Targeting inflammation in diabetic kidney disease: early clinical trials

References

• GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2015;385(9963):117–171. [Pubmed: 25530442].
   PubMed Web of Science ®Google Scholar
• Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2015;386(9995):743–800. [Pubmed: 26063472].
   PubMed Web of Science ®Google Scholar
• Murray CJ, Barber RM, Foreman KJ, et al. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. Lancet. 2015;386(10009):2145–2191. [Pubmed: 26321261].
   PubMed Web of Science ®Google Scholar
• Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med. 2015;373(18):1720–1732. [Pubmed: 26510021].
   PubMed Web of Science ®Google Scholar
• Fernandez-Fernandez B, Ortiz A, Gomez-Guerrero C, et al. Therapeutic approaches to diabetic nephropathy–beyond the RAS. Nat Rev Nephrol. 2014;10(6):325–346. [Pubmed: 24802062].
   PubMed Web of Science ®Google Scholar
• Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1–150.
   Web of Science ®Google Scholar
• Perez-Gomez MV, Sanchez-Nino MD, Sanz AB, et al. Horizon 2020 in diabetic kidney disease: the clinical trial pipeline for add-on therapies on top of renin angiotensin system blockade. J Clin Med. 2015;4(6):1325–1347. [Pubmed: 26239562].
   PubMed Web of Science ®Google Scholar
• Moreno JA, Izquierdo MC, Sanchez-Nino MD, et al. The inflammatory cytokines TWEAK and TNFalpha reduce renal klotho expression through NFkappaB. J Am Soc Nephrol. 2011;22(7):1315–1325. [Pubmed: 21719790].
   PubMed Web of Science ®Google Scholar
• Poveda J, Sanz AB, Rayego-Mateos S, et al. NFkappaBiz protein downregulation in acute kidney injury: modulation of inflammation and survival in tubular cells. Biochim Biophys Acta. 2016;1862(4):635–646. [Pubmed: 26776679]
   PubMed Web of Science ®Google Scholar
• Ruiz-Andres O, Suarez-Alvarez B, Sanchez-Ramos C, et al. The inflammatory cytokine TWEAK decreases PGC-1alpha expression and mitochondrial function in acute kidney injury. Kidney Int. 2015;89(2):399–410. [Pubmed: 26535995]
   Web of Science ®Google Scholar
• Sanchez-Nino MD, Sanz AB, Ortiz A. Klotho to treat kidney fibrosis. J Am Soc Nephrol. 2013;24(5):687–689. [Pubmed: 23599385].
   PubMed Web of Science ®Google Scholar
• De Boer IH, Rue TC, Cleary PA, et al. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the diabetes control and complications trial/epidemiology of diabetes interventions and complications cohort. Arch Intern Med. 2011;171(5):412–420. [Pubmed: 21403038].
   PubMed Web of Science ®Google Scholar
• Ortiz A, Fernandez-Fernandez B. Humble kidneys predict mighty heart troubles. Lancet Diabetes Endocrinol. 2015;3(7):489–491. [Pubmed: 26028595].
   PubMed Web of Science ®Google Scholar
• Sanchez-Nino MD, Fernandez-Fernandez B, Perez-Gomez MV, et al. Albumin-induced apoptosis of tubular cells is modulated by BASP1. Cell Death Dis. 2015;6:e1644. [Pubmed: 25675304].
   PubMed Web of Science ®Google Scholar
• Vallon V. The proximal tubule in the pathophysiology of the diabetic kidney. Am J Physiol Regul Integr Comp Physiol. 2011;300(5):R1009–R1022. [Pubmed: 21228342].
   PubMed Web of Science ®Google Scholar
• Blasi ER, Rocha R, Rudolph AE, et al. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int. 2003;63(5):1791–1800. [Pubmed: 12675855].
   PubMed Web of Science ®Google Scholar
• Ekinci EI, Jerums G, Skene A, et al. Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Diabetes Care. 2013;36(11):3620–3626. [Pubmed: 23835690].
   PubMed Web of Science ®Google Scholar
• Kramer HJ, Nguyen QD, Curhan G, et al. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA. 2003;289(24):3273–3277. [Pubmed: 12824208].
   PubMed Web of Science ®Google Scholar
• Sanchez-Nino MD, Poveda J, Sanz AB, et al. 3,4-DGE is cytotoxic and decreases HSP27/HSPB1 in podocytes. Arch Toxicol. 2014;88(3):597–608. [Pubmed: 24337777].
