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.
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ABSTRACT: Apoptosis, a predominant cause of neuronal death after stroke, can be executed in a caspase-dependent or apoptosis inducing factor (AIF)-dependent manner. Herpes simplex virus (HSV) vectors expressing caspase inhibitors p35 and crmA have been shown to be neuroprotective against various excitotoxic insults. Here we further evaluated the possible neuroprotective role of p35 and crmA in a rat stroke model. Overexpression of p35, but not crmA, significantly increased neuronal survival. Results of double immunofluorescence staining indicate that compared with neurons infected with crmA or control vectors, p35-infected neurons had less active caspase-3 expression, cytosolic cytochrome c and nuclear AIF translocation.Neuroscience 12/2007; 149(4):804-12. · 3.12 Impact Factor
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ABSTRACT: Immune complexes may cause an irreversible onset of chronic renal disease. Most patients with chronic renal disease undergo a final common pathway, marked by glomerulosclerosis and interstitial fibrosis. We attempted to draw a molecular map of anti-glomerular basement membrane (GBM) glomerulonephritis in mice using oligonucleotide microarray technology. Kidneys were harvested at days 1, 3, 7, 11, and 16 after inducing glomerulonephritis by using anti-GBM antibody. In parallel with examining the biochemical and histologic changes, gene expression profiles were acquired against five pooled control kidneys. Gene expression levels were cross-validated by either reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR, or immunohistochemistry. Pathologic changes in anti-GBM glomerulonephritis were confirmed in both BALB/c and C57BL/6 strains. Among the 13,680 spotted 65mer oligonucleotides, 1112 genes showing significant temporal patterns by permutation analysis of variance (ANOVA) with multiple testing correction [false discovery ratio (FDR) < 0.05] were chosen for cluster analysis. From the expression profile, acute inflammatory reactions characterized by the elevation of various cytokines, including interleukin (IL)-1 and IL-6, were identified within 3 days of disease onset. After 7 days, tissue remodeling response was prominent with highly induced extracellular-matrix (ECM) genes. Although cytokines related to lymphocyte activation were not detected, monocyte or mesangial cell proliferation-related genes were increased. Tumor necrosis factor-alpha (TNF-alpha) and nuclear factor-kappaB (NF-kappaB) pathway were consistently activated along the entire disease progression, inducing various target genes like complement 3, IL-1b, IL-6, Traf1, and Saa1. We made a large-scale gene expression time table for mouse anti-GBM glomerulonephritis model, providing a comprehensive overview on the mechanism governing the initiation and the progression of inflammatory renal disease.Kidney International 12/2004; 66(5):1826-37. · 7.92 Impact Factor
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ABSTRACT: Hepatocyte apoptosis and stellate cell activation are both features of chronic liver diseases, but a relationship between these events has not been explored. In macrophages, engulfment of apoptotic bodies induces expression of transforming growth factor-beta (TGF-beta), a profibrogenic cytokine. We examined whether a similar response occurs in stellate cells. Fluorescently labeled hepatocyte apoptotic bodies were added to cultures of primary and immortalized human stellate cells. Stellate cells, but not hepatocytes, readily engulfed apoptotic bodies in a time-dependent manner as assessed by confocal microscopy. The activation of primary and immortalized human stellate cells after incubation with apoptotic bodies, as well as their fibrogenic activity, was indicated by an increase in alpha-smooth muscle actin (primary cells), TGF-beta1, and collagen alpha1(I) mRNA (primary and immortalized cells). The profibrogenic response was dependent upon apoptotic body engulfment, because nocodazole, a microtubule-inhibiting agent, blocked both the engulfment and the increase of TGF-beta1 and collagen alpha1(I) mRNA. As described in primary rodent stellate cells, up-regulation of collagen alpha1(I) mRNA was inhibited by a PI-3K inhibitor (LY294002) and a p38 mitogen-activated protein kinase inhibitor (SB203580) in LX-1 cells. In conclusion, these data support a model in which engulfment of hepatocyte apoptotic bodies by stellate cells leads to a fibrogenic response by eliciting a kinase-signaling pathway.Laboratory Investigation 06/2003; 83(5):655-63. · 3.96 Impact Factor