycosylatiuon end-products in human fibroblasts: a potential mechanism for expansion of extracellular matrix in diabetes mellitus.  Endocrinology. 2001a;  , in press
• 228 Twigg SM, Chen MM, Joly AH, Chakrapani SD, Tsubaki J, Kim HS, Oh Y, Rosenfeld RG. Advanced glycosylation end products up-regulate connective tissue growth factor (insulin-like growth factor-binding protein-related protein 2) in human fibroblasts: A potential mechanism for expansion of extracellular matrix in diabetes mellitus.  Endocrinology. 2001b;  142 1760-1769
• 229 Uribarri J, Peppa M, Cai W, Goldberg T, Lu M, He C, Vlassara H. Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients.  J Am Soc Nephrol. 2003;  14 728-731
• 230 Vasan S, Zhang X, Zhang X, Kapurniotu A, Bernhagen J, Teichberg S, Basgen J, Wagle D, Shih D, Terlecky I, Bucala R, Cerami A, Egan J, Ulrich P. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo.  Nature. 1996;  382 275-278
• 231 Veelken R, Hilgers KF, Hartner A, Haas A, Bohmer KP, Sterzel RB. Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy.  Journal of the American Society of Nephrology. 2000;  11 71-79
• 232 Vlassara H, Striker LJ, Teichberg S, Fuh H, Li YM, Steffes M. Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats.  Proc Natl Acad Sci USA. 1994;  91 11704-11708
• 233 Wautier JL, Zoukourian C, Chappey O, Wautier MP, Guillausseau PJ, Cao R, Hori O, Stern D, Schmidt AM. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats.  J Clin Invest. 1996;  97 238-243
• 234 Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE.  Am J Physiol Endocrinol Metab. 2001;  280 E685-694
• 235 Weigert C, Brodbeck K, Lehmann R, Haring HU, Schleicher ED. Overexpression of glutamine : fructose- 6-phosphate-amidotransferase induces transforming growth factor-beta 1 synthesis in NIH-3T3 fibroblasts.  FEBS Letters. 2001;  488 95-99
• 236 Wells-Knecht KJ, Brinkmann E, Wells-Knecht MC, Litchfield JE, Ahmed MU, Reddy S, Zyzak DV, Thorpe SR, Baynes JW. New biomarkers of maillard reaction damage to proteins.  Nephrol Dial Transplantation. 1996;  11 ((Suppl 5)) 41-47
• 237 Wendt TM, Tanji N, Guo J, Kislinger TR, Qu W, Lu Y, Bucciarelli LG, Rong LL, Moser B, Markowitz GS, Stein G, Bierhaus A, Liliensiek B, Arnold B, Nawroth PP, Stern DM, D'Agati VD, Schmidt AM. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy.  Am J Pathol. 2003;  162 1123-1137
• 238 Wilkinson-Berka JL, Gibbs N, Skinner SL, Cooper ME, Kelly DJ. Renoprotective and anti-hypertensive effects of combined valsartan and perindopril in progressive diabetic nephropathy in the transgenic (mRen-2)27 rat.  Nephrology, Dialysis, Transplantation. 2001;  in press
• 239 Williams B, Baker AQ, Gallacher B, Lodwick D. Angiotensin II increases vascular permeability factor gene expression by human vascular smooth muscle cells.  Hypertension. 1995;  25 913-917
• 240 Williamson JR, Chang K, Frangos M, Hasan KS, Ido Y, Kawamura T, Nyengaard JR, van den Enden M, Kilo C, Tilton RG. Hyperglycemic pseudohypoxia and diabetic complications.  Diabetes. 1993;  42 801-813
• 241 Wolf G. Molecular mechanisms of angiotensin II in the kidney: emerging role in the progression of renal disease: beyond haemodynamics.  Nephrol Dial Transplant. 1998;  13 1131-1142
• 242 Wolf G. Cell cycle regulation in diabetic nephropathy.  Kidney International. 2000;  58 S59-S66
• 243 Wolf G, Ziyadeh FN. The role of angiotensin II in diabetic nephropathy: emphasis on nonhemodynamic mechanisms.  Am J Kidney Dis. 1997;  29 153-163
