2,540
Views
132
CrossRef citations to date
0
Altmetric
Review

Diabetic nephropathy: an insight into molecular mechanisms and emerging therapies

, &
Pages 579-591 | Received 18 Feb 2019, Accepted 23 May 2019, Published online: 03 Jun 2019

References

  • Collins AJ, Foley RN, Chavers B, et al. US renal data system 2013 annual data report. Am J Kidney Dis. 2014;63(1 Suppl):A7. PubMed PMID: 24360288.
  • Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861–869. PubMed PMID: 11565518.
  • Parving HH, Lehnert H, Bröchner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870–878. PubMed PMID: 11565519.
  • Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The collaborative study group. N Engl J Med. 1993;329(20):1456–1462. PubMed PMID: 8413456.
  • Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851–860. PubMed PMID: 11565517.
  • Ruggenenti P, Cravedi P, Remuzzi G. The RAAS in the pathogenesis and treatment of diabetic nephropathy. Nat Rev Nephrol. 2010;6(6):319–330. Epub 2010/05/04PubMed PMID: 20440277.
  • Mogensen CE, Neldam S, Tikkanen I, et al. 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. 2000;321(7274):1440–1444. PubMed PMID: 11110735; PubMed Central PMCID: PMCPMC27545.
  • Andersen NH, Poulsen PL, Knudsen ST, et al. Long-term dual blockade with candesartan and lisinopril in hypertensive patients with diabetes: the CALM II study. Diabetes Care. 2005;28(2):273–277. PubMed PMID: 15677778.
  • Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–1559. Epub 2008/03/31. PubMed PMID: 18378520.
  • Parving HH, Persson F, Lewis JB, et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358(23):2433–2446. PubMed PMID: 18525041.
  • Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204–2213. Epub 2012/11/03. PubMed PMID: 23121378.
  • Chrysostomou A, Becker G. Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease. PubMed PMID: 11565535 N Engl J Med. 2001;34512:925–926.
  • Ando K, Ohtsu H, Uchida S, et al. Anti-albuminuric effect of the aldosterone blocker eplerenone in non-diabetic hypertensive patients with albuminuria: a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(12):944–953. PubMed PMID: 25466242.
  • Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J. 2013;34(31):2453–2463. Epub 2013/ 05/27. PubMed PMID: 23713082; PubMed Central PMCID: PMCPMC3743070.
  • Kolkhof P, Borden SA. Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics. Mol Cell Endocrinol. 2012;350(2):310–317. Epub 2011/ 07/13. PubMed PMID: 21771637.
  • Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: A randomized clinical trial. Jama . 2015;314(9):884–894. PubMed PMID: 26325557.
  • Tikellis C, Johnston CI, Forbes JM, et al. Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy. Hypertension. 2003;41(3):392–397. Epub 2003/02/24. PubMed PMID: 12623933. .
  • Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411–415. PubMed PMID: 2451132.
  • Hocher B, Thöne-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(6):1380–1389. PubMed PMID: 9077548; PubMed Central PMCID: PMCPMC507954.
  • Shin SJ, Lee YJ, Tsai JH. The correlation of plasma and urine endothelin-1 with the severity of nephropathy in Chinese patients with type 2 diabetes. Scand J Clin Lab Invest. 1996;56(6): 571–576. PubMed PMID: 8903119.
  • Simonson MS, Ismail-Beigi F. Endothelin-1 increases collagen accumulation in renal mesangial cells by stimulating a chemokine and cytokine autocrine signaling loop. J Biol Chem. 2011;286(13):11003–11008. Epub 2010/ 12/17. PubMed PMID: 21169360; PubMed Central PMCID: PMCPMC3064155.
  • Krum H, Viskoper RJ, Lacourciere Y, et al. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan hypertension investigators. N Engl J Med. 1998;338(12):784–790. PubMed PMID: 9504938.
  • Boels MG, Avramut MC, Koudijs A. et al. Atrasentan reduces albuminuria by restoring the glomerular endothelial glycocalyx barrier in diabetic nephropathy. Diabetes. 2016; 65(8): 2429–2439. Epub 2016/ 03/25. PubMed PMID: 27207530.
