급성 허혈성 신손상 백서에서 α-Melanocyte Stimulating Hormone 이 아포프토시스와 Fas 발현에 미치는 영향에 대한 연구

초록

Apoptosis frequently occurs in acute renal injury but molecular mechanisms responsible for this distinct form of cell death are largely unknown. Fas belongs to the TNF/nerve growth factor superfamily and engagement by Fas ligand induces apoptosis in various epithelial cells. To investigate the role of apoptosis and associated molecular mechanisms, we examined the occurrence of apoptosis and Fas expression as well as the therapeutic effect of α-MSH, a potent anti-inflammatory cytokine in ischemic ARF rat model as well as its effect on Fas expression. The expression of Fas was studied by western blot analysis and semiquantitative RT-PCR. Apoptosis was assessed by the TUNEL method and the degree of apoptosis and Fas expression, as well as biochemical, histological data were compared between the α-MSH and the vehicle treated groups in 40 minute renal artery clamping ischemic ARF rat models. Intraperitoneally administered α-MSH significantly reduced renal injury, measured by plasma blood urea nitrogen, creatinine level and the degree of tubular necrosis(106.5±13.3/54.7±5.45mg/dL for BUN, 1.77+0.29/1.03±0.06mg/dL for creatinine 24 hours after ischemia)(p=0.003, p=0.01), (5.4±1.94/2.6±0.7 for injury score 24 hours after ischemia)(p=0.01). Ischemia caused significant upregulation of Fas mRNA and protein and was accompanied by morphological evidence of apoptosis. α-MSH significantly reduced the degree of apoptosis, as well as Fas[(mean apoptotic cell: 23.7±12.5/11.0±5.7 per 200 field at 4 hours after ischemia(p=0.04), 31.6±24.7/18.1±11.5 per 200 field at 24 hours after ischemia(p=0.25)]. (Fas protein expression: sham: 1409±355DI(densitometric index)) 2818.3±1100/1306±643.4DI at 24 hours and 5541.5±1597.5/2866.7±788.9DI at 72 hours after ischemia)(p=0.07, 0.047). These results suggest that Fas upregulation induced tubular cell apoptosis may contribute to the pathogenesis of ischemic ARF and the beneficial effect of α-MSH is partially mediated by these inhibitory effects on Fas system.

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