   PubMed Web of Science ®Google Scholar
• Justo P, Sanz AB, Egido J, et al. A. 3,4-Dideoxyglucosone-3-ene induces apoptosis in renal tubular epithelial cells. Diabetes. 2005;54(8):2424–2429. [Pubmed: 16046310].
   PubMed Web of Science ®Google Scholar
• Sanchez-Nino MD, Sanz AB, Lorz C, et al. BASP1 promotes apoptosis in diabetic nephropathy. J Am Soc Nephrol. 2010;21(4):610–621. [Pubmed: 20110383].
   PubMed Web of Science ®Google Scholar
• Ruggenenti P, Perticucci E, Cravedi P, et al. Role of remission clinics in the longitudinal treatment of CKD. J Am Soc Nephrol. 2008;19(6):1213–1224. [Pubmed: 18354029].
   PubMed Web of Science ®Google Scholar
• Esteras R, Perez-Gomez MV, Rodriguez-Osorio L, et al. Combination use of medicines from two classes of renin-angiotensin system blocking agents: risk of hyperkalemia, hypotension, and impaired renal function. Ther Adv Drug Saf. 2015;6(4):166–176. [Pubmed: 26301070].
   PubMed Web of Science ®Google Scholar
• American Diabetes Association. Standards of medical care in diabetes–2014. Diabetes Care. 2014;37 (Suppl 1):S14–S80. [Pubmed: 24357209].
   PubMedGoogle Scholar
• Gentile G, Remuzzi G, Ruggenenti P. Dual renin-angiotensin system blockade for nephroprotection: still under scrutiny. Nephron. 2015;129(1):39–41. [Pubmed: 25531311].
   PubMed Web of Science ®Google Scholar
• 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: 11565517].
   PubMed Web of Science ®Google Scholar
• Ortiz A, Sanchez-Nino MD, Izquierdo MC, et al. Translational value of animal models of kidney failure. Eur J Pharmacol. 2015;759:205–220. [Pubmed: 25814248].
   PubMed Web of Science ®Google Scholar
• Sanchez-Nino MD, Bozic M, Cordoba-Lanus E, et al. Beyond proteinuria: VDR activation reduces renal inflammation in experimental diabetic nephropathy. Am J Physiol Renal Physiol. 2012;302(6):F647–F657. [Pubmed: 22169009].
   PubMed Web of Science ®Google Scholar
• Fernandez FB, Elewa U, Sanchez-Nino MD, et al. 2012 update on diabetic kidney disease: the expanding spectrum, novel pathogenic insights and recent clinical trials. Minerva Med. 2012;103(4):219–234. [Pubmed: 22805616].
   PubMed Web of Science ®Google Scholar
• Alicic RZ, Tuttle KR. Novel therapies for diabetic kidney disease. Adv Chronic Kidney Dis. 2014;21(2):121–133. [Pubmed: 24602462].
   PubMed Web of Science ®Google Scholar
• 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:26325557].
   PubMed Web of Science ®Google Scholar
• Morgado-Pascual JL, Rayego-Mateos S, Valdivielso JM, et al. Paricalcitol inhibits aldosterone-induced proinflammatory factors by modulating epidermal growth factor receptor pathway in cultured tubular epithelial cells. Biomed Res Int. 2015;2015:783538. [Pubmed: 26064952].
   PubMed Web of Science ®Google Scholar
• 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(9):2850–2865. [Pubmed: 20525641].
   PubMed Web of Science ®Google Scholar
• 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. [Pubmed: 26378978].
   PubMed Web of Science ®Google Scholar
• Wanner C, Lachin JM, Fitchett DH, et al. Empagliflozin and cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease. J Am Soc Nephrol. 2015;26:B1, abstract.
   Web of Science ®Google Scholar
• Panchapakesan U, Pegg K, Gross S, et al. Effects of SGLT2 inhibition in human kidney proximal tubular cells–renoprotection in diabetic nephropathy? PLoS One. 2013;8(2):e54442. [Pubmed: 23390498].
   PubMed Web of Science ®Google Scholar
• Lim AK, Tesch GH. Inflammation in diabetic nephropathy. Mediators Inflamm. 2012;2012:146154. [Pubmed: 22969168].
