title: Effects of cell-type-specific expression of a pan-caspase inhibitor on renal fibrogenesis.
abstract: BACKGROUND
  The caspase family of enzymes is grouped into two major sub-families, namely apoptotic and inflammatory caspases, which play central roles in the induction of apoptosis, regulation of inflammation and immunity, and cellular differentiation.
  
  
  METHODS
  The role of caspase activation in tubular epithelium and interstitial cells of 3 lines of transgenic mice with obstructed nephropathy was examined: p35 mice bearing the pan-caspase inhibitor protein expressed by the p35 gene separated from the universal CAG promoter by a floxed STOP sequence were crossed with γGT.Cre and FSP1.Cre mice that express Cre recombinase in the cortical tubular epithelium and FSP1(+) interstitial cells, respectively. The γGT.Cre;p35, FSP1.Cre;p35 and p35 control mice were then challenged with unilateral ureter obstruction (UUO).
  
  
  RESULTS
  Proinflammatory parameters such as protein levels of active IL-1β subunit and mRNA levels of TNF-α and NOD-like receptor pyrin domain containing-3, and profibrogenic parameters such as interstitial matrix deposition and mRNA levels of fibronectin EIIIA isoform and α1 chain of procollagen type I in the kidneys were significantly increased at 7 days in the FSP1.Cre;p35- and p35-UUO mice, but not in the γGT.Cre;p35-UUO mice. These changes paralleled the numbers of apoptotic nuclei in tubules, but not in interstitial cells, and the protein levels of active caspase-3 subunit in the kidneys of FSP1.Cre;p35-, p35- and γGT.Cre;p35-UUO mice.
  
  
  CONCLUSIONS
  This study provides evidence of the critical role of caspase activation in the tubular epithelium, but not in FSP1(+) interstitial cells, in apoptosis and inflammasome induction, leading to proinflammatory and profibrogenic processes in fibrous kidneys with UUO.
authors: Department of Nephrology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Irumagun, Saitama, 350-0451, Japan.|Division of Project Research, Saitama Medical University Research Center of Genomic Medicine, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
authors: Tsutomu
authors: T
authors: Inoue
authors: Division of Project Research, Saitama Medical University Research Center of Genomic Medicine, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.|Department of General Internal Medicine, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Irumagun, Saitama, 350-0451, Japan.
authors: Takeru
authors: T
authors: Kusano
authors: Department of Nephrology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Irumagun, Saitama, 350-0451, Japan.
authors: Kouji
authors: K
authors: Tomori
authors: Department of General Internal Medicine, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Irumagun, Saitama, 350-0451, Japan.
authors: Hidetomo
authors: H
authors: Nakamoto
authors: Department of Nephrology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Irumagun, Saitama, 350-0451, Japan.|Division of Project Research, Saitama Medical University Research Center of Genomic Medicine, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
authors: Hiromichi
authors: H
authors: Suzuki
authors: Department of Nephrology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Irumagun, Saitama, 350-0451, Japan. hirookda@saitama-med.ac.jp.|Division of Project Research, Saitama Medical University Research Center of Genomic Medicine, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan. hirookda@saitama-med.ac.jp.|Department of General Internal Medicine, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Irumagun, Saitama, 350-0451, Japan. hirookda@saitama-med.ac.jp.
authors: Hirokazu
authors: H
authors: Okada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D020169:Caspases / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D004789:Enzyme Activation; D005353:Fibronectins / Q000235:genetics; D005355:Fibrosis; D015870:Gene Expression; D019426:Integrases / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism; D007672:Kidney Cortex / Q000201:enzymology / Q000473:pathology*; D007684:Kidney Tubules / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010770:Phosphotransferases / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014517:Ureteral Obstruction / Q000473:pathology; D019459:Urothelium / Q000201:enzymology*; D005723:gamma-Glutamyltransferase / Q000235:genetics
chemical_list: D002352:Carrier Proteins; C491768:Ccl2 protein, mouse; C492236:Cdk5r1 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D005353:Fibronectins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D012333:RNA, Messenger; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D005723:gamma-Glutamyltransferase; D010770:Phosphotransferases; C045073:Cre recombinase; D019426:Integrases; D020169:Caspases
keywords: Apoptosis; Caspase; Fibrogenesis; Inflammasome; Inflammation; p35