  • Mann JF, Green D, Jamerson K, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010;21(3):527–535. Epub 2010/02/18. PubMed PMID: 20167702; PubMed Central PMCID: PMCPMC2831858. .
  • Kohan DE, Pritchett Y, Molitch M, et al. Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. J Am Soc Nephrol. 2011;22(4):763–772. Epub 2011/03/03. PubMed PMID: 21372210; PubMed Central PMCID: PMCPMC3065231. .
  • Smolander J, Vogt B, Maillard M, et al. Dose-dependent acute and sustained renal effects of the endothelin receptor antagonist avosentan in healthy subjects. Clin Pharmacol Ther. 2009;85(6):628–634. Epub 2009/03/11. PubMed PMID: 19279566. .
  • Opgenorth TJ, Adler AL, Calzadilla SV, et al. Pharmacological characterization of A-127722: an orally active and highly potent ETA-selective receptor antagonist. J Pharmacol Exp Ther. 1996;276(2):473–481. PubMed PMID: 8632312.
  • de Zeeuw D, Coll B, Andress D, et al. The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy. J Am Soc Nephrol. 2014;25(5):1083–1093. Epub 2014/04/10. PubMed PMID: 24722445; PubMed Central PMCID: PMCPMC4005314. .
  • Heerspink HJL, Parving H, Andress DL, et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet. In press. Epub 14 April 2019. 2019. DOI:10.1016/S0140-6736(19)30772-X.
  • Liu JJ, Lee T, DeFronzo RA. Why Do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans? PubMed PMID: 22923645; PubMed Central PMCID: PMCPMC3425428 Diabetes. 2012;619:2199–2204.
  • Rahmoune H, Thompson PW, Ward JM, et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54(12):3427–3434. PubMed PMID: 16306358.
  • Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262–274. PubMed PMID: 24026259.
  • Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in Type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128. Epub 2015/09/17. PubMed PMID: 26378978.
  • Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in Type 2 diabetes. N Engl J Med. 2017;377(21): 2099. PubMed PMID: 29166232.
  • Gembardt F, Bartaun C, Jarzebska N, et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol. 2014;307(3):F317–F25. Epub 2014/06/18. PubMed PMID: 24944269. .
  • Terami N, Ogawa D, Tachibana H, et al. Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS One. 2014;9(6):e100777. Epub 2014/06/24. PubMed PMID: 24960177; PubMed Central PMCID: PMCPMC4069074.
  • Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463–473. Epub 2013/03/28. PubMed PMID: 23464594; PubMed Central PMCID: PMCPMC3654568.
  • Thomas MC, Cherney DZI. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia. 2018;6110. 2098–2107. Epub 2018/08/22 PubMed PMID: 30132034
  • Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in Type 2 diabetes. N Engl J Med. 2016;375(4):323–334.
  • Heerspink HJ, Perkins BA, Fitchett DH, et al. Sodium glucose cotransporter 2 Inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134(10):752–772. Epub 2016/ 07/28. PubMed PMID: 27470878.
  • Rajasekeran H, Lytvyn Y, Bozovic A, et al. Urinary adenosine excretion in type 1 diabetes. Am J Physiol Renal Physiol. 2017;313(2):F184–F91. Epub 2017/04/05. PubMed PMID: 28381459.
  • Cherney D, Perkins BA, Lytvyn Y, et al. The effect of sodium/glucose cotransporter 2 (SGLT2) inhibition on the urinary proteome. PLoS One. 2017;12(10):e0186910. Epub 2017/ 10/30. PubMed PMID: 29084249; PubMed Central PMCID: PMCPMC5662219.
  • Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2018. Epub 2018/ 11/09. PubMed PMID: 30424892. DOI:10.1016/S0140-6736(18)32590-X.
  • Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in Type 2 diabetes and nephropathy. N Engl J Med. 2019.
  • Wells RG, Pajor AM, Kanai Y, et al. Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter. Am J Physiol. 1992;263(3 Pt 2):F459–F65. PubMed PMID: 1415574.