   PubMed Web of Science ®Google Scholar
• Navarro-Gonzalez JF, Mora-Fernandez C, Muros De FM, et al. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7(6):327–340. [Pubmed: 21537349].
   PubMed Web of Science ®Google Scholar
• Reidy K, Kang HM, Hostetter T, et al. Molecular mechanisms of diabetic kidney disease. J Clin Invest. 2014;124(6):2333–2340. [Pubmed: 24892707].
   PubMed Web of Science ®Google Scholar
• Wada J, Makino H. Innate immunity in diabetes and diabetic nephropathy. Nat Rev Nephrol. 2016;12(1):13–26. [Pubmed: 26568190].
   PubMed Web of Science ®Google Scholar
• Gomez-Chiarri M, Ortiz A, Seron D, et al. The intercrine superfamily and renal disease. Kidney Int Suppl. 1993;39:S81–S85. [Pubmed: 8468931].
   PubMedGoogle Scholar
• Moreno JA, Moreno S, Rubio-Navarro A, et al. Role of chemokines in proteinuric kidney disorders. Expert Rev Mol Med. 2014;16:e3. [Pubmed: 24534600].
   PubMed Web of Science ®Google Scholar
• Moreno JA, Moreno S, Rubio-Navarro A, et al. Targeting chemokines in proteinuria-induced renal disease. Expert Opin Ther Targets. 2012;16(8):833–845. [Pubmed: 22793382].
   PubMed Web of Science ®Google Scholar
• Verhave JC, Bouchard J, Goupil R, et al. Clinical value of inflammatory urinary biomarkers in overt diabetic nephropathy: a prospective study. Diabetes Res Clin Pract. 2013;101(3):333–340. [Pubmed: 23880038].
   PubMed Web of Science ®Google Scholar
• Sanchez-Nino MD, Sanz AB, Ihalmo P, et al. The MIF receptor CD74 in diabetic podocyte injury. J Am Soc Nephrol. 2009;20(2):353–362. [Pubmed: 18842989].
   PubMed Web of Science ®Google Scholar
• Ortiz A, Bustos C, Alonso J, et al. Involvement of tumor necrosis factor-alpha in the pathogenesis of experimental and human glomerulonephritis. Adv Nephrol Necker Hosp. 1995;24:53–77. [Pubmed: 7572422].
   PubMedGoogle Scholar
• Sanz AB, Izquierdo MC, Sanchez-Nino MD, et al. TWEAK and the progression of renal disease: clinical translation. Nephrol Dial Transplant. 2014;29 Suppl 1:i54–i62. [Pubmed: 24493870].
   PubMed Web of Science ®Google Scholar
• Sayyed SG, Ryu M, Kulkarni OP, et al. An orally active chemokine receptor CCR2 antagonist prevents glomerulosclerosis and renal failure in type 2 diabetes. Kidney Int. 2011;80(1):68–78. [Pubmed: 21508925].
   PubMed Web of Science ®Google Scholar
• Sullivan T, Miao Z, Dairaghi DJ, et al. CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice. Am J Physiol Renal Physiol. 2013;305(9):F1288–F1297. [Pubmed: 23986513].
   PubMed Web of Science ®Google Scholar
• Sullivan TJ, Miao Z, Zhao BN, et al. Experimental evidence for the use of CCR2 antagonists in the treatment of type 2 diabetes. Metabolism. 2013;62(11):1623–1632. [Pubmed: 23953944].
   PubMed Web of Science ®Google Scholar
• De Zeeuw D, Bekker P, Henkel E, et al. The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial. Lancet Diabetes Endocrinol. 2015;3(9):687–696. [Pubmed: 26268910].
   PubMed Web of Science ®Google Scholar
• Seok SJ, Lee ES, Kim GT, et al. Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice. Nephrol Dial Transplant. 2013;28(7):1700–1710. [Pubmed: 23794669].
   PubMed Web of Science ®Google Scholar
• Haller HG, Baumann M, Eulberg D. CCL2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria. 51st ERA-EDTA Congress; 2014; Amsterdam. [cited 2016 May 23]. Available from: https://www.era-edta.org/press/4079_Haller_CCL2_Inhibition.pdf.
   Google Scholar
• Oberthur D, Achenbach J, Gabdulkhakov A, et al. Crystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2. Nat Commun. 2015;6:6923. [Pubmed: 25901662].
