New approaches to the treatment of nephropathy in diabetes

Expert Opinion on Investigational Drugs

Volumn 20, Issue 8, 2011, Pages 1057-1071

  Thomas, Merlin C ^a,b   Groop, Per Henrik ^a,b,c  

^a BAKER IDI HEART AND DIABETES INSTITUTE   (Australia)

^b UNIVERSITY OF HELSINKI   (Finland)

^c HELSINKI UNIVERSITY CENTRAL HOSPITAL   (Finland)

Author keywords

Albuminuria; Chronic kidney disease; Diabetes; Diabetic nephropathy; Renoprotective agents

Indexed keywords

ADVANCED GLYCATION END PRODUCT RECEPTOR INHIBITOR; ALISKIREN; ANGIOTENSIN RECEPTOR ANTAGONIST; ANTIFIBROTIC AGENT; ANTIINFLAMMATORY AGENT; ANTIOXIDANT; CHYMASE INHIBITOR; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ENDOTHELIN RECEPTOR ANTAGONIST; FENOFIBRATE; FIBRIC ACID DERIVATIVE; LOSARTAN; PARICALCITOL; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PIOGLITAZONE; PLACEBO; PROTEIN KINASE C INHIBITOR; RECEPTOR BLOCKING AGENT; RENIN INHIBITOR; RHO KINASE INHIBITOR; ROSIGLITAZONE; SIMVASTATIN; SPIRONOLACTONE; SPP 1148; SPP 635; SPP 676; TPC 806; UNCLASSIFIED DRUG; UNINDEXED DRUG; VITAMIN D;

ALBUMINURIA; BLADDER CANCER; CARDIOVASCULAR DISEASE; CHRONIC KIDNEY DISEASE; CLINICAL TRIAL (TOPIC); DIABETIC NEPHROPATHY; DRUG DOSE INCREASE; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG FATALITY; ENDOTHELIAL DYSFUNCTION; ENZYME ACTIVATION; FEEDBACK SYSTEM; FIBROGENESIS; FRACTURE; GLUCOSE BLOOD LEVEL; HEART FAILURE; HEART MUSCLE ISCHEMIA; HUMAN; HYPERKALEMIA; HYPERTENSION; INSULIN DEPENDENT DIABETES MELLITUS; KIDNEY FIBROSIS; MACROALBUMINURIA; META ANALYSIS (TOPIC); MICROALBUMINURIA; NEPHRITIS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PHASE 2 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); RENAL PROTECTION; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; TREATMENT OUTCOME;

ANIMALS; DIABETES MELLITUS; DIABETIC NEPHROPATHIES; DRUG DISCOVERY; HUMANS; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 79960371057     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2011.591785     Document Type: Review

References (169)

1. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414:782-7 (Pubitemid 34000780)
2. Federation ID. IDF Diabetes Atlas. 4th edition. International Diabetes Federation. Brussels, Belgium; 2009
3. Hogan P, Dall T, Nikolov P. Economic costs of diabetes in the US in 2002. Diabetes Care 2003;26:917-32
4. Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999;341:1127-33 (Pubitemid 29466226)
5. U. S. Renal Data System, USRDS 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Bethesda, MD, USA; 2004
6. Groop PH, Thomas MC, Moran JL, et al. The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes. Diabetes 2009;58:1651-8
7. Stephenson JM, Kenny S, Stevens LK, et al. Proteinuria and mortality in diabetes: the WHO Multinational Study of Vascular Disease in Diabetes. Diabet Med 1995;12:149-55
8. Adler AI, Stevens RJ, Manley SE, et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63:225-32 (Pubitemid 35463925)
9. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93 (Pubitemid 36159355)
10. Cicoira M, Zanolla L, Rossi A, et al. Failure of aldosterone suppression despite angiotensin-converting enzyme (ACE) inhibitor administration in chronic heart failure is associated with ACE DD genotype. J Am Coll Cardiol 2001;37:1808-12 (Pubitemid 32499963)
11. Staessen J, Lijnen P, Fagard R, et al. Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol 1981;91:457-65 (Pubitemid 12203819)
12. Lee AF, MacFadyen RJ, Struthers AD. Neurohormonal reactivation in heart failure patients on chronic ACE inhibitor therapy: a longitudinal study. Eur J Heart Fail 1999;1:401-6 (Pubitemid 30131049)
13. Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol 2007;3:486-92 (Pubitemid 47313030)
14. Schjoedt KJ, Andersen S, Rossing P, et al. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 2004;47:1936-9 (Pubitemid 40110201)
15. Horita Y, Taura K, Taguchi T, et al. Aldosterone breakthrough during therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in proteinuric patients with immunoglobulin A nephropathy. Nephrology (Carlton) 2006;11:462-6 (Pubitemid 44470097)
16. Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 2003;41:64-8 (Pubitemid 36056793)
17. Tang WH, Vagelos RH, Yee YG, et al. Neurohormonal and clinical responses to high- versus low-dose enalapril therapy in chronic heart failure. J Am Coll Cardiol 2002;39:70-8 (Pubitemid 34059863)
18. Pitt B. "Escape" of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther 1995;9:145-9
19. Struthers AD. The clinical implications of aldosterone escape in congestive heart failure. Eur J Heart Fail 2004;6:539-45 (Pubitemid 39070505)
20. Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension 2002;39:E1-8
21. Parving HH, Persson F, Lewis JB, et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008;358:2433-46 (Pubitemid 351793017)
22. Persson F, Rossing P, Reinhard H, et al. Renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension, and albuminuria. Diabetes Care 2009;32:1873-9
23. Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren trial in type 2 diabetes using cardio-renal endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant 2009;24:1663-71
24. MacFadyen RJ, Lee AF, Morton JJ, et al. How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart 1999;82:57-61 (Pubitemid 29309237)
25. Urata H, Kinoshita A, Misono KS, et al. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem 1990;265:22348-57 (Pubitemid 120014308)
26. Huang XR, Chen WY, Truong LD, Lan HY. Chymase is upregulated in diabetic nephropathy: implications for an alternative pathway of angiotensin II-mediated diabetic renal and vascular disease. J Am Soc Nephrol 2003;14:1738-47 (Pubitemid 36750469)
27. Ritz E. Chymase: a potential culprit in diabetic nephropathy? J Am Soc Nephrol 2003;14:1952-4 (Pubitemid 36750492)
28. Kobori H, Nangaku M, Navar LG, Nishiyama A. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 2007;59:251-87 (Pubitemid 47481436)
29. Maeda Y, Inoguchi T, Takei R, et al. Inhibition of chymase protects against diabetes-induced oxidative stress and renal dysfunction in hamsters. Am J Physiol Renal Physiol 2010;299:1328-38
30. Tikellis C, Johnston CI, Forbes JM, et al. Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy. Hypertension 2003;41:392-7 (Pubitemid 36314606)
31. Lely AT, Hamming I, van Goor H, Navis GJ. Renal ACE2 expression in human kidney disease. J Pathol 2004;204:587-93 (Pubitemid 39585958)
32. Oudit GY, Liu GC, Zhong J, et al. Human recombinant ACE2 reduces the progression of diabetic nephropathy. Diabetes 2010;59:529-38
33. Rossing K, Schjoedt KJ, Smidt UM, et al. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care 2005;28:2106-12 (Pubitemid 41242452)
34. Mehdi UF, Adams-Huet B, Raskin P, et al. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 2009;20:2641-50
35. Epstein M, Williams GH, Weinberger M, et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol 2006;1:940-51
36. Smulders YM, van Eeden AE, Stehouwer CD, et al. Can reduction in hypertriglyceridaemia slow progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus? Eur J Clin Invest 1997;27:997-1002 (Pubitemid 28012621)