  • Lapuerta P, Zambrowicz B, Strumph P, et al. Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor. Diab Vasc Dis Res. 2015;12(2):101–110. PubMed PMID: 25690134.
  • Park CW, Kim HW, Ko SH, et al. Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice. J Am Soc Nephrol. 2007;18(4):1227–1238. Epub 2007/03/14. PubMed PMID: 17360951. .
  • Liu WJ, Xie SH, Liu YN, et al. Dipeptidyl peptidase IV inhibitor attenuates kidney injury in streptozotocin-induced diabetic rats. J Pharmacol Exp Ther. 2012;340(2):248–255. Epub 2011/ 10/24. doi: . PubMed PMID: 22025647.
  • Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24(1):275–286. PubMed PMID: 18053320.
  • Makdissi A, Ghanim H, Vora M, et al. Sitagliptin exerts an antinflammatory action. J Clin Endocrinol Metab. 2012;97(9):3333–3341. Epub 2012/06/28. PubMed PMID: 22745245; PubMed Central PMCID: PMCPMC3431580.
  • Lovshin JA, Rajasekeran H, Lytvyn Y, et al. Dipeptidyl Peptidase 4 inhibition stimulates distal tubular natriuresis and increases in circulating SDF-1α. Diabetes Care. 2017;40(8):1073–1081. Epub 2017/05/26. PubMed PMID: 28550195.
  • Tonneijck L, Smits MM, Muskiet MH, et al. Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 Receptor agonist liraglutide in overweight patients with Type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2016;39(11):2042–2050. Epub 2016/ 09/01. PubMed PMID: 27585605.
  • Takashima S, Fujita H, Fujishima H, et al. Stromal cell-derived factor-1 is upregulated by dipeptidyl peptidase-4 inhibition and has protective roles in progressive diabetic nephropathy. Kidney Int. 2016;90(4):783–796. Epub 2016/07/27. PubMed PMID: 27475229.
  • Alter ML, Ott IM, von Websky K, et al. DPP-4 inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy. Kidney Blood Press Res. 2012;36(1):119–130. Epub 2012/10/15. PubMed PMID: 23171828.
  • Gangadharan Komala M, Gross S, Zaky A, et al. Saxagliptin reduces renal tubulointerstitial inflammation, hypertrophy and fibrosis in diabetes. Nephrology (Carlton). 2016;21(5):423–431. PubMed PMID: 26375854.
  • Ishibashi Y, Matsui T, Maeda S, et al. Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cardiovasc Diabetol. 2013;12:125. PubMed PMID: 23984879; PubMed Central PMCID: PMCPMC3765742 Epub 2013/08/28.
  • Groop PH, Cooper ME, Perkovic V, et al. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care. 2013;36(11):3460–3468. Epub 2013/09/11. PubMed PMID: 24026560; PubMed Central PMCID: PMCPMC3816860.
  • Cooper ME, Perkovic V, McGill JB, et al. Kidney disease end points in a pooled analysis of individual patient-level data from a large clinical trials program of the Dipeptidyl Peptidase 4 inhibitor linagliptin in Type 2 Diabetes. Am J Kidney Dis. 2015;66(3):441–449. Epub 2015/05/07. PubMed PMID: 25960304.
  • Groop PH, Cooper ME, Perkovic V, et al. Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D trial. Diabetes Obes Metab. 2017 11;19:1610–1619. Epub 2017/ 07/31. PubMed PMID: 28636754; PubMed Central PMCID: PMCPMC5655723.
  • Rosenstock J, Perkovic V, Johansen OE, et al. Effect of Linagliptin vs Placebo on major cardiovascular events in adults with Type 2 Diabetes and High Cardiovascular and Renal Risk: the CARMELINA Randomized Clinical Trial. Jama. 2018. Epub 2018/ 11/09. PubMed PMID: 30418475. DOI:10.1001/jama.2018.18269.
  • Cornel JH, Bakris GL, Stevens SR, et al. Effect of sitagliptin on kidney function and respective cardiovascular outcomes in Type 2 diabetes: outcomes From TECOS. Diabetes Care. 2016;39(12):2304–2310. Epub 2016/ 10/14. PubMed PMID: 27742728.
