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Toll-like receptor-4 signaling mediates inflammation and tissue injury in diabetic nephropathy

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Abstract

Toll-like receptors (TLRs) are a class of receptors of the innate immune system which detect pathogen-associated and danger-associated molecular patterns in order to initiate an inflammatory response. TLR2 and TLR4 downward signaling causes the production of proinflammatory cytokines that can induce insulin resistance and cardiovascular damage in obesity and type 2 diabetes mellitus. In diabetic nephropathy, TLR4, nucleotide-binding oligomerization domain-containing protein 2 (NOD2), and NLRP3 inflammasome are involved in the production and persistence of inflammation. The activation of TLRs stimulates the expression of several inflammatory cytokines and chemokines such as CCL2 and tumor necrosis factor (TNF)-α, which are associated with the progression of diabetic nephropathy. Different inflammatory mechanisms seem to take place in the early and late stages of diabetic kidney disease, with activation of the innate immunity response and enhanced chemiotactic effects in native kidney cells at an early stage, followed by tubulointerstitial monocyte infiltration at a more advanced disease state. Overall, available data indicate that the upregulated TLR4 response in the kidney translates the metabolic alterations of diabetes into kidney damage.

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References

  1. Navarro-González JF, Mora-Fernández CJ (2008) The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol 19(3):433–442

    Article  PubMed  Google Scholar 

  2. Furuta T, Saito T, Ootaka T, Soma J, Obara K, Abe K, Yoshinaga K (1993) The role of macrophages in diabetic glomerulosclerosis. Am J Kidney Dis 21(5):480–485

    Article  CAS  PubMed  Google Scholar 

  3. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11(5):373–84

    Article  CAS  PubMed  Google Scholar 

  4. Wada J, Makino H (2016) Innate immunity in diabetes and diabetic nephropathy. Nat Rev Nephrol 12(1):13–26

    Article  CAS  PubMed  Google Scholar 

  5. Leemans JC, Stokman G, Claessen N, Rouschop KM, Teske GJ, Kirschning CJ, Akira S, van der Poll T, Weening JJ, Florquin S (2005) Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J Clin Invest 115(10):2894–2903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Den Dekker WK, Cheng C, Pasterkamp G, Duckers HJ (2010) Toll like receptor 4 in atherosclerosis and plaque destabilization. Atherosclerosis 209(2):314–320

    Article  CAS  PubMed  Google Scholar 

  7. Fric J, Zelante T, Wong AY, Mertes A, Yu HB, Ricciardi-Castagnoli P (2012) NFAT control of innate immunity. Blood 16(7):1380–1389

    Article  Google Scholar 

  8. Osborn O, Olefsky JM (2012) The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 6 18(3):363–374

    Article  CAS  PubMed  Google Scholar 

  9. Thameem F, Puppala S, Farook VS, Kasinath BS, Blangero J, Duggirala R, Abboud HE (2016) Genetic variants in toll-Like receptor 4 gene and their association analysis with estimated glomerular filtration rate in mexican american families. Cardiorenal Med 6(4):301–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Velloso LA, Folli F, Saad MJ (2015) TLR4 at the crossroads of nutrients, gut microbiota, and metabolic inflammation. Endocr Rev 36(3):245–271

    Article  CAS  PubMed  Google Scholar 

  11. Devaraj S, Dasu MR, Park SH, Jialal I (2009) Increased levels of ligands of Toll-like receptors 2 and 4 in type 1 diabetes. Diabetologia 52:1665–1668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Creely SJ, McTernan PG, Kusminski CM, Fisher fM, Da Silva NF, Khanolkar M, Evans M, Harte AL, Kumar S (2007) Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab 292:E740–E747

    Article  CAS  PubMed  Google Scholar 

  13. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56(7):1761–1772

    Article  CAS  PubMed  Google Scholar 

  14. Di Baise JK, Zhang H, Crowell MD, Krajmalnik-Brown R, Decker GA, Rittmann BE (2008) Gut microbiota and its possible relationship with obesity. Mayo Clin Proc 83(4):460–469