   PubMed Web of Science ®Google Scholar
• Gilbert J, Lekstrom-Himes J, Donaldson D, et al. Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region. Am J Cardiol. 2011;107(6):906–911. [Pubmed: 21247529].
   PubMed Web of Science ®Google Scholar
• Vergunst CE, Gerlag DM, Lopatinskaya L, et al. Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum. 2008;58(7):1931–1939. [Pubmed: 18576354].
   PubMed Web of Science ®Google Scholar
• Gale JD, Gilbert SA, Blumenthal SS, et al. Selective inhibition of CCR2/5 chemokine receptors reduces macroalbuminuria in subjects with type 2 diabetes and overt nephropathy. J Am Soc Nephrol. 2015;26:9A–10A, abstract.
   Google Scholar
• Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov. 2014;13(6):465–476. [Pubmed: 24854413].
   PubMed Web of Science ®Google Scholar
• Esser N, Paquot N, Scheen AJ. Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease. Expert Opin Investig Drugs. 2015;24(3):283–307. [Pubmed: 25345753].
   PubMed Web of Science ®Google Scholar
• Ortiz A, Egido J. Is there a role for specific anti-TNF strategies in glomerular diseases? Nephrol Dial Transplant. 1995;10(3):309–311. [Pubmed: 7792022].
   PubMed Web of Science ®Google Scholar
• Gohda T, Niewczas MA, Ficociello LH, et al. Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes. J Am Soc Nephrol. 2012;23(3):516–524. [Pubmed: 22266664].
   PubMed Web of Science ®Google Scholar
• Sfikakis PP, Grigoropoulos V, Emfietzoglou I, et al. Infliximab for diabetic macular edema refractory to laser photocoagulation: a randomized, double-blind, placebo-controlled, crossover, 32-week study. Diabetes Care. 2010;33(7):1523–1528. [Pubmed: 20413522].
   PubMed Web of Science ®Google Scholar
• Wolkow PP, Niewczas MA, Perkins B, et al. Association of urinary inflammatory markers and renal decline in microalbuminuric type 1 diabetics. J Am Soc Nephrol. 2008;19(4):789–797. [Pubmed: 18256362].
   PubMed Web of Science ®Google Scholar
• Saraheimo M, Teppo AM, Forsblom C, et al. Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients. Diabetologia. 2003;46(10):1402–1407. [Pubmed: 12928771].
   PubMed Web of Science ®Google Scholar
• Ellingsgaard H, Hauselmann I, Schuler B, et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med. 2011;17(11):1481–1489. [Pubmed: 22037645].
   PubMed Web of Science ®Google Scholar
• Ellingsgaard H, Ehses JA, Hammar EB, et al. Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc Natl Acad Sci U S A. 2008;105(35):13163–13168. [Pubmed: 18719127].
   PubMed Web of Science ®Google Scholar
• Cavelti-Weder C, Babians-Brunner A, Keller C, et al. Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. Diabetes Care. 2012;35(8):1654–1662. [Pubmed: 22699287].
   PubMed Web of Science ®Google Scholar
• Larsen CM, Faulenbach M, Vaag A, et al. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care. 2009;32(9):1663–1668. [Pubmed: 19542207].
   PubMed Web of Science ®Google Scholar
• Moran A, Bundy B, Becker DJ, et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013;381(9881):1905–1915. [Pubmed: 23562090].
   PubMed Web of Science ®Google Scholar
• Blech M, Peter D, Fischer P, et al. One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1beta. J Mol Biol. 2013;425(1):94–111. [Pubmed: 23041424].
   PubMed Web of Science ®Google Scholar
• Issafras H, Corbin JA, Goldfine ID, et al. Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1beta antibody with differential receptor-modulating properties. J Pharmacol Exp Ther. 2014;348(1):202–215. [Pubmed: 24194526].
   PubMed Web of Science ®Google Scholar
• Beidler CB, Petrovan RJ, Conner EM, et al. Generation and activity of a humanized monoclonal antibody that selectively neutralizes the epidermal growth factor receptor ligands transforming growth factor-alpha and epiregulin. J Pharmacol Exp Ther. 2014;349(2):330–343. [Pubmed: 24518034].
   PubMed Web of Science ®Google Scholar
• Laouari D, Burtin M, Phelep A, et al. TGF-alpha mediates genetic susceptibility to chronic kidney disease. J Am Soc Nephrol. 2011;22(2):327–335. [Pubmed: 21183591].