37. Nagai T, Tomizawa T, Nakajima K, Mori M. Effect of bezafibrate or pravastatin on serum lipid levels and albuminuria in NIDDM patients. J Atheroscler Thromb 2000;7:91-6
38. Park CW, Zhang Y, Zhang X, et al. PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int 2006;69:1511-17
39. Ren S, Xin C, Beck KF, et al. PPARalpha activation upregulates nephrin expression in human embryonic kidney epithelial cells and podocytes by a dual mechanism. Biochem Biophys Res Commun 2005;338:1818-24 (Pubitemid 41643096)
40. Zhao X, Li LY. PPAR-alpha agonist fenofibrate induces renal CYP enzymes and reduces blood pressure and glomerular hypertrophy in Zucker diabetic fatty rats. Am J Nephrol 2008;28:598-606 (Pubitemid 351832447)
41. Gonzalez FJ. Recent update on the PPAR alpha-null mouse. Biochimie 1997;79:139-44 (Pubitemid 27290357)
42. Hattori Y, Hattori S, Kasai K. Troglitazone upregulates nitric oxide synthesis in vascular smooth muscle cells. Hypertension 1999;33:943-8 (Pubitemid 29186389)
43. Chawla A, Barak Y, Nagy L, et al. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 2001;7:48-52 (Pubitemid 32095641)
44. Ansquer JC, Foucher C, Rattier S, et al. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis 2005;45:485-93 (Pubitemid 40341327)
45. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61
46. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-4
47. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010;362:1563-74
48. Isshiki K, Haneda M, Koya D, et al. Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats. Diabetes 2000;49:1022-32 (Pubitemid 30349426)
49. Ko GJ, Kang YS, Han SY, et al. Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. Nephrol Dial Transplant 2008;23:2750-60
50. Gumieniczek A. Effect of the new thiazolidinedione-pioglitazone on the development of oxidative stress in liver and kidney of diabetic rabbits. Life Sci 2003;74:553-62 (Pubitemid 37419966)
51. Gumieniczek A. Effects of pioglitazone on hyperglycemia-induced alterations in antioxidative system in tissues of alloxan-treated diabetic animals. Exp Toxicol Pathol 2005;56:321-6 (Pubitemid 40312757)
52. Isshiki K, Haneda M, Koya D, et al. Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats. Diabetes 2000;49:1022-32 (Pubitemid 30349426)
53. Fujii M, Takemura R, Yamaguchi M, et al. Troglitazone (CS-045) ameliorates albuminuria in streptozotocin-induced diabetic rats. Metabolism 1997;46:981-3 (Pubitemid 27371810)
54. Sarafidis PA, Stafylas PC, Georgianos PI, et al. Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a meta-analysis. Am J Kidney Dis 2010;55:835-47
55. Nissen SE, Wolski K. Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med 2010;170:1191-201
56. Betteridge DJ. CHICAGO, PERISCOPE and PROactive: CV risk modification in diabetes with pioglitazone. Fundam Clin Pharmacol 2009;23:675-9
57. Tanaka H, Hamano T, Fujii N, et al. The impact of diabetes mellitus on vitamin D metabolism in predialysis patients. Bone 2009;45:949-55
58. Rojas-Rivera J, De La Piedra C, Ramos A, et al. The expanding spectrum of biological actions of vitamin D. Nephrol Dial Transplant 2010;25:2850-65
59. Li YC, Kong J, Wei M, et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002;110:229-38 (Pubitemid 34787360)
60. Porsti IH. Expanding targets of vitamin D receptor activation: downregulation of several RAS components in the kidney. Kidney Int 2008;74:1371-3
61. Freundlich M, Quiroz Y, Zhang Z, et al. Suppression of renin-angiotensin gene expression in the kidney by paricalcitol. Kidney Int 2008;74:1394-402