  • Mosenzon O, Leibowitz G, Bhatt DL, et al. Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial. Diabetes Care. 2017;40(1):69–76. Epub 2016/ 10/17. doi: . PubMed PMID: 27797925.
  • Thomas MC. The potential and pitfalls of GLP-1 receptor agonists for renal protection in type 2 diabetes. Diabetes Metab. 2017;43 Suppl 1:2S20–2S7. PubMed PMID: 28431667.
  • Gutzwiller JP, Tschopp S, Bock A, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab. 2004;89(6):3055–3061. PubMed PMID: 15181098.
  • Tonneijck L, Smits MM, Muskiet MHA, et al. Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial. Diabetologia. 2016;59(7):1412–1421. Epub 2016/ 04/01. PubMed PMID: 27038451; PubMed Central PMCID: PMCPMC4901099.
  • Skov J, Dejgaard A, Frøkiær J, et al. Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin-angiotensin-aldosterone system in healthy men. J Clin Endocrinol Metab. 2013;98(4):E664–E71. Epub 2013/ 03/05. PubMed PMID: 23463656.
  • Skov J, Pedersen M, Holst JJ, et al. Short-term effects of liraglutide on kidney function and vasoactive hormones in type 2 diabetes: a randomized clinical trial. Diabetes Obes Metab. 2016;18(6):581–589. Epub 2016/ 03/22. PubMed PMID: 26910107.
  • Yu M, Moreno C, Hoagland KM, et al. Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats. J Hypertens. 2003;21(6):1125–1135. PubMed PMID: 12777949.
  • Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with Type 2 diabetes. N Engl J Med. 2016;375(19):1834–1844. Epub 2016/09/15. PubMed PMID: 27633186.
  • Mann JFE, Ørsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in Type 2 diabetes. N Engl J Med. 2017;377(9):839–848. PubMed PMID: 28854085.
  • Muskiet MHA, Tonneijck L, Huang Y, et al. Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018 11;6:859–869. Epub 2018/ 10/03. PubMed PMID: 30292589
  • Tuttle KR, McKinney TD, Davidson JA, et al. Effects of once-weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials. Diabetes Obes Metab. 2017;19(3):436–441. Epub 2016/ 11/24. doi: . PubMed PMID: 27766728; PubMed Central PMCID: PMCPMC5347883.
  • Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 2018;6(8):605–617. Epub 2018/ 06/14. PubMed PMID: 29910024.
  • Brownlee M. Biochemistry and molecular cell biology of diabetic complications. PubMed PMID: 11742414 Nature. 2001;4146865:813–820.
  • Forbes JM, Cooper ME. Mechanisms of diabetic complications. PubMed PMID: 23303908 Physiol Rev. 2013;931:137–188.
  • Badal SS, Danesh FR. New insights into molecular mechanisms of diabetic kidney disease. PubMed PMID: 24461730; PubMed Central PMCID: PMCPMC3932114 Am J Kidney Dis. 2014;632 Suppl 2:S63–S83.
  • Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404(6779):787–790. PubMed PMID: 10783895.
  • Sourris KC, Harcourt BE, Tang PH, et al. Ubiquinone (coenzyme Q10) prevents renal mitochondrial dysfunction in an experimental model of type 2 diabetes. Free Radic Biol Med. 2012;52(3):716–723. Epub 2011/ 11/21. PubMed PMID: 22172526.
  • Huang SS, Ding DF, Chen S, et al. Resveratrol protects podocytes against apoptosis via stimulation of autophagy in a mouse model of diabetic nephropathy. Sci Rep. 2017;7:45692. PubMed PMID: 28374806; PubMed Central PMCID: PMCPMC5379482 Epub 2017/04/04.
  • Lee EY, Lee MY, Hong SW, et al. Blockade of oxidative stress by vitamin C ameliorates albuminuria and renal sclerosis in experimental diabetic rats. Yonsei Med J. 2007;48(5):847–855. PubMed PMID: 17963344; PubMed Central PMCID: PMCPMC2628153.