   PubMed Web of Science ®Google Scholar
• Rayego-Mateos S, Morgado-Pascual JL, Sanz AB, et al. TWEAK transactivation of the epidermal growth factor receptor mediates renal inflammation. J Pathol. 2013;231(4):480–494. [Pubmed: 24037740].
   PubMed Web of Science ®Google Scholar
• Afsar B, Ortiz A, Covic A, et al. Phosphodiesterase type 5 inhibitors and kidney disease. Int Urol Nephrol. 2015;47(9):1521–1528. [Pubmed: 26242375].
   PubMed Web of Science ®Google Scholar
• Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013;11:CD002309. [Pubmed: 24190161].
   PubMed Web of Science ®Google Scholar
• Matera MG, Rogliani P, Calzetta L, et al. Phosphodiesterase inhibitors for chronic obstructive pulmonary disease: what does the future hold? Drugs. 2014;74(17):1983–1992. [Pubmed: 25300411].
   PubMed Web of Science ®Google Scholar
• Vollert S, Kaessner N, Heuser A, et al. The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice. Diabetologia. 2012;55(10):2779–2788. [Pubmed: 22790061].
   PubMed Web of Science ®Google Scholar
• Wouters EF, Bredenbroker D, Teichmann P, et al. Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012;97(9):E1720–E1725. [Pubmed: 22723325].
   PubMed Web of Science ®Google Scholar
• Tikoo K, Lodea S, Karpe PA, et al. Calorie restriction mimicking effects of roflumilast prevents diabetic nephropathy. Biochem Biophys Res Commun. 2014;450(4):1581–1586. [Pubmed: 25035926].
   PubMed Web of Science ®Google Scholar
• Zhong Y, Wu Y, Liu R, et al. Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure. Kidney Int. 2012;81(9):856–864. [Pubmed: 22258322].
   PubMed Web of Science ®Google Scholar
• Semmler J, Gebert U, Eisenhut T, et al. Xanthine derivatives: comparison between suppression of tumour necrosis factor-alpha production and inhibition of cAMP phosphodiesterase activity. Immunology. 1993;78(4):520–525. [Pubmed: 8388363].
   PubMed Web of Science ®Google Scholar
• Shan D, Wu HM, Yuan QY, et al. Pentoxifylline for diabetic kidney disease. Cochrane Database Syst Rev. 2012;2:CD006800. [Pubmed: 22336824].
   PubMed Web of Science ®Google Scholar
• Navarro-Gonzalez JF, Mora-Fernandez C, De FM M, et al. Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. J Am Soc Nephrol. 2015;26(1):220–229. [Pubmed: 24970885].
   PubMed Web of Science ®Google Scholar
• Tang X, Bridson G, Ke J, et al. Quantitative analyses of CTP-499 and five major metabolites by core-structure analysis. J Chromatogr B Analyt Technol Biomed Life Sci. 2014;963:1–9. [Pubmed: 24927417].
   PubMed Web of Science ®Google Scholar
• Sabounjian LA, Neutel J, Dao M, et al. A first in patient, multi-center, double-blind, 2-arm, placebo-controlled, randomized safety and tolerability study of a novel oral drug candidate, CTP-499, in chronic kidney disease. Clin Pharmacol Drug Dev. Forthcoming 2016. doi:10.1002/cpdd.241.
   PubMed Web of Science ®Google Scholar
• Singh B, Diamond SA, Pergola SE, et al. Effect of CTP-499 on renal function in patients with type 2 diabetes and kidney disease. Am J Kidney Dis. 2014;63:A1–A120.
   PubMed Web of Science ®Google Scholar
• Kawarazaki Y, Ichijo H, Naguro I. Apoptosis signal-regulating kinase 1 as a therapeutic target. Expert Opin Ther Targets. 2014;18(6):651–664. [Pubmed: 24660755].
   PubMed Web of Science ®Google Scholar
• Yamaguchi K, Takeda K, Kadowaki H, et al. Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic ss cell exhaustion. Biochim Biophys Acta. 2013;1830(6):3656–3663. [Pubmed: 23416061].
   PubMed Web of Science ®Google Scholar
• Wang F, Wu Y, Gu H, et al. Ask1 gene deletion blocks maternal diabetes-induced endoplasmic reticulum stress in the developing embryo by disrupting the unfolded protein response signalosome. Diabetes. 2015;64(3):973–988. [Pubmed: 25249581].