62. Wu-Wong JR. Potential for vitamin D receptor agonists in the treatment of cardiovascular disease. Br J Pharmacol 2009;158:395-412
63. Zhang Z, Sun L, Wang Y, et al. Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int 2008;73:163-71
64. Alborzi P, Patel NA, Peterson C, et al. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension 2008;52:249-55
65. Agarwal R, Acharya M, Tian J, et al. Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int 2005;68:2823-8 (Pubitemid 43251029)
66. Fishbane S, Chittineni H, Packman M, et al. Oral paricalcitol in the treatment of patients with CKD and proteinuria: a randomized trial. Am J Kidney Dis 2009;54:647-52
67. de Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 2010;376:1543-51
68. Witham MD, Dove FJ, Dryburgh M, et al. The effect of different doses of vitamin D(3) on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial. Diabetologia 2010;53:2112-19
69. Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003;349:446-56 (Pubitemid 36910023)
70. Tentori F, Hunt WC, Stidley CA, et al. Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int 2006;70:1858-65 (Pubitemid 44684819)
71. Burns WC, Thomas MC. The molecular mediators of type 2 epithelial to mesenchymal transition (EMT) and their role in renal pathophysiology. Expert Rev Mol Med 2010;12:e17
72. Bhowmick NA, Ghiassi M, Aakre M, et al. TGF-beta-induced RhoA and p160ROCK activation is involved in the inhibition of Cdc25A with resultant cell-cycle arrest. Proc Natl Acad Sci USA 2003;100:15548-53 (Pubitemid 38021027)
73. Rodrigues-Diez R, Carvajal-Gonzalez G, Sanchez-Lopez E, et al. Pharmacological modulation of epithelial mesenchymal transition caused by angiotensin II. Role of ROCK and MAPK pathways. Pharm Res 2008;25:2447-61
74. Guo X, Wang L, Chen B, et al. ERM protein moesin is phosphorylated by advanced glycation end products and modulates endothelial permeability. Am J Physiol Heart Circ Physiol 2009;297:H238-46
75. Komers R, Oyama TT, Beard DR, et al. Rho kinase inhibition protects kidneys from diabetic nephropathy without reducing blood pressure. Kidney Int 2011;79:432-42
76. Kolavennu V, Zeng L, Peng H, et al. Targeting of RhoA/ROCK signaling ameliorates progression of diabetic nephropathy independent of glucose control. Diabetes 2008;57:714-23
77. Noma K, Oyama N, Liao JK. Physiological role of ROCKs in the cardiovascular system. Am J Physiol Cell Physiol 2006;290:C661-8
78. Laufs U, Marra D, Node K, Liao JK. 3-Hydroxy-3-methylglutaryl- CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem 1999;274:21926-31
79. Colhoun HM, Betteridge DJ, Durrington PN, et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis 2009;54:810-19
80. Douglas K, O?Malley PG, Jackson JL. Meta-analysis: the effect of statins on albuminuria. Ann Intern Med 2006;145:117-24 (Pubitemid 46780585)
81. Peng F, Wu D, Gao B, et al. RhoA/Rho-kinase contribute to the pathogenesis of diabetic renal disease. Diabetes 2008;57:1683-92
82. Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006;98:322-34
83. Soulis-Liparota T, 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;38:387-94
84. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813-20 (Pubitemid 34000785)
85. Soulis-Liparota T, Cooper M, Papazoglou D, et al. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat. Diabetes 1991;40:1328-34
86. Vlassara H, Striker LJ, Teichberg S, et al. Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats. Proc Natl Acad Sci USA 1994;91:11704-8 (Pubitemid 24356413)
