Gene Transfer-Induced Local Heme Oxygenase-1 Overexpression Protects Rat Kidney Transplants From Ischemia/Reperfusion Injury

Abstract

Abstract. 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-␤-gal, or PBS, stored at 4°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-␤-galtreated controls, with median survival of 100, 7, and 7 d, respectively (P Ͻ 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 Ͻ 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-␤-gal, as compared with the Ad-HO-1 group (12.0 and 9.8 versus 5.0; P Ͻ 0.005); histologically, ATN and glomerulosclerosis was more severe in Ad-␤-gal group at all time points. Reverse transcriptase-PCRbased HO-1 gene expression was significantly increased before reperfusion (P Ͻ 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-␤-gal controls (P Ͻ 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.

Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection

“…This suggests that HO-1 induction is not only T cell-dependent, but operational HO-1 cytoprotection does require the blockade of Stat4 signaling. We have shown that pharmacologic or gene therapyinduced HO-1 overexpression prevents hepatic 10,33 cardiac 34 and renal 35 I/R injury. Because HO-1 has been identified as a downstream effector of IL-10, 36 we then asked whether or not HO-1 may have been involved in Stat4 disruption-mediated effects in this study.…”

Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction

“…However, few studies examined the role of HO-1 and CO in kidney injury, and the functional role of CO in the context of renal fibrosis has not been previously examined. HO-1 overexpression or CO administration has been shown to protect experimental kidney transplants from ischemia-reperfusion injury (4,30). Moreover, the administration of CO donor compounds, namely carbon monoxide-releasing molecules (CORM-3), protected against cisplatin nephrotoxicity and ischemia-reperfusion-induced renal injury (44,47).…”

A cell penetrating heme oxygenase protein protects heart graft against ischemia/reperfusion injury

“…[16][17][18][28][29][30] In most of these studies, the introduction of HO-1 in grafts is achieved by metalloporphyrin (mainly cobalt protoporphyrin), gene transfer or transgenic engineering. These methods need to treat grafts in advance or are limited on transgenic animal models.…”