  • Chacko BK, Reily C, Srivastava A, et al. Prevention of diabetic nephropathy in Ins2(+/)⁻(AkitaJ) mice by the mitochondria-targeted therapy MitoQ. Biochem J. 2010;432(1):9–19. PubMed PMID: 20825366; PubMed Central PMCID: PMCPMC2973231.
  • Pokrzywinski KL, Biel TG, Kryndushkin D, et al. Therapeutic targeting of the mitochondria initiates excessive superoxide production and mitochondrial depolarization causing decreased mtDNA integrity. PLoS One. 2016;11(12):e0168283. Epub 2016/12/28. PubMed PMID: 28030582; PubMed Central PMCID: PMCPMC5193408.
  • Etoh T, Inoguchi T, Kakimoto M, et al. Increased expression of NAD(P)H oxidase subunits, NOX4 and p22phox, in the kidney of streptozotocin-induced diabetic rats and its reversibity by interventive insulin treatment. Diabetologia. 2003;46(10):1428–1437.
  • Sedeek M, Callera G, Montezano A, et al. Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. Am J Physiol Renal Physiol. 2010;299(6):F1348–F58. PubMed PMID: 20630933.
  • Jha JC, Gray SP, Barit D, et al. Genetic targeting or pharmacologic inhibition of NADPH oxidase nox4 provides renoprotection in long-term diabetic nephropathy. J Am Soc Nephrol. 2014;25(6):1237–1254. Epub 2014/02/07. PubMed PMID: 24511132; PubMed Central PMCID: PMCPMC4033375.
  • Gray SP, Di Marco E, Okabe J, et al. NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis. Circulation. 2013;127(18):1888–1902. Epub 2013/04/05. PubMed PMID: 23564668.
  • Jha JC, Banal C, Okabe J, et al. NADPH Oxidase Nox5 accelerates renal injury in diabetic nephropathy. Diabetes. 2017;66(10):2691–2703. PubMed PMID: 28747378 Epub 2017/07/26.
  • Bierhaus A, Schiekofer S, Schwaninger M, et al. Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. Diabetes. 2001;50(12):2792–2808. PubMed PMID: 11723063.
  • Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997;33615:1066–1071. PubMed PMID: 9091804.
  • Moi P, Chan K, Asunis I, et al. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A. 1994;91(21):9926–9930. PubMed PMID: 7937919; PubMed Central PMCID: PMCPMC44930.
  • Rangan GK, Wang Y, Tay YC, et al. Inhibition of nuclear factor-kappaB activation reduces cortical tubulointerstitial injury in proteinuric rats. Kidney Int. 1999;56(1):118–134. PubMed PMID: 10411685.
  • de Zeeuw D, Akizawa T, Audhya P. et al., Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013;369(26). 2492–2503. PubMed PMID: 24206459; PubMed Central PMCID: PMCPMC4496027.
  • Chin MP, Wrolstad D, Bakris GL, et al. Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. J Card Fail. 2014;20(12):953–958. PubMed PMID: 25307295.
  • Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988;31820:1315–1321. PubMed PMID: 3283558.
  • 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(4):1123–1137. PubMed PMID: 12651605; PubMed Central PMCID: PMCPMC1851245.
  • Tan AL, Sourris KC, Harcourt BE, et al. Disparate effects on renal and oxidative parameters following RAGE deletion, AGE accumulation inhibition, or dietary AGE control in experimental diabetic nephropathy. Am J Physiol Renal Physiol. 2010;298(3):F763–F70. Epub 2009/ 12/16. doi: . PubMed PMID: 20015941.
  • Chen JL, Francis J. Pyridoxamine, advanced glycation inhibition, and diabetic nephropathy. J Am Soc Nephrol. 2012;23(1):6–8. Epub 2011/ 12/08. doi: . PubMed PMID: 22158434.
  • Rabbani N, Alam SS, Riaz S, et al. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study. Diabetologia. 2009;52(2):208–212. Epub 2008/ 12/05. PubMed PMID: 19057893.