87. Wendt TM, Tanji N, Guo J, et al. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 2003;162:1123-37 (Pubitemid 36350658)
88. Morcos M, Sayed AA, Bierhaus A, et al. Activation of tubular epithelial cells in diabetic nephropathy. Diabetes 2002;51:3532-44 (Pubitemid 35403461)
89. Reiniger N, Lau K, McCalla D, et al. Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse. Diabetes 2010;59:2043-54
90. Bolton WK, Cattran DC, Williams ME, et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol 2004;24:32-40 (Pubitemid 38250484)
91. La Selva M, Beltramo E, Pagnozzi F, et al. Thiamine corrects delayed replication and decreases production of lactate and advanced glycation end-products in bovine retinal and human umbilical vein endothelial cells cultured under high glucose conditions. Diabetologia 1996;39:1263-8 (Pubitemid 26356052)
92. Thornalley PJ. The potential role of thiamine (vitamin B1) in diabetic complications. Curr Diabetes Rev 2005;1:287-98
93. Babaei-Jadidi R, Karachalias N, Ahmed N, et al. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 2003;52:2110-20 (Pubitemid 36919806)
94. Abaterusso C, Gambaro G. The role of glycosaminoglycans and sulodexide in the treatment of diabetic nephropathy. Treat Endocrinol 2006;5:211-22 (Pubitemid 44166672)
95. Alkhalaf A, Klooster A, van Oeveren W, et al. A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with diabetic nephropathy. Diabetes Care 2010;33:1598-601
96. Nagaraj RH, Sarkar P, Mally A, et al. Effect of pyridoxamine on chemical modification of proteins by carbonyls in diabetic rats: characterization of a major product from the reaction of pyridoxamine and methylglyoxal. Arch Biochem Biophys 2002;402:110-19 (Pubitemid 34848300)
97. Degenhardt TP, Alderson NL, Arrington DD, et al. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocindiabetic rat. Kidney Int 2002;61:939-50 (Pubitemid 34175462)
98. Alderson NL, Chachich ME, Youssef NN, et al. The AGE inhibitor pyridoxamine inhibits lipemia and development of renal and vascular disease in Zucker obese rats. Kidney Int 2003;63:2123-33 (Pubitemid 36605823)
99. Williams ME, Bolton WK, Khalifah RG, et al. Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am J Nephrol 2007;27:605-14 (Pubitemid 350014947)
100. Cooper ME, Thallas V, Forbes J, et al. The cross-link breaker, N-phenacylthiazolium bromide prevents vascular advanced glycation end-product accumulation. Diabetologia 2000;43:660-4 (Pubitemid 30322084)
101. Thallas-Bonke V, Lindschau C, Rizkalla B, et al. 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;53:2921-30 (Pubitemid 39425918)
102. Zieman SJ, Melenovsky V, Clattenburg L, et al. Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension. J Hypertens 2007;25:577-83 (Pubitemid 46213796)
103. Twigg SM, Cooper ME. The time has come to target connective tissue growth factor in diabetic complications. Diabetologia 2004;47:965-8 (Pubitemid 38918153)
104. Okada H, Kikuta T, Kobayashi T, et al. Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis. J Am Soc Nephrol 2005;16:133-43 (Pubitemid 43073165)
105. Oemar BS, Luscher TF. Connective tissue growth factor. Friend or foe? Arterioscler Thromb Vasc Biol 1997;17:1483-9 (Pubitemid 27387766)
106. Grotendorst GR. Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev 1997;8:171-9 (Pubitemid 28077925)
107. Goldschmeding R, Aten J, Ito Y, et al. Connective tissue growth factor: just another factor in renal fibrosis? Nephrol Dial Transplant 2000;15:296-9 (Pubitemid 30116458)
108. Burns WC, Kantharidis P, Thomas MC. The role of tubular epithelialmesenchymal transition in progressive kidney disease. Cells Tissues Organs 2007;185:222-31 (Pubitemid 46956862)
