[HTML][HTML] Expression of apoptosis regulatory genes in chronic cyclosporine nephrotoxicity favors apoptosis
FS Shihab, TF Andoh, AM Tanner, H Yi, WM Bennett - Kidney international, 1999 - Elsevier
FS Shihab, TF Andoh, AM Tanner, H Yi, WM Bennett
Kidney international, 1999•ElsevierExpression of apoptosis regulatory genes in chronic cyclosporine nephrotoxicity favors
apoptosis. Background Chronic cyclosporine (CsA) nephrotoxicity is characterized by
interstitial fibrosis, tubular dropout, and loss of cellularity in areas of fibrosis. Apoptosis was
found to play a role in CsA-induced fibrosis. We evaluated the role of the death genes p53,
Bax, and Fas-L (ligand), survival gene Bcl-2, interleukin-converting enzyme (ICE), and
caspase-3. Methods Salt-depleted rats were administered CsA 15 mg/kg/day or vehicle (VH) …
apoptosis. Background Chronic cyclosporine (CsA) nephrotoxicity is characterized by
interstitial fibrosis, tubular dropout, and loss of cellularity in areas of fibrosis. Apoptosis was
found to play a role in CsA-induced fibrosis. We evaluated the role of the death genes p53,
Bax, and Fas-L (ligand), survival gene Bcl-2, interleukin-converting enzyme (ICE), and
caspase-3. Methods Salt-depleted rats were administered CsA 15 mg/kg/day or vehicle (VH) …
Expression of apoptosis regulatory genes in chronic cyclosporine nephrotoxicity favors apoptosis.
Background
Chronic cyclosporine (CsA) nephrotoxicity is characterized by interstitial fibrosis, tubular dropout, and loss of cellularity in areas of fibrosis. Apoptosis was found to play a role in CsA-induced fibrosis. We evaluated the role of the death genes p53, Bax, and Fas-L (ligand), survival gene Bcl-2, interleukin-converting enzyme (ICE), and caspase-3.
Methods
Salt-depleted rats were administered CsA 15 mg/kg/day or vehicle (VH) and were sacrificed at 7 or 28 days. Apoptosis was detected by TdT-mediated dUTP-biotin nick end labeling assay. p53 and Bax expressions were evaluated by Northern and Western blot analysis. Fas-L and Bcl-2 expressions were evaluated by immunofluorescence. In addition to ICE mRNA, caspase-3 enzymatic activity was assayed.
Results
Although no differences were seen at one week, apoptosis-positive cells increased with CsA at four weeks (P < 0.05) and correlated with tubular atrophy and interstitial fibrosis (r = 0.8, P < 0.05). CsA induced the expression of p53 (P < 0.05) and Bax (P < 0.01) and decreased that of Bcl-2 (P < 0.05). CsA up-regulated Fas-L expression (P < 0.001). ICE mRNA and caspase-3 activity were also increased (P < 0.01). The changes occurred as early as one week and remained statistically significant at four weeks.
Conclusions
Specific apoptotic genes are increased in chronic CsA nephrotoxicity. The balance favors the induction of apoptosis. Increased apoptosis could explain the tubular dropout and loss of cellularity with fibrosis. This then may impair the ability of the tubulointerstitium to remodel. Apoptosis could also contribute to some of CsA immunosuppressive effects on activated lymphocytes.
Elsevier