    Article  Google Scholar 

  15. Mehta NN, McGillicuddy FC, Anderson PD, Hinkle CC, Shah R, Pruscino L, Tabita-Martinez J, Sellers KF, Rickels MR, Reilly MP (2010) Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes 59(1):172–181

    Article  CAS  PubMed  Google Scholar 

  16. Moreira AP, Alves RD, Teixeira TF, Macedo VS, De Oliveira LL, Costa NM, Bressan J, Do Carmo Gouveia Peluzio M, Mattes R, de Cássia Gonçalves Alfenas R (2015) Higher plasma lipopolysaccharide concentrations are associated with less favorable phenotype in overweight/obese men. Eur J Nutr. 54(8):1363–1370

    Article  CAS  PubMed  Google Scholar 

  17. Pussinen PJ, Havulinna AS, Lehto M, Sundvall J, Salomaa V (2011) Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care 34:392–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lassenius MI, Pietiläinen KH, Kaartinen K, Pussinen PJ, Syrjänen J, Forsblom C, Pörsti I, Rissanen A, Kaprio J, Mustonen J, Groop PH, Lehto M, FinnDiane Study Group (2011) Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Diabetes Care Aug;34(8):1809–1815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Boutagy NE, McMillan RP, Frisard MI, Hulver MW (2016) Metabolic endotoxemia with obesity: Is it real and is it relevant?. Biochimie124:11–20

  20. Wang F, Zhang P, Jiang H, Cheng S (2012) Gut bacterial translocation contributes to microinflammation in experimental uremia. Dig Dis Sci 57(11):2856–2862

    Article  CAS  PubMed  Google Scholar 

  21. Apostolopoulos V, de Courten MP, Stojanovska L, Blatch GL, Tangalakis K, de Courten B (2016) The complex immunological and inflammatory network of adipose tissue in obesity. Mol Nutr Food Res 60(1):43–57

    Article  CAS  PubMed  Google Scholar 

  22. Yang M, Gan H, Shen Q, Tang W, Du X, Chen D (2012) Proinflammatory CD14 + CD16 + monocytes are associated with microinflammation in patients with type 2 diabetes mellitus and diabetic nephropathy uremia. Inflammation 35(1):388–396

    Article  CAS  PubMed  Google Scholar 

  23. Dasu M, Devaraj S (2008) High glucose induces toll-like receptor expression in human monocytes: mechanism of activation. Diabetes 57:3090–3098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dasu MR, Devaraj S, Park S, Jialal I (2010) Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care 33:861–868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N, Ohtsuka-Kowatari N, Kumagai K, Sakamoto K, Kobayashi M, Yamauchi T, Ueki K, Oishi Y, Nishimura S, Manabe I, Hashimoto H, Ohnishi Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Nagai R, Kadowaki T (2006) Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 8(36):26602–26614

    Article  Google Scholar 

  26. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116(6):1494–1505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 293:1673–1677

    Article  CAS  PubMed  Google Scholar 

  28. Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 21 420(6913):333–6002

    Article  CAS  PubMed  Google Scholar 

  29. Zhang J, Gao Z, Yin J, Quon MJ, Ye J (2008) S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-α signaling through IKK2. J Biol Chem 283:35375–35382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fan Y, Yu Y, Shi Y, Sun W, Xie M, Ge N, Mao R, Chang A, Xu G, Schneider MD, Zhang H, Fu S, Qin J, Yang J (2010) Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for tumor necrosis factor α- and interleukin-1β-induced IKK/NF-κB and JNK/AP-1 activation. J Biol Chem 285:5347–5360

    Article  CAS  PubMed  Google Scholar 

  31. Jager J, Gremeaux T, Cormont M, Le Marchand-Brustel Y, Tanti JF (2007) Interleukin-1β-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology 148:241–251

    Article  CAS  PubMed  Google Scholar 

  32. Boucher J1, Kleinridders A, Kahn CR (2014) Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol 1; 6

  33. Boden G, Chen X, Rosner J, Barton M (1995) Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes 44:1239–1242

    Article  CAS  PubMed  Google Scholar 

  34. Bajaj M, Suraamornkul S, Kashyap S, Cusi K, Mandarino L, DeFronzo RA (2004) Sustained reduction in plasma free fatty acid levels improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes. J Clin Endocrinol Metab 89:4649–4655