109. Burns WC, Twigg SM, Forbes JM, et al. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. J Am Soc Nephrol 2006;17:2484-94 (Pubitemid 44300964)
110. Lassila M, Jandeleit-Dahm K, Seah KK, et al. Imatinib attenuates diabetic nephropathy in apolipoprotein E-knockout mice. J Am Soc Nephrol 2005;16:363-73 (Pubitemid 41725131)
111. Mokhtari D, Welsh N. Potential utility of small tyrosine kinase inhibitors in the treatment of diabetes. Clin Sci (Lond) 2009;118:241-7
112. Mogyorosi A, Ziyadeh FN. What is the role of decorin in diabetic kidney disease? Nephrol Dial Transplant 1999;14:1078-81 (Pubitemid 29209286)
113. Miric G, Dallemagne C, Endre Z, et al. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol 2001;133:687-94 (Pubitemid 32642874)
114. RamachandraRao SP, Zhu Y, Ravasi T, et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol 2009;20:1765-75
115. Cho ME, Smith DC, Branton MH, et al. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2007;2:906-13
116. Tan SM, Zhang Y, Cox AJ, et al. Tranilast attenuates the up-regulation of thioredoxin-interacting protein and oxidative stress in an experimental model of diabetic nephropathy. Nephrol Dial Transplant
117. Mifsud S, Kelly DJ, Qi W, et al. Intervention with tranilast attenuates renal pathology and albuminuria in advanced experimental diabetic nephropathy. Nephron Physiol 2003;95:83-91
118. Soma J, Sugawara T, Huang YD, et al. Tranilast slows the progression of advanced diabetic nephropathy. Nephron 2002;92:693-8
119. Soma J, Sato K, Saito H, Tsuchiya Y. Effect of tranilast in early-stage diabetic nephropathy. Nephrol Dial Transplant 2006;21:2795-9 (Pubitemid 44542233)
120. Zammit SC, Cox AJ, Gow RM, et al. Evaluation and optimization of antifibrotic activity of cinnamoyl anthranilates. Bioorg Med Chem Lett 2009;19:7003-6
121. Meier M, Park JK, Overheu D, et al. Deletion of protein kinase C-beta isoform in vivo reduces renal hypertrophy but not albuminuria in the streptozotocin-induced diabetic mouse model. Diabetes 2007;56:346-54
122. Koya D, Haneda M, Nakagawa H, et al. 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 J 2000;14:439-47 (Pubitemid 30143162)
123. Ishii H, Jirousek MR, Koya D, et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996;272:728-31 (Pubitemid 26000279)
124. Tuttle KR, Bakris GL, Toto RD, et al. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care 2005;28:2686-90 (Pubitemid 43951160)
125. Tuttle KR, McGill JB, Haney DJ, et al. Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. Clin J Am Soc Nephrol 2007;2:631-6
126. Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 2008;57:1446-54
127. Chacko B, Reily C, Srivastava A, et al. Prevention of diabetic nephropathy in Ins2+/-AkitaJ mice by the mitochondria-targeted therapy Mito Q. Biochem J 2010;432:9-19
128. Gorin Y, Block K, Hernandez J, et al. Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J Biol Chem 2005;280:39616-26 (Pubitemid 41713921)
129. Asaba K, Tojo A, Onozato ML, et al. Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney Int 2005;67:1890-8 (Pubitemid 40577724)
130. Lonn E, Yusuf S, Hoogwerf B, et al. Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care 2002;25:1919-27 (Pubitemid 41071045)
131. Mann JF, Lonn EM, Yi Q, et al. Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: results of the HOPE study. Kidney Int 2004;65:1375-80 (Pubitemid 38406976)
132. Yokoyama M, Torita M, Yoshizawa M, Usuda R. Indication of vitamin E on microalbuminuria in patients with incipient diabetic nephropathy. Diabetes Metab 2001;27:611-12 (Pubitemid 33051712)
