Expression of apoptosis regulatory genes in chronic cyclosporine nephrotoxicity favors apoptosis

Background. Chronic cyclosporine (CsA) nephrotoxicity is characterized by i nterstitial fibrosis, tubular dropout, and loss of cellularity in areas of fibrosis. Apoptosis was found to play a role in CsA-induced fibrosis. We ev aluated 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-medi ated dUTP-biotin nick end labeling assay. p53 and Bar expressions were eval uated by Northern and Western blot analysis. Fas-L and Bcl-2 expressions we re evaluated by immunofluorescence. In addition to ICE mRNA, caspase-3 enzy matic 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 tubul ar atrophy and interstitial fibrosis (r = 0.8, P < 0.05). CsA induced the e xpression 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 cas pase-3 activity were also increased (P < 0.01). The changes occurred as ear ly as one week and remained statistically significant at four weeks. Conclusions. Specific apoptotic genes are increased in chronic CsA nephroto xicity. The balance favors the induction of apoptosis. Increased apoptosis could explain the tubular dropout and loss of cellularity with fibrosis, Th is then may impair the ability of the tubulointerstitium to remodel. Apopto sis could also contribute to some of CsA immunosuppressive effects on activ ated lymphocytes.