Gene transfer-induced local heme oxygenase-1 overexpression protects rat kidney transplants from ischemia/reperfusion injury.
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 4 degrees C 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-beta-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.
Blydt-Hansen
Tom D
TD
Division of Pediatric Nephrology, University of California at Los Angeles, USA.
Katori
Masamichi
M
Lassman
Charles
C
Ke
Bibo
B
Coito
Ana J
AJ
Iyer
Suhasani
S
Buelow
Roland
R
Ettenger
Robert
R
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy W
JW
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003080:Cold Temperature; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D006085:Graft Survival / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007150:Immunohistochemistry; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D016030:Kidney Transplantation; D007683:Kidney Tubular Necrosis, Acute / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index
D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1