    Article  CAS  PubMed  Google Scholar 

  35. Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hwang D (2001) Modulation of the expression of cyclooxygenase-2 by fatty acids mediated through toll-like receptor 4-derived signaling pathways. FASEB J 15:2556–2564

    Article  CAS  PubMed  Google Scholar 

  37. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI (2001) Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 108:437–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–3025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Song MJ, Kim KH, Yoon JM, Kim JB (2006) Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes. Biochem Biophys Res Commun 346:739–745

    Article  CAS  PubMed  Google Scholar 

  40. Reyna SM, Ghosh S, Tantiwong P, Meka CS, Eagan P, Jenkinson CP, Cersosimo E, Defronzo RA, Coletta DK, Sriwijitkamol A, Musi N (2008) Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes 57(10):2595–2602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, Schenka AA, Araujo EP, Vassallo J, Curi R, Velloso LA, Saad MJ (2007) Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56:1986–1998

    Article  CAS  PubMed  Google Scholar 

  42. Radin MS, Sinha S, Bhatt BA, Dedousis N, O’Doherty RM (2008) Inhibition or deletion of the lipopolysaccharide receptor Toll-like receptor-4 confers partial protection against lipid-induced insulin resistance in rodent skeletal muscle. Diabetologia 51:336–346

    Article  CAS  PubMed  Google Scholar 

  43. Liang H, Hussey SE, Sanchez-Avila A, Tantiwong P, Musi N (2013) Effect of lipopolysaccharide on inflammation and insulin action in human muscle. PLoS One 21(5):e63983

    Article  Google Scholar 

  44. Sell H, Dietze-Schroeder D, Kaiser U, Eckel J (2006) Monocyte chemotactic protein-1 is a potential player in the negative cross-talk between adipose tissue and skeletal muscle. Endocrinology 147:2458–2467

    Article  CAS  PubMed  Google Scholar 

  45. Nieto-Vazquez I, Fernandez-Veledo S, de Alvaro C, Lorenzo M (2008) Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle. Diabetes 57:3211–3221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Verzola D, Bonanni A, Sofia A, Montecucco F, D’Amato E, Cademartori V, Parodi EL, Viazzi F, Venturelli C, Brunori G, Garibotto G (2017) Toll-like receptor 4 signalling mediates inflammation in skeletal muscle of patients with chronic kidney disease. J Cachexia Sarcopenia Muscle 8(1):131–144

    Article  PubMed  Google Scholar 

  47. Roberts RL, Van Rij AM, Phillips LV, Young S, McCormick SP, Merriman TR, Jones GT (2011) Interaction of the inflammasome genes CARD8 and NLRP3 in abdominal aortic aneurysms. Atherosclerosis 218(1):123–126

    Article  CAS  PubMed  Google Scholar 

  48. Jialal I, Pahwa R (2015) The evolving role of toll-like receptors in diabetic vascular complications. J Diabetes Complications 29(5):617–620

    Article  PubMed  Google Scholar 

  49. Stone KE, Chiquette E, Chilton RJ (2007) Diabetic endovascular disease: role of coronary artery revascularization. Am J Cardiol 99:105B–112B

    Article  PubMed  Google Scholar 

  50. Zhang LL, Gao CY, Fang CQ, Wang YJ, Gao D, Yao GE, Xiang J, Wang JZ, Li JC (2011) PPARγ attenuates intimal hyperplasia by inhibiting TLR4-mediated inflammation in vascular smooth muscle cells. Cardiovasc Res 1 92(3):484–93

    Article  CAS  PubMed  Google Scholar 

  51. Pi Y, Zhang LL, Li BH, Guo L, Cao XJ, Gao CY, Li JC (2013) Inhibition of reactive oxygen species generation attenuates TLR4-mediated proinflammatory and proliferative phenotype of vascular smooth muscle cells. Lab Invest 93(8):880–887

    Article  CAS  PubMed  Google Scholar 

  52. Carrillo-Sepulveda MA, Spitler K, Pandey D, Berkowitz DE, Matsumoto T (2015) Inhibition of TLR4 attenuates vascular dysfunction and oxidative stress in diabetic rats. J Mol Med (Berl) 93(12):1341–1354