  • Peppa M, Brem H, Cai W, et al. Prevention and reversal of diabetic nephropathy in db/db mice treated with alagebrium (ALT-711). Am J Nephrol. 2006;26(5):430–436. Epub 2006/ 09/13. PubMed PMID: 16974073.
  • 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(1):32–40.
  • Flyvbjerg A, Denner L, Schrijvers BF, et al. Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice. Diabetes. 2004;53(1):166–172. PubMed PMID: 14693711.
  • Galasko D, Bell J, Mancuso JY, et al. Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease. Neurology. 2014;82(17):1536–1542. Epub 2014/04/02. PubMed PMID: 24696507; PubMed Central PMCID: PMCPMC4011464.
  • Noh H, King GL, The role of protein kinase C activation in diabetic nephropathy. Kidney Int Suppl. 2007106:S49–S53. PubMed PMID: 17653211. DOI:10.1038/sj.ki.5002386.
  • Koya D, Jirousek MR, Lin YW, et al. 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. J Clin Invest. 1997;100(1):115–126. PubMed PMID: 9202063; PubMed Central PMCID: PMCPMC508171.
  • Ohshiro Y, Ma RC, Yasuda Y, et al. Reduction of diabetes-induced oxidative stress, fibrotic cytokine expression, and renal dysfunction in protein kinase Cbeta-null mice. Diabetes. 2006;55(11):3112–3120. PubMed PMID: 17065350.
  • Dvornik E, Simard-Duquesne N, Krami M, et al. Polyol accumulation in galactosemic and diabetic rats: control by an aldose reductase inhibitor. Science. 1973;182(4117):1146–1148. PubMed PMID: 4270794.
  • Brosius FC, Tuttle KR, Kretzler M. JAK inhibition in the treatment of diabetic kidney disease. Diabetologia. 2016;59(8):1624–1627. PubMed PMID: 27333885; PubMed Central PMCID: PMCPMC4942738. Epub 2016/06/22. DOI:10.1007/s00125-016-4021-5.
  • ElGamal H, Munusamy S. Aldose reductase as a drug target for treatment of diabetic nephropathy: promises and challenges. Protein Pept Lett. 2017;241:71–77. PubMed PMID: 27894247.
  • Passariello N, Sepe J, Marrazzo G, et al. Effect of aldose reductase inhibitor (tolrestat) on urinary albumin excretion rate and glomerular filtration rate in IDDM subjects with nephropathy. Diabetes Care. 1993;16(5):789–795. PubMed PMID: 8495620.
  • Foppiano M, Lombardo G. Worldwide pharmacovigilance systems and tolrestat withdrawal. Lancet. 1997;3499049:399–400. PubMed PMID: 9033472.
  • Iso K, Tada H, Kuboki K, et al. Long-term effect of epalrestat, an aldose reductase inhibitor, on the development of incipient diabetic nephropathy in Type 2 diabetic patients. J Diabetes Complications. 2001;15(5):241–244. PubMed PMID: 11522497.
  • Zhang H, Nair V, Saha J, et al. Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice. Kidney Int. 2017;92(4):909–921. Epub 2017/05/26. PubMed PMID: 28554737; PubMed Central PMCID: PMCPMC5610635.
  • Tuttle KR, Fc B, Adler SG, et al. JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial. Nephrol Dial Transplant. 2018;33(11):1950–1959. PubMed PMID: 29481660; PubMed Central PMCID: PMCPMC6212720.
  • Ding Y, Choi ME. Autophagy in diabetic nephropathy. J Endocrinol. 2015;224(1):R15–R30. Epub 2014/ 10/27. PubMed PMID: 25349246; PubMed Central PMCID: PMCPMC4238413.
  • Cuervo AM, Bergamini E, Brunk UT, et al. Autophagy and aging: the importance of maintaining “clean” cells. Autophagy. 2005;1(3):131–140. Epub 2005/10/13.PubMed PMID: 16874025
  • Peng KY, Horng LY, Sung HC, et al. Hepatocyte growth factor has a role in the amelioration of diabetic vascular complications via autophagic clearance of advanced glycation end products: dispo85E, an HGF inducer, as a potential botanical drug. Metabolism. 2011;60(6):888–892. Epub 2010/ 10/30. doi: . PubMed PMID: 21040934.
