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

Journal of Nephrology

Volumn 30, Issue 6, 2017, Pages 719-727

  Garibotto, Giacomo ^a   Carta, Annalisa ^a   Picciotto, Daniela ^a   Viazzi, Francesca ^a   Verzola, Daniela ^a  

^a UNIVERSITY OF GENOA   (Italy)

Author keywords

Albuminuria; Diabetic kidney disease; Inflammation; Toll like receptors

Indexed keywords

CASPASE RECRUITMENT DOMAIN PROTEIN 15; CRYOPYRIN; DIACYLGLYCEROL; ENDOTOXIN; GLUCOSE TRANSPORTER; HEMOGLOBIN A1C; INFLAMMASOME; INTERCELLULAR ADHESION MOLECULE 1; INTERLEUKIN 1BETA; INTERLEUKIN 6; MANGANESE SUPEROXIDE DISMUTASE; MONOCYTE CHEMOTACTIC PROTEIN 1; MYELOID DIFFERENTIATION FACTOR 88; PROTEIN KINASE C; PROTEIN SERINE THREONINE KINASE; SUPPRESSOR OF CYTOKINE SIGNALING 3; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 4; TUMOR NECROSIS FACTOR; GLUCOSE;

ALBUMINURIA; CLINICAL PRACTICE; DIABETIC NEPHROPATHY; DISEASE COURSE; ENDOPLASMIC RETICULUM STRESS; ESTIMATED GLOMERULAR FILTRATION RATE; FAT INTAKE; FATTY ACID BLOOD LEVEL; GASTROINTESTINAL TRACT; GENE EXPRESSION; HUMAN; IMMUNE RESPONSE; IMMUNOHISTOCHEMISTRY; INNATE IMMUNITY; INSULIN RESISTANCE; INTESTINE FLORA; KIDNEY INJURY; KIDNEY TUBULE ABSORPTION; METABOLIC SYNDROME X; MRNA EXPRESSION ASSAY; NEPHRITIS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PROTEIN DEGRADATION; PROTEIN EXPRESSION; REVIEW; ANIMAL; COMPLICATION; IMMUNOLOGY; INFLAMMATION; KIDNEY; METABOLISM; PATHOLOGY; PHYSIOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; DIABETIC NEPHROPATHIES; ENDOTOXINS; GLUCOSE; HUMANS; IMMUNITY, INNATE; INFLAMMATION; KIDNEY; OBESITY; SIGNAL TRANSDUCTION; TOLL-LIKE RECEPTOR 4;

EID: 85035206928     PISSN: 11218428     EISSN: 17246059     Source Type: Journal    
DOI: 10.1007/s40620-017-0432-8     Document Type: Review

References (94)

1. Navarro-González JF, Mora-Fernández CJ (2008) The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol 19(3):433–442
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
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
4. Wada J, Makino H (2016) Innate immunity in diabetes and diabetic nephropathy. Nat Rev Nephrol 12(1):13–26
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
23. Dasu M, Devaraj S (2008) High glucose induces toll-like receptor expression in human monocytes: mechanism of activation. Diabetes 57:3090–3098
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
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
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
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
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
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
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
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
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
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
35. Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176
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
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
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
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
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
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
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
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
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
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
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
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
48. Jialal I, Pahwa R (2015) The evolving role of toll-like receptors in diabetic vascular complications. J Diabetes Complications 29(5):617–620
49. Stone KE, Chiquette E, Chilton RJ (2007) Diabetic endovascular disease: role of coronary artery revascularization. Am J Cardiol 99:105B–112B
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
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
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
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
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
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
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
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
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
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
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
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
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
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
64. Anders HJ, Schlöndorff D (2007) Toll-like receptors: emerging concepts in kidney disease. Curr Opin Nephrol Hypertens 16:177–183
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
88. INK4A and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int 65:510–520
89. Tessari P (2015) Nitric oxide in the normal kidney and in patients with diabetic nephropathy. J Nephrol 28:257–268
90. Glassock RJ, Denic A, Rule A (2017) The conundrums of chronic kidney disease and aging. J Nephrol 30:477–483
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
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
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
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