title: FK506 ameliorates podocyte injury in type 2 diabetic nephropathy by down-regulating TRPC6 and NFAT expression.
abstract: Diabetic nephropathy (DN) is the leading cause of end-stage renal failure, and podocyte injury plays a major role in the development of DN. In this study, we investigated whether tacrolimus (FK506), an immunosuppressor, can attenuate podocyte injury in a type 2 diabetic mellitus (T2DM) rat model with DN. Transmission electron microcopy was used to morphologically evaluate renal injury. The urinary albumin (UAL), creatinine clearance rate (Ccr) and major biochemical parameters, including glucose, insulin, serum creatinine (Scr), urea nitrogen, total cholesterol (CHO) and triglyceride (TG), were examined 12 weeks after the administration of FK506. The expressions of the canonical transient receptor potential 6 (TRPC6), nuclear factor of activated T-cells (NFAT) and nephrin were detected by Western blotting and qPCR. In the rat model of DN, the expressions of TRPC6 and NFAT were significantly elevated compared with the normal rat group; however, the treatment with FK506 normalized the increased expression of TRPC6 and NFAT and attenuated podocyte ultrastructure injury. UAL, Ccr and the biochemical parameters were also improved by the use of FK506. In cell experiments, FK506 improved the decreased expression of nephrin and suppressed the elevated expression of both TRPC6 and NFAT caused by high glucose in accordance with TRPC6 blocker U73122. Our results demonstrated that FK506 could ameliorate podocyte injury in T2DM, which may be related to suppressed expressions of TRPC6 and NFAT.
authors.affiliation: Department of Nephrology, Affiliated Hospital of Qingdao University Qingdao, China.
authors.forename: Ruixia
authors.initials: R
authors.lastname: Ma
authors.affiliation: Department of Nephrology, Affiliated Hospital of Qingdao University Qingdao, China.
authors.forename: Liqiu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Affiliated Hospital of Qingdao University Qingdao, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Special Medicine, Qingdao University Qingdao, China.
authors.forename: Yanjuan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Urology, Peking University First Hospital Beijing, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Song
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015536:Down-Regulation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D017208:Rats, Wistar; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D050052:TRPC Cation Channels; C492145:Trpc6 protein, rat; C113267:nephrin; D003404:Creatinine; D016559:Tacrolimus
keywords: Diabetic nephropathy; NFAT; TRPC6; podocyte; tacrolimus
references.citation: Curr Diabetes Rev. 2013 Jan 1;9(1):62-77
references.pmid: 23167665
references.citation: J Am Soc Nephrol. 2009 Dec;20(12):2641-50
references.pmid: 19926893
references.citation: J Nephrol. 2012 Nov-Dec;25(6):918-25
references.pmid: 22865594
references.citation: Diabetes. 2010 Aug;59(8):1915-25
references.pmid: 20522599
references.citation: Anat Cell Biol. 2014 Jun;47(2):91-100
references.pmid: 24987545
references.citation: J Clin Invest. 2006 Dec;116(12):3114-26
references.pmid: 17099778
references.citation: Nat Med. 2008 Sep;14(9):931-8
references.pmid: 18724379
references.citation: Nephrol Dial Transplant. 2008 Sep;23(9):2743-5
references.pmid: 18503100
references.citation: Anat Embryol (Berl). 1995 Nov;192(5):385-97
references.pmid: 8546330
references.citation: Curr Opin Nephrol Hypertens. 2008 Jan;17(1):32-6
references.pmid: 18090667
references.citation: Diabetes. 2003 Apr;52(4):1023-30
references.pmid: 12663475
references.citation: J Biol Chem. 2004 Apr 9;279(15):15561-70
references.pmid: 14742441
references.citation: Kidney Int Suppl. 2007 Aug;(106):S36-42
references.pmid: 17653209
references.citation: Biochim Biophys Acta. 2013 Jun;1833(6):1434-42
references.pmid: 23499875
references.citation: J Pharmacol Sci. 2012;119(4):314-23
references.pmid: 22850612
references.citation: J Clin Invest. 2006 Feb;116(2):288-96
references.pmid: 16453013
references.citation: J Am Soc Nephrol. 2007 Jan;18(1):29-36
references.pmid: 17167110
references.citation: Diabetes Metab. 2009 Dec;35(6):425-30
references.pmid: 19786360
references.citation: Am J Pathol. 2014 Jun;184(6):1715-26
references.pmid: 24731445
references.citation: Int Immunopharmacol. 2006 Mar;6(3):445-53
references.pmid: 16428080
references.citation: PLoS One. 2013;8(10):e76703
references.pmid: 24098551
references.citation: World J Diabetes. 2014 Aug 15;5(4):431-43
references.pmid: 25126391
references.citation: Diabetes Res Clin Pract. 2008 Nov 13;82 Suppl 1:S38-41
references.pmid: 18842317
references.citation: Science. 2005 Jun 17;308(5729):1801-4
references.pmid: 15879175
references.citation: Nephrology (Carlton). 2010 Feb;15(1):75-83
references.pmid: 20377774
references.citation: Int Immunopharmacol. 2011 Oct;11(10):1613-9
references.pmid: 21640200
references.citation: Curr Diab Rep. 2008 Dec;8(6):470-6
references.pmid: 18990304
references.citation: Am J Physiol Renal Physiol. 2003 Jan;284(1):F144-54
references.pmid: 12388427
references.citation: Am J Pathol. 2011 Oct;179(4):1719-32
references.pmid: 21839714
references.citation: Am J Nephrol. 2012;35(4):312-20
references.pmid: 22456060
references.citation: PLoS Biol. 2013;11(2):e1001492
references.pmid: 23468591
references.citation: J Cell Physiol. 2009 Nov;221(2):288-95
references.pmid: 19562677
references.citation: N Engl J Med. 2001 Sep 20;345(12):861-9
references.pmid: 11565518
references.citation: Am J Physiol Renal Physiol. 2007 Oct;293(4):F1381-90
references.pmid: 17699555
references.citation: J Physiol. 2006 Dec 1;577(Pt 2):479-95
references.pmid: 16973707
references.citation: EMBO J. 2006 Nov 15;25(22):5305-16
references.pmid: 17082763
references.citation: Kidney Int. 2008 Jul;74(1):22-36
references.pmid: 18418356
references.citation: ScientificWorldJournal. 2009;9:1127-39
references.pmid: 19838599