   PubMed Web of Science ®Google Scholar
• Yokoi T, Fukuo K, Yasuda O, et al. Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells. Diabetes. 2006;55(6):1660–1665. [Pubmed: 16731828].
   PubMed Web of Science ®Google Scholar
• Lin JH, Zhang JJ, Lin SL, et al. Design of a phase 2 clinical trial of an ASK1 inhibitor, GS-4997, in patients with diabetic kidney disease. Nephron. 2015;129(1):29–33. [Pubmed: 25531162].
   PubMed Web of Science ®Google Scholar
• Berthier CC, Zhang H, Schin M, et al. Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes. 2009;58(2):469–477. [Pubmed: 19017763].
   PubMed Web of Science ®Google Scholar
• Fernandez-Sanchez R, Berzal S, Sanchez-Nino MD, et al. AG490 promotes HIF-1alpha accumulation by inhibiting its hydroxylation. Curr Med Chem. 2012;19(23):4014–4023. [Pubmed: 22709000].
   PubMed Web of Science ®Google Scholar
• Goncalves S, Fernandez-Sanchez R, Sanchez-Nino MD, et al. Tyrphostins as potential therapeutic agents for acute kidney injury. Curr Med Chem. 2010;17(10):974–986. [Pubmed: 20156166].
   PubMed Web of Science ®Google Scholar
• Ortiz-Munoz G, Lopez-Parra V, Lopez-Franco O, et al. Suppressors of cytokine signaling abrogate diabetic nephropathy. J Am Soc Nephrol. 2010;21(5):763–772. [Pubmed: 20185635].
   PubMed Web of Science ®Google Scholar
• Brosius FC, Tuttle KR, Adler SG, et al. Baricitinib in diabetic kidney disease: biomarker analysis from a phase 2, randomized, double-blind, placebo-controlled study. J Am Soc Nephrol. 2015;26:10A, abstract.
   Google Scholar
• Poveda J, Tabara LC, Fernandez-Fernandez B, et al. TWEAK/Fn14 and non-canonical NF-kappaB signaling in kidney disease. Front Immunol. 2013;4:447. [Pubmed: 24339827].
   PubMed Web of Science ®Google Scholar
• Sanz AB, Sanchez-Nino MD, Ramos AM, et al. NF-kappaB in renal inflammation. J Am Soc Nephrol. 2010;21(8):1254–1262. [Pubmed: 20651166].
   PubMed Web of Science ®Google Scholar
• Mora E, Guglielmotti A, Biondi G, et al. Bindarit: an anti-inflammatory small molecule that modulates the NFkappaB pathway. Cell Cycle. 2012;11(1):159–169. [Pubmed: 22189654].
   PubMed Web of Science ®Google Scholar
• Ble A, Mosca M, Di LG, et al. Antiproteinuric effect of chemokine C-C motif ligand 2 inhibition in subjects with acute proliferative lupus nephritis. Am J Nephrol. 2011;34(4):367–372. [Pubmed: 21876349].
   PubMed Web of Science ®Google Scholar
• Ruggenenti, P. Effects of MCP-1 inhibition by bindarit therapy in type 2 diabetes subjects with micro- or macro-albuminuria. J Am Soc Nephrol. 2010;21(Suppl. 1):44A, abstract.
   Google Scholar
• Colombo A, Basavarajaiah S, Limbruno U, et al. A double-blind randomised study to evaluate the efficacy and safety of bindarit in preventing coronary stent restenosis. EuroIntervention. 2015;11(8). [Epub ahead of print; Pubmed: 26690313].
   Google Scholar
• Yoon S, Gingras D, Bendayan M. Alterations of vitronectin and its receptor alpha(v) integrin in the rat renal glomerular wall during diabetes. Am J Kidney Dis. 2001;38(6):1298–1306. [Pubmed: 11728964].
   PubMed Web of Science ®Google Scholar
• Maile LA, Busby WH, Gollahon KA, et al. Blocking ligand occupancy of the alphaVbeta3 integrin inhibits the development of nephropathy in diabetic pigs. Endocrinology. 2014;155(12):4665–4675. [Pubmed: 25171599].
   PubMed Web of Science ®Google Scholar
• Yu PH, Wright S, Fan EH, et al. Physiological and pathological implications of semicarbazide-sensitive amine oxidase. Biochim Biophys Acta. 2003;1647(1–2):193–199. [Pubmed: 12686132].