• 244 Wolf G, Ziyadeh FN, Zahner G, Stahl RAK. Angiotensin II-Stimulated Expression of Transforming Growth Factor Beta in Renal Proximal Tubular Cells - Attenuation after Stable Transfection with the CMas Oncogene.  Kidney International. 1995;  48 1818-1827
• 245 Wrana JL, Attisano L, Wieser R, Ventura F, Massagu J. Mechanisms of activation of the TGF-ß receptor.  Nature. 1994;  370 341-346
• 246 Xia P, Inoguchi T, Kern TS, Engerman RL, Oates PJ, King GL. Characterization of the Mechanism for the Chronic Activation of Diacylglycerol-Protein Kinase C Pathway in Diabetes and Hypergalactosemia.  Diabetes. 1994;  43 1122-1129
• 247 Yagihashi S. Pathogenetic mechanisms of diabetic neuropathy: lessons from animal models.  J Peripher Nerv Syst. 1997;  2 113-132
• 248 Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, Border WA. Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy.  Proc Natl Acad Sci USA. 1993;  90 1814-1818
• 249 Yamamoto T, Noble NA, Cohen AH, Nast CC, Hishida A, Gold LI, Border WA. Expression of transforming growth factor-beta isoforms in human glomerular diseases.  Kidney Int. 1996;  49 461-469
• 250 Yamamoto Y, Kato I, Doi T, Yonekura H, Ohashi S, Takeuchi M, Watanabe T, Yamagishi S, Sakurai S, Takasawa S, Okamoto H, Yamamoto H. Development and prevention of advanced diabetic nephropathy in RAGE- overexpressing mice.  J Clin Invest. 2001;  108 261-268
• 251 Yan SD, Schmidt AM, Anderson GM, Zhang JH, Brett J, Zou YS, Pinsky D, Stern D. Enhanced Cellular Oxidant Stress by the Interaction of Advanced Glycation End Products with Their Receptors Binding Proteins.  Journal of Biological Chemistry. 1994;  269 9889-9897
• 252 Yokoi H, Mukoyama M, Nagae T, Mori K, Suganami T, Sawai K, Yoshioka T, Koshikawa M, Nishida T, Takigawa M, Sugawara A, Nakao K. Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis.  J Am Soc Nephrol. 2004;  15 1430-1440
• 253 Yonekura H, Yamamoto Y, Sakurai S, Petrova RG, Abedin MJ, Li H, Yasui K, Takeuchi M, Makita Z, Takasawa S, Okamoto H, Watanabe T, Yamamoto H. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury.  Biochem J. 2003;  370 1097-1109
• 254 Zatz R, Dunn BR, Meyer TW, Brenner B. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension.  J Clin Invest. 1986;  77 1925-1930
• 255 Zatz R, Meyer TW, Rennke HG, Brenner BM. Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy.  Proc Natl Acad Sci (USA). 1985;  82 5963-5967
• 256 Zhang SL, Filep JG, Hohman TC, Tang SS, Ingelfinger JR, Chan JSD. Molecular mechanisms of glucose action on angiotensinogen gene expression in rat proximal tubular cells.  Kidney International. 1999;  55 454-464
• 257 Zhang SL, Tang SS, Chen X, Filep JG, Ingelfinger JR, Chan JSD. High levels of glucose stimulate angiotensinogen gene expression via the p38 mitogen-activated protein kinase pathway in rat kidney proximal tubular cells.  Endocrinology. 2000;  141 4637-4646
• 258 Zimpelmann J, Kumar D, Levine DZ, Wehbi G, Imig JD, Navar LG, Burns KD. Early diabetes mellitus stimulates proximal tubule renin mRNA expression in the rat.  Kidney International. 2000;  58 2320-2330
• 259 Ziyadeh FN, Hoffman BB, Han DC, Iglesias-de la Cruz MC, Hong SW, Isono M, Chen S, McGowan TA, Sharma K. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice.  Proceedings of the National Academy of Sciences of the United States of America. 2000;  97 8015-8020

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