    Article  CAS  Google Scholar 

  53. Mudaliar H, Pollock C, Ma J, Wu H, Chadban S, Panchapakesan U (2014) The role of TLR2 and 4-mediated inflammatory pathways in endothelial cells exposed to high glucose. PLoS One 10(10):e108844

    Article  Google Scholar 

  54. Pahwa R, Nallasamy P, Jialal I (2016) Toll-like receptors 2 and 4 mediate hyperglycemia induced macrovascular aortic endothelial cell inflammation and perturbation of the endothelial glycocalyx. J Diabetes Complications 30(4):563–572

    Article  PubMed  Google Scholar 

  55. Lu Z, Zhang X, Li Y, Jin J, Huang Y (2013) TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice. J Endocrinol 216:61–71

    Article  CAS  PubMed  Google Scholar 

  56. Dong B, Qi D, Yang L, Huang Y, Xiao X, Tai N, Wen L, Wong FS (2012) TLR4 regulates cardiac lipid accumulation and diabetic heart disease in the nonobese diabetic mouse model of type 1 diabetes. Am J Physiol Heart Circ Physiol 15(6):H732-42

    Google Scholar 

  57. Zhang Y, Peng T, Zhu H, Zheng X, Zhang X, Jiang N, Cheng X, Lai X, Shunnar A, Singh M, Riordan N, Bogin V, Tong N, Min WP (2010) Prevention of hyperglycemia-induced myocardial apoptosis by gene silencing of Toll-like receptor-4. J Transl Med 15:8:133

    Google Scholar 

  58. Buraczynska M, Zukowski P, Ksiazek K, Wacinski P, Dragan M (2016) The effect of Toll-like receptor 4 gene polymorphism on vascular complications in type 2 diabetes patients. Diabetes Res Clin Pract 116:7–13

    Article  CAS  PubMed  Google Scholar 

  59. Chow F, Ozols E, Nikolic-Paterson DJ, Atkins RC, Tesch GH (2004) Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney Int 65(1):116–128

    Article  CAS  PubMed  Google Scholar 

  60. Lin M, Yiu WH, Wu HJ, Chan LY, Leung JC, Au WS, Chan KW, Lai KN, Tang SC (2012) Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. J Am Soc Nephrol 23(1):86–102

    Article  CAS  PubMed  Google Scholar 

  61. Kuwabara T, Mori K, Mukoyama M, Kasahara M, Yokoi H, Saito Y, Ogawa Y, Imamaki H, Kawanishi T, Ishii A, Koga K, Mori KP, Kato Y, Sugawara A, Nakao K (2012) Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice. Diabetologia 55(8):2256–2266

    Article  CAS  PubMed  Google Scholar 

  62. Kaur H, Chien A, Jialal I (2012) Hyperglycemia induced Toll like receptor 4 Expression and Activity in Mouse Mesangial cells: Relevance to Diabetic Nephropathy. Am J Physiol Renal Physiol 303(8):F1145-115

    Article  Google Scholar 

  63. Mudaliar H, Pollock C, Komala MG, Chadban S, Wu H, Panchapakesan U (2013) The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules. Am J Physiol Renal Physiol 15(2):F143-54

    Google Scholar 

  64. Anders HJ, Schlöndorff D (2007) Toll-like receptors: emerging concepts in kidney disease. Curr Opin Nephrol Hypertens 16:177–183

    Article  CAS  PubMed  Google Scholar 

  65. Verzola D, Cappuccino L, D’Amato E, Villaggio B, Gianiorio F, Mij M, Simonato A, Viazzi F, Salvidio G, Garibotto G (2014) Enhanced glomerular Toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria. Kidney Int 86(6):1229–1243

    Article  CAS  PubMed  Google Scholar 

  66. Wu C, Lv C, Chen F, Ma X, Shao Y, Wang Q (2015) The function of miR-199a-5p/Klotho regulating TLR4/NF-κB p65/NGAL pathways in rat mesangial cells cultured with high glucose and the mechanism. Mol Cell Endocrinol 5:417:84–93

