Targeted expression of a pan-caspase inhibitor in tubular epithelium attenuates interstitial inflammation and fibrogenesis in nephritic but not nephrotic mice.

Abstract

The caspase family of enzymes participates in apoptotic and proinflammatory reactions in any cell. Here we studied the role of caspase activation in the tubular epithelium of diseased kidneys using mice transgenic for the baculovirus pan-caspase inhibitor p35 gene held in a nonexpressed state (control mice) but target-expressed in the renal proximal tubule cells when crossed with mice expressing Cre recombinase under the control of the γ-glutamyltransferase promoter. Proinflammatory and profibrogenic parameters such as the number of monocytes and fibroblasts in the kidneys were significantly increased at 28 days in the control mice, but not in the renal tubule-targeted mice expressing p35 in a nephrotoxic serum nephritis model of disease. These cellular changes paralleled the number of apoptotic tubular cells and protein levels of active caspase-3 in the kidneys at 7 and 28 days of both the control and proximal tubule-targeted mice. Surprisingly, all of these parameters were not significantly affected at 7 and 28 days by targeted p35 expression in tubular epithelium when compared with nontargeted control mice in a model of adriamycin nephrosis. Thus, our study shows the critical role of caspase activation in the tubular epithelium in apoptosis along with proinflammatory and profibrogenic processes in nephrotoxic serum nephritis but not adriamycin nephrosis.