Antisense oligonucleotides for ICAM-1 attenuate reperfusion injury and renal failure in the rat

Abstract

The leukocyte adhesion molecule ICAM-1 is implicated in ischemic renal reperfusion injury. We tested the utility of an ICAM-1 antisense oligodeoxyribonucleotide (ODN) with lipofectin, six hours prior to 30 minutes of bilateral renal ischemia in the rat. We measured ICAM-1 expression by immunohistochemistry and Western blot. Our antisense ODN showed a specific ICAM-1 surface expression inhibition in vitro. We then assessed ICAM-1 expression, leukocyte infiltration, serum creatinine, serum urea concentration, and renal histology in rats subjected to renal ischemia and controls. Serum creatinine and urea concentrations 12 and 24 hours post-ischemia were increased in saline treated and reverse ODN treated rats, compared to antisense ODN treated or sham operated rats (P < 0.05). Western blotting showed decreased ICAM-1 protein in antisense ODN-treated kidneys, compared to reverse ODN treated and saline treated ischemic controls (P < 0.05). Antisense ODN also ameliorated the ischemia-induced infiltration of granulocytes and macrophages (P < 0.05), and resulted in less cortical renal damage as assessed by a quantitative pathological grading scale (P < 0.05), compared to reverse ODN or saline treatment. Thus, antisense ODN for ICAM-1 protected the kidney against ischemic renal failure. The clinical applicability of these findings extends beyond ischemic acute renal failure.

Endothelial Krüppel-Like Factor 4 Mediates the Protective Effect of Statins against Ischemic AKI

“…In response to I/R, ECs increase the expression of cell adhesion molecules, such as vascular cell adhesion molecule 1 (Vcam1) and Icam1, which recruit and activate circulating inflammatory cells in the kidneys. [3][4][5][6][7] The results of previous studies have demonstrated that administration of blocking antibodies against Vcam1 or Icam1 ameliorated renal I/R injury in rodents. [3][4][5] Likewise, antisense oligonucleotides for Icam1 attenuated ischemic AKI in rats.…”

“…[3][4][5] Likewise, antisense oligonucleotides for Icam1 attenuated ischemic AKI in rats. 6 Moreover, Kelly et al 7 showed that Icam1-deficient mice were protected from I/R injury to the kidneys. These results suggest that regulation of cell adhesion molecules is critical for controlling ischemic AKI.…”

Renal Ischemia/Reperfusion Injury

“…Leukocyte adhesion molecules seem to facilitate polymorphonuclear neutrophils recruitment during reperfusion, being implicated as mediators of renal IRI (5,6). Complementary studies using mAb, antisense oligonucleotides, or gene "knockout" indicate that blockade of ␤2 integrins and/or intercellular adhesion molecule-1 attenuates IRI in some experimental models (7)(8)(9)(10)(11)(12)(13). Furthermore, it was proposed recently that T cells might also mediate IRI through the interaction with renal tubular epithelial cells (14).…”

Pro-inflammatory role of angiotensin II in mercuric chloride-induced nephropathy in rats

“…Adhesion molecules expressed on cell surfaces mediate specific cell-cell interactions in embryogenesis, histogenesis, immune responses, and inflammatory reactions (Galkina and Ley, 2007). Several studies using different anti-ICAM-1 strategies have shown attenuation of functional impairment and histological changes during acute renal failure (Kelly et al, 1991(Kelly et al, , 1996Haller et al, 1996). During this study, increased expression of ICAM-1 in interstitial area and in tubules was observed.…”