    Article  Google Scholar 

  67. Pirkko J, Pussinen PHD, Aki S, Havulinna MSC, Markku Lehto PHD, Jouko Sundvall MSC, Veikko Salomaa, MD (2011) Endotoxemia Is Associated With an Increased Risk of Incident Diabetes. Diabetes Care 2011 Feb; 34(2): 392–397

    Google Scholar 

  68. Nymark M, Pussinen PJ, Tuomainen AM, Forsblom C, Groop PH, Lehto M, FinnDiane Study Group (2009) Serum lipopolysaccharide activity is associated with the progression of kidney disease in finnish patients with type 1 diabetes. Diabetes Care 32(9):1689–1693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Saurus P, Kuusela S, Lehtonen E, Hyvönen ME, Ristola M, Fogarty CL, Tienari J, Lassenius MI, Forsblom C, Lehto M, Saleem MA, Groop PH, Holthöfer H, Lehtonen S (2015) Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway. Cell Death Dis 7 6:e1752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Steffes MW, Schmidt D, McCrery R, Basgen JM, International Diabetic Nephropathy Study Group (2001) Glomerular cell number in normal subjects and in type 1 diabetic patients. Kidney Int 59: 2104–2113

    Article  CAS  PubMed  Google Scholar 

  71. Verzola D, Gandolfo MT, Ferrario F, Rastaldi MP, Villaggio B, Gianiorio F, Giannoni M, Rimoldi L, Lauria F, Miji M, Deferrari G, Garibotto G (2007) Apoptosis in the kidneys of patients with type II diabetic nephropathy. Kidney Int 72:1262–1272

    Article  CAS  PubMed  Google Scholar 

  72. Meyer TW, Bennett PH, Nelson RG (1999) Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria. Diabetologia 42:1341–1344

    Article  CAS  PubMed  Google Scholar 

  73. Cha JJ, Hyun YY, Lee MH, Kim JE, Nam DH, Song HK, Kang YS, Lee JE, Kim HW, Han JY, Cha DR (2013) Renal protective effects of toll-like receptor 4 signaling blockade in type 2 diabetic mice. Endocrinology 154(6):2144–2155

    Article  CAS  PubMed  Google Scholar 

  74. Lin M, Yiu WH, Li RX, Wu HJ, Wong DW, Chan LY, Leung JC, Lai KN, Tang SC (2013) The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy. Kidney Int 83(5):887–900

    Article  CAS  PubMed  Google Scholar 

  75. Ma J, Chadban SJ, Zhao CY, Chen X, Kwan T, Panchapakesan U, Pollock CA, Wu H (2014) TLR4 activation promotes podocyte injury and interstitial fibrosis in diabetic nephropathy. PLoS One 19(5):e97985

    Article  Google Scholar 

  76. Jialal I, Major AM, Devaraj S (2014) Global Toll-like receptor 4 knockout results in decreased renal inflammation, fibrosis and podocytopathy. J Diabetes Complications 28(6):755–761

    Article  PubMed  Google Scholar 

  77. Peri F, Calabrese V (2014) Toll-like receptor 4 (TLR4) modulation by synthetic and natural compounds: an update. J Med Chem 8(9):3612–3622

    Article  Google Scholar 

  78. Leon CG, Tory R, Jia J, Sivak O, Wasan KM (2008) Discovery and development of toll-like receptor 4 (TLR4) antagonists: a new paradigm for treating sepsis and other diseases. Pharm Res 25:1751–1761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Sha T, Sunamoto M, Kitazaki T, Sato J, Ii M, Iizawa Y (2007) Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model. Eur J Pharmacol 571:231–239

    Article  CAS  PubMed  Google Scholar 

  80. Panchapakesan U, Pegg K, Gross S, Komala MG, Mudaliar H, Forbes J, Pollock C, Mather A (2013) Effects of SGLT2 inhibition in human kidney proximal tubular cells–renoprotection in diabetic nephropathy? PLoS One 8(2):e54442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Verzola D, Gandolfo MT, Gaetani G, Ferraris A, Mangerini R, Ferrario F, Villaggio B, Gianiorio F, Tosetti F, Weiss U, Traverso P, Mji M, Deferrari G, Garibotto G (2008) Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. Am J Physiol Renal Physiol 295(5):F1563–73

