Gene transfer-induced local heme oxygenase-1 overexpression protects rat kidney transplants from ischemia/reperfusion injury
Gene transfer-induced local heme oxygenase-1 overexpression protects rat kidney transplants from ischemia/reperfusion injury
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DOI：
10.1097/01.asn.0000050760.87113.25
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发表时间：
2003-03-01
影响因子：
13.6
通讯作者：
Buelow, R
中科院分区：
文献类型：
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作者：
Blydt-Hansen, TD;Katori, M;Buelow, R
基因转移过表达血红素加氧酶-1(HO-1)可保护大鼠肝脏免受缺血/再灌注(I/R)损伤。本研究在大鼠同系肾移植模型中评价了Ad-HO-1基因转移的效果。供体Lew肾灌注Ad-HO-1、Ad-β-Gal或PBS，4℃保存24 h，原位移植于Lew受体，对侧自体肾切除。分析两组大鼠的血肌酐、尿蛋白/肌酐比值、组织学改变程度、HO-1mRNA/蛋白表达和HO酶活性。与PBS和Ad-β-Gal治疗的对照组相比，Ad-HO-1基因转移具有生存优势，中位生存期分别为100、7和7d(P<；0.01)。Ad-HO-1组血清肌酐水平在第7天开始升高(2.2~5.8 mg/dl)，但在第14天恢复到1.0 mg/dl(P<；0.01)，此后维持不变。与Ad-HO-1组(12.0和9.8vs5.0；P<；0.005)相比，PBS组和Ad-β-Gal组第7天尿蛋白/肌酐比值均升高(P<0.005)，肾小球硬化和ATN在各时间点均明显加重。逆转录-聚合酶链式反应显示HO-1基因表达在再灌流前显著升高(P<；0.001)，且在移植后3d仍保持高表达。同时，在移植时和移植后3d，Ad-HO-1组HO酶活性高于Ad-β-Gal对照组(P<；0.05)；仅在Ad-HO-1组移植后早期可观察到管状HO-1的表达。这些发现与HO-1过表达对严重肾I/R损伤的保护作用是一致的，减少了死亡率和减轻了组织损伤。
Heme oxygenase-1 (HO-1) overexpression using gene transfer protects rat livers against ischemia/reperfusion (I/R) injury. This study evaluates the effects of Ad-HO-1 gene transfer in a rat renal isograft model. Donor LEW kidneys were perfused with Ad-HO-1, Ad-beta-gal, or PBS, stored at 4degreesC for 24 h, and transplanted orthotopically into LEW recipients, followed by contralateral native nephrectomy. Serum creatinine, urine protein/creatinine ratios, severity of histologic changes, HO-1 mRNA/protein expression, and HO enzymatic activity were analyzed. Ad-HO-1 gene transfer conferred a survival advantage when compared with PBS- and Ad-beta-gal-treated controls, with median survival of 100, 7, and 7 d, respectively (P < 0.01). Serum creatinine levels were elevated at day 7 in all groups (range, 2.2 to 5.8 mg/dl) but recovered to 1.0 mg/dl by day 14 (P < 0.01) in Ad-HO-1 group, which was sustained thereafter. Urine protein/creatinine ratio at day 7 was elevated in both PBS and Ad-beta-gal, as compared with the Ad-HO-1 group (12.0 and 9.8 versus 5.0; P < 0.005); histologically, ATN and glomerulosclerosis was more severe in Ad-p-gal group at all time points. Reverse transcriptase-PCR-based HO-1 gene expression was significantly increased before reperfusion (P < 0.001) and remained increased in the Ad-HO-1-treated group for 3 d after transplantation. Concomitantly, HO enzymatic activity was increased at transplantation and at 3 d posttransplant in the Ad-HO-1 group, compared with Ad-beta-gal controls (P < 0.05); tubular HO-1 expression was discernible early posttransplant in the Ad-HO-1 group alone. These findings are consistent with protective effects of HO-1 overexpression using a gene transfer approach against severe renal I/R injury, with reduced mortality and attenuation of tissue injury.