   PubMed Web of Science ®Google Scholar
• Calvier L, Martinez-Martinez E, Miana M, et al. The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries. JACC Heart Fail. 2015;3(1):59–67. [Pubmed: 25458174].
   PubMed Web of Science ®Google Scholar
• Dang Z, MacKinnon A, Marson LP, et al. Tubular atrophy and interstitial fibrosis after renal transplantation is dependent on galectin-3. Transplantation. 2012;93(5):477–484. [Pubmed: 22306573].
   PubMed Web of Science ®Google Scholar
• Kikuchi Y, Kobayashi S, Hemmi N, et al. Galectin-3-positive cell infiltration in human diabetic nephropathy. Nephrol Dial Transplant. 2004;19(3):602–607. [Pubmed: 14767015].
   PubMed Web of Science ®Google Scholar
• Pergola PE, Block GA, Singh B, et al. Weekly doses of GCS-100, a galectin-3 antagonist, resulted in significant improvement in eGFR in patients with CKD in a randomized, phase 2 study. J Am Soc Nephrol. 2014;25:212A, abstract.
   Web of Science ®Google Scholar
• Pugliese G, Pricci F, Iacobini C, et al. Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice. FASEB J. 2001;15(13):2471–2479. [Pubmed: 11689472].
   PubMed Web of Science ®Google Scholar
• Gorin Y, Cavaglieri RC, Khazim K, et al. Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes. Am J Physiol Renal Physiol. 2015;308(11):F1276–F1287. [Pubmed: 25656366].
   PubMed Web of Science ®Google Scholar
• GKT137831 trial results. Available from: http://www.genkyotex.com/genkyotex/index.cfm/news-events/genkyotex-announces-top-line-results-of-phase-2-clinical-program/.
   Google Scholar
• Jha JC, Thallas-Bonke V, Banal C, et al. Podocyte-specific Nox4 deletion affords renoprotection in a mouse model of diabetic nephropathy. Diabetologia. 2016;59(2):379–389. [Pubmed: 26508318].
   PubMed Web of Science ®Google Scholar
• Holterman CE, Thibodeau JF, Kennedy CR. NADPH oxidase 5 and renal disease. Curr Opin Nephrol Hypertens. 2015;24(1):81–87. [Pubmed: 25415612].
   PubMed Web of Science ®Google Scholar
• Sanchez-Nino MD, Sanz AB, Sanchez-Lopez E, et al. HSP27/HSPB1 as an adaptive podocyte antiapoptotic protein activated by high glucose and angiotensin II. Lab Invest. 2012;92(1):32–45. [Pubmed: 21931298].
   PubMed Web of Science ®Google Scholar
• Lorz C, Benito-Martin A, Boucherot A, et al. The death ligand TRAIL in diabetic nephropathy. J Am Soc Nephrol. 2008;19(5):904–914. [Pubmed: 18287563].
   PubMed Web of Science ®Google Scholar
• Sanchez-Nino MD, Carpio D, Sanz AB, et al. Lyso-Gb3 activates Notch1 in human podocytes. Hum Mol Genet. 2015;24(20):5720–5732. [Pubmed: 26206887].
   PubMed Web of Science ®Google Scholar
• Khan IM, Perrard XY, Brunner G, et al. Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance. Int J Obes (Lond). 2015;39(11):1607–1618. [Pubmed: 26041698].
   PubMed Web of Science ®Google Scholar
• Mohamed R, Jayakumar C, Chen F, et al. Low-dose IL-17 therapy prevents and reverses diabetic nephropathy, metabolic syndrome, and associated organ fibrosis. J Am Soc Nephrol. 2015;27(3):745–765. [Pubmed: 26334030]
   PubMed Web of Science ®Google Scholar
• Sanchez-Nino MD, Ortiz A. HCV infection and miravirsen. N Engl J Med. 2013;369(9):877–878. [Pubmed: 23984740].
   PubMed Web of Science ®Google Scholar
• Bhatt K, Lanting LL, Jia Y, et al. Anti-inflammatory role of MicroRNA-146a in the pathogenesis of diabetic nephropathy. J Am Soc Nephrol. 2015. [Pubmed: 26647423].
   Web of Science ®Google Scholar
• 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–F325. [Pubmed: 24944269].
   PubMed Web of Science ®Google Scholar