title: Role and Association of Inflammatory and Apoptotic Caspases in Renal Tubulointerstitial Fibrosis.
abstract: OBJECTIVE
  Caspases, an evolutionary conserved family of aspartate-specific cystein proteases, play pivotal roles in apoptotic and inflammatory signaling. Thus far, 14 mammalian caspases are identified and categorized into 3 distinct sub-types: inflammatory caspases, apoptotic initiator and apoptotic executioner. Caspase-1 is an inflammatory caspase, while caspase-7 belongs to apoptotic executioner. The roles and association of these two distinct types of caspases in renal tubulointerstitial fibrosis (TIF) have not been well recognized.
  
  
  METHODS
  Caspase-1 inhibitor Z-YVAD-FMK and caspase-7 siRNA were used in tubular epithelial cell line NRK-52E (TECs) to test their effects on transforming growth factor-beta1 (TGF-β1) stimulation. In vivo, Unilateral ureteral obstruction (UUO) animal model was employed in wild-type (WT) and caspase-1 knock out (KO) (caspase-1-/-) mice.
  
  
  RESULTS
  In current study, we found that caspase-7 was obviously activated in cultured TECs stimulated by TGF-β1 and in UUO model of WT mice. While in UUO model of caspase-1 KO mice, the increased caspase-7 activation was suppressed significantly along with reduced trans-differentiation and minimized extracellular matrix (ECM) accumulation, as demonstrated by western blot, Masson trichrome staining and immunohistochemistry. In addition, pharmacological inhibition of caspase-1 dampened caspase-7 activation and TECs' transdifferentiation induced by TGF-β1 exposure, which was consistent with in vivo study. Notably, caspase-7 gene knock down by specific siRNA abrogated TGF-β1 driven TECs' trans-differentiation and reduced ECM accumulation.
  
  
  CONCLUSIONS
  Our study associated inflammatory and apoptotic caspases in TIF for the first time and we further confirmed that caspase-1 activation is an upstream event of apoptotic caspase-7 induction in TIF triggered by UUO and in TECs mediated by TGF-β1 induced transdifferentiation.
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: You
authors.initials: Y
authors.lastname: Ke
authors.forename: Hui
authors.initials: H
authors.lastname: Tang
authors.forename: Chen
authors.initials: C
authors.lastname: Ye
authors.forename: Chun-Tao
authors.initials: CT
authors.lastname: Lei
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.forename: Chun
authors.initials: C
authors.lastname: Zhang
authors.forename: Hua-Jun
authors.initials: HJ
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis; D020170:Caspase 1 / Q000502:physiology; D053179:Caspase 7 / Q000502:physiology; D020169:Caspases / Q000502:physiology*; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D005355:Fibrosis / Q000201:enzymology*; D006801:Humans; D007249:Inflammation / Q000201:enzymology; D007684:Kidney Tubules / Q000473:pathology*; D051379:Mice; D053773:Transforming Growth Factor beta1; D014517:Ureteral Obstruction
chemical_list: D053773:Transforming Growth Factor beta1; C505524:Casp7 protein, mouse; D053179:Caspase 7; D020169:Caspases; D020170:Caspase 1