133. Farvid MS, Jalali M, Siassi F, Hosseini M.comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in type 2 diabetes. Diabetes Care 2005;28:2458-64 (Pubitemid 41384294)
134. Gaede P, Poulsen HE, Parving HH, Pedersen O. Double-blind, randomised study of the effect of combined treatment with vitamin C and E on albuminuria in Type 2 diabetic patients. Diabet Med 2001;18:756-60 (Pubitemid 32955529)
135. Goicoechea M, de Vinuesa SG, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 2010;5:1388-93
136. Morcos M, Borcea V, Isermann B, et al. Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study. Diabetes Res Clin Pract 2001;52:175-83 (Pubitemid 32385330)
137. Zibadi S, Rohdewald PJ, Park D, Watson RR. Reduction of cardiovascular risk factors in subjects with type 2 diabetes by Pycnogenol supplementation. Nutr Res 2008;28:315-20 (Pubitemid 351609206)
138. Kar P, Laight D, Rooprai HK, et al. Effects of grape seed extract in type 2 diabetic subjects at high cardiovascular risk: a double blind randomized placebo controlled trial examining metabolic markers, vascular tone, inflammation, oxidative stress and insulin sensitivity. Diabet Med 2009;26:526-31
139. Kadhim HM, Ismail SH, Hussein KI, et al. Effects of melatonin and zinc on lipid profile and renal function in type 2 diabetic patients poorly controlled with metformin. J Pineal Res 2006;41:189-93 (Pubitemid 44141755)
140. DeRubertis FR, Craven PA, Melhem MF. Acceleration of diabetic renal injury in the superoxide dismutase knockout mouse: effects of tempol. Metabolism 2007;56:1256-64 (Pubitemid 47223266)
141. Gealekman O, Brodsky SV, Zhang F, et al. Endothelial dysfunction as a modifier of angiogenic response in Zucker diabetic fat rat: amelioration with Ebselen. Kidney Int 2004;66:2337-47 (Pubitemid 41115298)
142. Pergola PE, Krauth M, Huff JW, et al. Effect of bardoxolone methyl on kidney function in patients with T2D and stage 3b-4 CKD. Am J Nephrol 2011;33:469-76
143. Johnstone MT, Creager SJ, Scales KM, et al. Impaired endothelium- dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993;88:2510-16 (Pubitemid 23360174)
144. Williams SB, Cusco JA, Roddy M-A, et al. Impaired nitric oxide-mediated vasodilatation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996;27:567-74 (Pubitemid 26081917)
145. Gladwin MT. Deconstructing endothelial dysfunction: soluble guanylyl cyclase oxidation and the NO resistance syndrome. J Clin Invest 2006;116:2330-2 (Pubitemid 44330131)
146. Liu S, Ma X, Gong M, et al. Glucose down-regulation of cGMP-dependent protein kinase I expression in vascular smooth muscle cells involves NAD(P)H oxidase-derived reactive oxygen species. Free Radic Biol Med 2007;42:852-63 (Pubitemid 46274174)
147. Kuno Y, Iyoda M, Shibata T, et al. Sildenafil, a phosphodiesterase type 5 inhibitor, attenuates diabetic nephropathy in non-insulin-dependent Otsuka Long-Evans Tokushima Fatty rats. Br J Pharmacol 2011;162:1389-400
148. Grover-Paez F, Villegas Rivera G, Guillen Ortiz R. Sildenafil citrate diminishes microalbuminuria and the percentage of A1c in male patients with type 2 diabetes. Diabetes Res Clin Pract 2007;78:136-40 (Pubitemid 47351245)
149. Onozato ML, Tojo A, Goto A, Fujita T. Effect of combination therapy with dipyridamole and quinapril in diabetic nephropathy. Diabetes Res Clin Pract 2003;59:83-92 (Pubitemid 36135826)
150. Aizawa T, Suzuki S, Asawa T, et al. Dipyridamole reduces urinary albumin excretion in diabetic patients with normo- or microalbuminuria. Clin Nephrol 1990;33:130-5 (Pubitemid 20104001)