  • Yu L, McPhee CK, Zheng L, et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature. 2010;465(7300):942–946. Epub 2010/ 06/06. PubMed PMID: 20526321; PubMed Central PMCID: PMCPMC2920749.
  • Lieberthal W, Levine JS. The role of the mammalian target of rapamycin (mTOR) in renal disease. J Am Soc Nephrol. 2009;20(12):2493–2502. Epub 2009/ 10/29. doi: . PubMed PMID: 19875810.
  • Kajiwara M, Masuda SRole of mTOR inhibitors in kidney diseaseInt J Mol Sci201617(6). PubMed PMID: 27338360; PubMed Central PMCID: PMCPMC4926507. DOI:10.3390/ijms17060975.
  • Tesch GH, Ma FY, Han Y, et al. ASK1 Inhibitor halts progression of diabetic nephropathy in Nos3-deficient mice. Diabetes. 2015;64(11):3903–3913. Epub 2015/07/15. PubMed PMID: 26180085. .
  • Liles JT, Corkey BK, Notte GT, et al. ASK1 contributes to fibrosis and dysfunction in models of kidney disease. J Clin Invest. 2018;128(10):4485–4500. Epub 2018/07/19. PubMed PMID: 30024858; PubMed Central PMCID: PMCPMC6159961.
  • Koszegi S, Molnar A, Lenart L, et al. RAAS inhibitors directly reduce diabetes-induced renal fibrosis via growth factor inhibition. J Physiol. 2019;597(1):193–209. Epub 2018/ 11/02. PubMed PMID: 30324679; PubMed Central PMCID: PMCPMC6312411.
  • Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12(6):325–338. Epub 2016/ 04/25. PubMed PMID: 27108839.
  • Sato M, Muragaki Y, Saika S, et al. Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest. 2003;112(10):1486–1494. PubMed PMID: 14617750; PubMed Central PMCID: PMCPMC259132.
  • Voelker J, Berg PH, Sheetz M, et al. Anti–TGF-β1 antibody therapy in patients with diabetic nephropathy. J Am Soc Nephrol. 2017;28(3):953–962. Epub 2016/ 09/19. PubMed PMID: 27647855; PubMed Central PMCID: PMCPMC5328150.
  • Huynh P, Chai Z. Transforming growth factor β (TGFβ) and related molecules in chronic kidney disease (CKD). Clin Sci (Lond). 2019;133(2):287–313. Epub 2019/ 01/25. PubMed PMID: 30683713.
  • Chai Z, Wu T, Dai A, et al. Targeting the CDA1/CDA1BP1 Axis retards renal fibrosis in experimental diabetic nephropathy. Diabetes. 2019;68(2):395–408. Epub 2018/ 11/13. PubMed PMID: 30425061.
  • Wahab NA, Yevdokimova N, Weston BS, et al. Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. Biochem J. 2001;359(Pt 1):77–87. PubMed PMID: 11563971; PubMed Central PMCID: PMCPMC1222123.
  • Adler SG, Schwartz S, Williams ME, et al. Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. Clin J Am Soc Nephrol. 2010;5(8):1420–1428. Epub 2010/06/03. PubMed PMID: 20522536; PubMed Central PMCID: PMCPMC2924405. .
  • Hunt KJ, Jaffa MA, Garrett SM, et al. Levels of connective tissue growth factor (CTGF) predict development of kidney dysfunction in Type 2 diabetes-The VADT Study. Diabetes. 2018;67. DOI:10.2337/db18-528-P.
  • Kelly DJ, Zhang Y, Gow R, et al. Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model. J Am Soc Nephrol. 2004;15(10):2619–2629. PubMed PMID: 15466266.
  • Soma J, Sugawara T, Huang YD, et al. Tranilast slows the progression of advanced diabetic nephropathy. Nephron. 2002;92(3):693–698. PubMed PMID: 12372957.
