title: Chelation of dietary iron prevents iron accumulation and macrophage infiltration in the type I diabetic kidney.
abstract: We previously reported that the functional deletion of p21, a cyclin-dependent kinase inhibitor, in mice attenuated renal cell senescence in streptozotocin (STZ)-induced type 1 diabetic mice. In the present study, we investigated the effect of iron chelation on renal cell senescence and inflammation in the type 1 diabetic kidney. STZ-treated mice showed increase in iron accumulation, tubular cell senescence and macrophage infiltration at week 28 in the kidney. Administering deferasirox, which removes only dietary iron, significantly attenuated iron accumulation in proximal tubules and the number of infiltrating F4/80-positive cells without effecting blood glucose, hematocrit or hemoglobin levels. In contrast however, deferasirox did not influence renal cell senescence. The lack of p21 decreased the renal tubular iron accumulation and did not change tubular cell senescence. Interestingly, the STZ-treated animals showed an increase in p16, another cyclin-dependent kinase inhibitor. The results suggest that type 1 diabetes increases renal tubular iron accumulation and macrophage infiltration through a p21-dependent mechanism, and that the chelation of dietary iron attenuates these responses.
authors.affiliation: Department of Pharmacology, Kagawa University, 1750-1 Miki, Kita, Kagawa, Japan; The Second Department of Internal Medicine, Kansai Medical University, Japan.
authors.forename: Tatsuyori
authors.initials: T
authors.lastname: Morita
authors.affiliation: Department of Pharmacology, Kagawa University, 1750-1 Miki, Kita, Kagawa, Japan. Electronic address: dnakano@med.kagawa-u.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakano
authors.affiliation: Department of Pharmacology, Kagawa University, 1750-1 Miki, Kita, Kagawa, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Kitada
authors.affiliation: Department of Endocrinology and Hypertension, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morimoto
authors.affiliation: Department of Endocrinology and Hypertension, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Ichihara
authors.affiliation: Department of Pharmacology, Kagawa University, 1750-1 Miki, Kita, Kagawa, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hitomi
authors.affiliation: Department of Pharmacology, Kagawa University, 1750-1 Miki, Kita, Kagawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.affiliation: Department of Endocrinology and Hypertension, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
authors.affiliation: Department of Pharmacology, Kagawa University, 1750-1 Miki, Kita, Kagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics; D000077588:Deferasirox; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D055786:Gene Knockout Techniques; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019266:Iron, Dietary; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001565:Benzoates; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007502:Iron Chelating Agents; D019266:Iron, Dietary; D014230:Triazoles; D007501:Iron; D000077588:Deferasirox
keywords: Cellular senescence; Diabetic nephropathy; Iron; P21; Proximal tubular cells
references.citation: Thromb Haemost. 2001 Nov;86(5):1292-5
references.pmid: 11816720
references.citation: Diabetes. 2002 Aug;51(8):2348-54
references.pmid: 12145144
references.citation: Diabetes Care. 2002 Dec;25(12):2249-55
references.pmid: 12453969
references.citation: Cell. 2004 Apr 30;117(3):285-97
references.pmid: 15109490
references.citation: Lab Anim. 1990 Jul;24(3):253-64
references.pmid: 2144327
references.citation: Ren Fail. 1994;16(3):367-81
references.pmid: 8059020
references.citation: Circulation. 1998 Mar 17;97(10):1002-8
references.pmid: 9529269
references.citation: Exp Cell Res. 1961 Dec;25:585-621
references.pmid: 13905658
references.citation: Metabolism. 2006 Aug;55(8):1042-5
references.pmid: 16839839
references.citation: Br J Haematol. 2007 May;137(3):252-61
references.pmid: 17408467
references.citation: Kidney Int. 2009 Oct;76(8):838-48
references.pmid: 19657327
references.citation: Endocrinology. 2011 Feb;152(2):680-8
references.pmid: 21190955
references.citation: Arterioscler Thromb Vasc Biol. 2011 Mar;31(3):683-90
references.pmid: 21183736
references.citation: J Clin Invest. 2011 Mar;121(3):985-97
references.pmid: 21317534
references.citation: Blood. 2011 Mar 10;117(10):2800-6
references.pmid: 21239700
references.citation: Exp Diabetes Res. 2011;2011:269378
references.pmid: 21747824
references.citation: Cell Metab. 2011 Nov 2;14(5):647-57
references.pmid: 22055506
references.citation: Nat Rev Cancer. 2012 Jan;12(1):9-22
references.pmid: 22169972
references.citation: Diabetes Care. 2012 May;35(5):1112-8
references.pmid: 22410816
references.citation: PLoS One. 2012;7(7):e40465
references.pmid: 22792339
references.citation: Clin Exp Pharmacol Physiol. 2012 Oct;39(10):858-63
references.pmid: 23013131
references.citation: J Clin Invest. 2012 Oct;122(10):3529-40
references.pmid: 22996660
references.citation: Kidney Int. 2012 Oct;82(7):737-47
references.pmid: 22622492
references.citation: Exp Toxicol Pathol. 2013 Jan;65(1-2):81-9
references.pmid: 21741805
references.citation: Am J Physiol Renal Physiol. 2013 Jan 15;304(2):F156-67
references.pmid: 23152292
references.citation: Am J Physiol Renal Physiol. 2013 Apr 1;304(7):F1028-36
references.pmid: 23389454
references.citation: Ren Fail. 2013 Sep;35(8):1156-62
references.pmid: 23902566
references.citation: J Am Soc Nephrol. 2013 Nov;24(11):1769-81
references.pmid: 24092929
references.citation: Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):E4922-30
references.pmid: 24282296
references.citation: Kidney Int. 2014 Apr;85(4):871-9
references.pmid: 24336034
references.citation: Lancet Diabetes Endocrinol. 2014 May;2(5):427-36
references.pmid: 24795256
references.citation: J Diabetes Complications. 2014 Sep-Oct;28(5):604-11
references.pmid: 24996978
references.citation: Nat Rev Nephrol. 2014 Oct;10(10):574-86
references.pmid: 25048549
references.citation: Kidney Int. 2014 Dec;86(6):1150-60
references.pmid: 24918154
references.citation: Eur J Nutr. 2015 Aug;54(5):709-19
references.pmid: 25096756
references.citation: J Am Soc Nephrol. 2011 Apr;22(4):635-48
references.pmid: 21372211