title: NFAT2 inhibitor ameliorates diabetic nephropathy and podocyte injury in db/db mice.
abstract: OBJECTIVE
  Podocyte injury plays a key role in the development of diabetic nephropathy (DN). We have recently shown that 11R-VIVIT, an inhibitor of cell-permeable nuclear factor of activated T-cells (NFAT), attenuates podocyte apoptosis induced by high glucose in vitro. However, it is not known whether 11R-VIVIT has a protective effect on DN, especially podocyte injury, under in vivo diabetic conditions. Hence, we examined the renoprotective effects of 11R-VIVIT in diabetic db/db mice and the possible mechanisms underlying its protective effects on podocyte injury in vivo and in vitro.
  
  
  METHODS
  Type 2 diabetic db/db mice received i.p. injections of 11R-VIVIT (1 mg·kg(-1)) three times a week and were killed after 8 weeks. Immortalized mouse podocytes were cultured under different experimental conditions.
  
  
  RESULTS
  11R-VIVIT treatment markedly attenuated the albuminuria in diabetic db/db mice and also alleviated mesangial matrix expansion and podocyte injury. However, body weight, food and water intake, and glucose levels were unaffected. It also attenuated the increased NFAT2 activation and enhanced urokinase-type plasminogen activator receptor (uPA receptor) expression in glomerulor podocytes. In cultured podocytes, the increased nuclear accumulation of NFAT2 and uPA receptor expression induced by high glucose treatment was prevented by 11R-VIVIT or NFAT2-knockdown; this was accompanied by improvements in the filtration barrier function of the podocyte monolayer.
  
  
  CONCLUSIONS
  The NFAT inhibitor 11R-VIVIT might be a useful therapeutic strategy for protecting podocytes and treating DN. The calcinerin/NFAT2/uPA receptor signalling pathway should be exploited as a therapeutic target for protecting podocytes from injury in DN.
authors.affiliation: Southern Medical University, Guangzhou, China; Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Ruizhao
authors.initials: R
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Xinling
authors.initials: X
authors.lastname: Liang
authors.forename: Shuangxin
authors.initials: S
authors.lastname: Liu
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Ye
authors.forename: Chunping
authors.initials: C
authors.lastname: Yu
authors.forename: Yuanhan
authors.initials: Y
authors.lastname: Chen
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Wenjian
authors.initials: W
authors.lastname: Wang
authors.forename: Yuxiong
authors.initials: Y
authors.lastname: Lai
authors.forename: Jianchao
authors.initials: J
authors.lastname: Ma
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Li
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Tan
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology; D055785:Gene Knockdown Techniques; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology*; D050199:Podocytes / Q000473:pathology*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D009842:Oligopeptides; C524899:Plaur protein, mouse; D055293:Receptors, Urokinase Plasminogen Activator; C121611:VIVIT peptide; D019703:Calcineurin
keywords: 11R-VIVIT; activate nuclear factor of activated T-cells; diabetic nephropathy; podocyte; uPAR