    Article  PubMed  Google Scholar 

  82. Tchkonia T, Zhu Y, Van Deursen J, Campisi J, Kirkland J (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123(3):966–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Verzola D, Bertolotto MB, Villaggio B, Ottonello L, Dallegri F, Frumento G, Berruti V, Gandolfo MT, Garibotto G, Deferrari G (2002) Taurine prevents apoptosis induced by high ambient glucose in human tubule renal cells. J Investig Med 50(6): 443–451

  84. Verzola D, Bertolotto MB, Villaggio B, Ottonello L, Dallegri F, Salvatore F, Berruti V, Gandolfo MT, Garibotto G, Deferrari G (2004) Oxidative stress mediates apoptotic changes induced by hyperglycemia in human tubular kidney cells. J Am Soc Nephrol 15(Suppl 1):S85-7

    PubMed  Google Scholar 

  85. Verzola D, Villaggio B, Procopio V, Gandolfo MT, Gianiorio F, Famà A, Tosetti F, Traverso P, Deferrari G, Garibotto G (2009) Androgen-mediated apoptosis of kidney tubule cells: role of c-jun amino terminal kinase. Biochem Biophys Res Comm 387:531–536, I

    Article  CAS  PubMed  Google Scholar 

  86. Satriano J, Mansoury H, Deng A, Sharma K, Vallon V, Blantz RC, Thomson SC (2010) Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes. Am J Physiol Cell Physiol 299(2):C374-380

    Article  PubMed  Google Scholar 

  87. Ding G, Franki N, Rapasi AA, Reddy K, Gibbons N, Pravin Singhal PC (2001) Tubular cell senescence and expression of TGF-b1 and p21WAF1/CIP1 in tubulointerstitial fibrosis of aging rats. Exp Mol Pathol 70:43–53

    Article  CAS  PubMed  Google Scholar 

  88. Melk A, Schmidt BM, Takeuchi O, Sawitzki B, Rayner DC, Halloran PF (2004) Expression of p16INK4A and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int 65:510–520

    Article  CAS  PubMed  Google Scholar 

  89. Tessari P (2015) Nitric oxide in the normal kidney and in patients with diabetic nephropathy. J Nephrol 28:257–268

    Article  CAS  PubMed  Google Scholar 

  90. Glassock RJ, Denic A, Rule A (2017) The conundrums of chronic kidney disease and aging. J Nephrol 30:477–483

    Article  PubMed  Google Scholar 

  91. DeFronzo RA, Davidson JA, Del PS (2012) The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab 14:5–14

    Article  CAS  PubMed  Google Scholar 

  92. Kojima N, Williams JM, Takahashi T, Miyata N, Roman RJ (2013) Effects of a new SGLT2 inhibitor, luseogliflozin, on diabetic nephropathy in T2DN rats. J Pharmacol Exp Ther 345:464–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kohan DE, Fioretto P, Johnsson K, Parikh S, Ptaszynska A, Ying L (2016) The effect of dapagliflozin on renal function in patients with type 2 diabetes. J Nephrol 29:391–400

    Article  CAS  PubMed  Google Scholar 

  94. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, Von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinmann B (2016) Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 375:323–334

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Thanks to Dr. Barbara Villaggio and to Dr Samantha Milanesi for revision and technical support.

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  1. Universita degli Studi di Genova, DIMI and IRCCS AOU San Martino IST, Genova, Italy

    Giacomo Garibotto, Annalisa Carta, Daniela Picciotto, Francesca Viazzi & Daniela Verzola

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  1. Giacomo Garibotto
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Correspondence to Giacomo Garibotto.

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Results of studies with human participants performed by the authors reviewed in this manuscript were approved by the Ethical Committee of the Department of Internal Medicine, Genoa University.

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Garibotto, G., Carta, A., Picciotto, D. et al. Toll-like receptor-4 signaling mediates inflammation and tissue injury in diabetic nephropathy. J Nephrol 30, 719–727 (2017). https://doi.org/10.1007/s40620-017-0432-8

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  • DOI: https://doi.org/10.1007/s40620-017-0432-8

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