Effects of cell-type-specific expression of a pan-caspase inhibitor on renal fibrogenesis.

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-1ß 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. CONCLUSION: 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.