  • Gilbert RE, Zhang Y, Williams SJ, et al. A purpose-synthesised anti-fibrotic agent attenuates experimental kidney diseases in the rat. PLoS One. 2012;7(10):e47160. Epub 2012/10/10. PubMed PMID: 23071743; PubMed Central PMCID: PMCPMC3468513. .
  • RamachandraRao SP, Zhu Y, Ravasi T, et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol. 2009;20(8):1765–1775. Epub 2009/07/02. PubMed PMID: 19578007; PubMed Central PMCID: PMCPMC2723978.
  • Sharma K, Ix JH, Mathew AV, et al. Pirfenidone for diabetic nephropathy. J Am Soc Nephrol. 2011;22(6):1144–1151. Epub 2011/04/21. PubMed PMID: 21511828; PubMed Central PMCID: PMCPMC3103734.
  • Reddy MA, Natarajan R. Epigenetics in diabetic kidney disease. J Am Soc Nephrol. 2011;22(12):2182–2185. PubMed PMID: 22021712; PubMed Central PMCID: PMCPMC3250203 Epub 2011/10/21.
  • Bansal A, Pinney SE. DNA methylation and its role in the pathogenesis of diabetes. PubMed PMID: 28401680; PubMed Central PMCID: PMCPMC5394941 Pediatr Diabetes. 2017;183:167–177.
  • El-Osta A, Brasacchio D, Yao D, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med. 2008;205(10):2409–2417. Epub 2008/09/22. PubMed PMID: 18809715; PubMed Central PMCID: PMCPMC2556800.
  • Sun G, Reddy MA, Yuan H, et al. Epigenetic histone methylation modulates fibrotic gene expression. J Am Soc Nephrol. 2010;21(12):2069–2080. Epub 2010/10/07. PubMed PMID: 20930066; PubMed Central PMCID: PMCPMC3014020.
  • Majumder S, Thieme K, Batchu SN, et al. Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease. J Clin Invest. 2018;128(1):483–499. Epub 2017/ 12/11. PubMed PMID: 29227285; PubMed Central PMCID: PMCPMC5749498.
  • Natarajan R, Putta S, Kato M. MicroRNAs and diabetic complications. J Cardiovasc Transl Res. 2012;5(4):413–422. PubMed PMID: 22552970; PubMed Central PMCID: PMCPMC3396726 Epub 2012/05/03.
  • McClelland AD, Kantharidis P. microRNA in the development of diabetic complications. PubMed PMID: 24059587 Clin Sci (Lond). 2014;1262:95–110.
  • Regazzi R. MicroRNAs as therapeutic targets for the treatment of diabetes mellitus and its complications. Expert Opin Ther Targets. 2018;22(2):153–160. Epub 2017/ 12/22. PubMed PMID: 29257914.
  • Brennan EP, Mohan M, McClelland A, et al. Lipoxins regulate the early growth Response-1 network and reverse diabetic kidney disease. J Am Soc Nephrol. 2018;29(5):1437–1448. Epub 2018/02/28. PubMed PMID: 29490938; PubMed Central PMCID: PMCPMC5967780.
  • Jandeleit-Dahm K, Cao Z, Cox AJ, et al. Role of hyperlipidemia in progressive renal disease: focus on diabetic nephropathy. Kidney Int. 1999;56:S31–S6.
  • Qin X, Dong H, Fang K, et al. The effect of statins on renal outcomes in patients with diabetic kidney disease: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2017;33(6). PubMed PMID: 28477396. doi:10.1002/dmrr.2901
  • Kamari Y, Bitzur R, Cohen H, et al. Should all diabetic patients be treated with a statin? Diabetes Care. 2009;32(suppl_2):S378–S83.
  • Lewis EJ, Lewis JB, Greene T, et al. Sulodexide for kidney protection in Type 2 diabetes patients with microalbuminuria: a randomized controlled trial. Am J Kidney Diseases. 2011;58(5):729–736.
  • Gambaro G, Venturini AP, Noonan DM, et al. Treatment with a glycosaminoglycan formulation ameliorates experimental diabetic nephropathy. Kidney Int. 1994;46(3):797–806.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.