151. Gambaro G, Cavazzana AO, Luzi P, et al. Glycosaminoglycans prevent morphological renal alterations and albuminuria in diabetic rats. Kidney Int 1992;42:285-91
152. Achour A, Kacem M, Dibej K, et al. One year course of oral sulodexide in the management of diabetic nephropathy. J Nephrol 2005;18:568-74 (Pubitemid 41824477)
153. van der Pijl JW, van der Woude FJ, Geelhoed-Duijvestijn PH, et al. Danaparoid sodium lowers proteinuria in diabetic nephropathy. J Am Soc Nephrol 1997;8:456-62 (Pubitemid 127454181)
154. Gambaro G, Kinalska I, Oksa A, et al. Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N.A.S. randomized trial. J Am Soc Nephrol 2002;13:1615-25 (Pubitemid 34579250)
155. Sulikowska B, Olejniczak H, Muszynska M, et al. Effect of sulodexide on albuminuria, NAG excretion and glomerular filtration response to dopamine in diabetic patients. Am J Nephrol 2006;26:621-8 (Pubitemid 46143884)
156. Blouza S, Dakhli S, Abid H, et al. Efficacy of low-dose oral sulodexide in the management of diabetic nephropathy. J Nephrol 2010;23:415-24
157. Navarro JF, Mora C, Muros M, Garcia J. Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: a short-term, randomized, controlled trial. J Am Soc Nephrol 2005;16:2119-26 (Pubitemid 41716443)
158. Aminorroaya A, Janghorbani M, Rezvanian H, et al.comparison of the effect of pentoxifylline and captopril on proteinuria in patients with type 2 diabetes mellitus. Nephron Clin Pract 2005;99:c73-7
159. Moriwaki Y, Inokuchi T, Yamamoto A, et al. Effect of TNF-alpha inhibition on urinary albumin excretion in experimental diabetic rats. Acta Diabetol 2007;44:215-18 (Pubitemid 350132266)
160. DiPetrillo K, Coutermarsh B, Gesek FA. Urinary tumor necrosis factor contributes to sodium retention and renal hypertrophy during diabetes. Am J Physiol Renal Physiol 2003;284:F113-21 (Pubitemid 35471291)
161. Neuhofer W, Pittrow D. Role of endothelin and endothelin receptor antagonists in renal disease. Eur J Clin Invest 2006;36(Suppl 3):78-88 (Pubitemid 44179788)
162. Hocher B, Thone-Reineke C, Rohmeiss P, et al. Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. J Clin Invest 1997;99:1380-9 (Pubitemid 27142776)
163. Nakamura T, Ebihara I, Fukui M, et al. Effect of a specific endothelin receptor A antagonist on mRNA levels for extracellular matrix components and growth factors in diabetic glomeruli. Diabetes 1995;44:895-9
164. Dhein S, Hochreuther S, Aus Dem Spring C, et al. Long-term effects of the endothelin(A) receptor antagonist LU 135252 and the angiotensin-converting enzyme inhibitor trandolapril on diabetic angiopathy and nephropathy in a chronic type I diabetes mellitus rat model. J Pharmacol Exp Ther 2000;293:351-9 (Pubitemid 30244081)
165. Hocher B, Schwarz A, Reinbacher D, et al. Effects of endothelin receptor antagonists on the progression of diabetic nephropathy. Nephron 2001;87:161-9 (Pubitemid 32215829)
166. Sasser JM, Sullivan JC, Hobbs JL, et al. Endothelin A receptor blockade reduces diabetic renal injury via an anti-inflammatory mechanism. J Am Soc Nephrol 2007;18:143-54 (Pubitemid 46053429)
167. Mann JF, Green D, Jamerson K, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 2010;21:655-64
168. Wenzel RR, Littke T, Kuranoff S, et al. Avosentan reduces albumin excretion in diabetics with macroalbuminuria. J Am Soc Nephrol 2009;20:655-64
169. Hernandez Prada JA, Ferreira AJ, Katovich MJ, et al. Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension 2008;51:1312-17 (Pubitemid 351555943)