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D Dragun

Publications and source records attributed to D Dragun.

22 records · Page 2Linked to original sources
PubMed1997

Vascular angiotensin-converting enzyme expression regulates local angiotensin II.

We tested the hypothesis that changes in angiotensin-converting enzyme (ACE) gene expression can regulate the rate of local vascular angiotensin II (Ang II) production. We perfused isolated rat hindlimbs with an artificial medium and infused renin and Ang I via the perfusate. Ang I and II were measured by radioimmunoassay. We then increased ACE gene expression and ACE levels in the rat aorta by producing two-kidney, one clip (2K1C) hypertension for 4 weeks. Gene expression was measured by RNAse protection assay, and ACE activity in the vessel wall was measured by the Cushman-Cheung assay. Angiotensin I infusion at 1, 10, 100, and 1000 pmol/mL led to 371 +/- 14 (+/-SEM), 3611 +/- 202, 44,828 +/- 1425, and 431,503 +/- 16,439 fmol/mL Ang II released, respectively, from the hindlimbs (r = .98, P < .001). Thus, the conversion rate did not change across four orders of magnitude, and the system was not saturable under these conditions. In 2K1C hindlimbs, Ang I infusion (0.5 pmol/mL) resulted in increased Ang II generation (157 +/- 16 versus 123 +/- 23 fmol/mL, P = .014 at minute 10) compared with controls. ACE gene expression and ACE activity were increased in 2K1C hindlimbs compared with controls (36 +/- 4 versus 17 +/- 1 mU/mg protein, P < .001). Ang II degradation in the two groups did not differ. To investigate the conversion of locally generated Ang I, we infused porcine renin (0.5 milliunits per mL) into 2K1C and control hindlimbs. Despite markedly higher Ang I release in sham-operated than in 2K1C rats (71 +/- 8 versus 37 +/- 6 pmol/mL, P = .008 at minute 12), Ang II was only moderately increased (36 +/- 3 versus 25 +/- 6 pmol/mL, P = .12 at minute 12). This difference between 2K1C rats and controls reflected a higher rate of conversion in 2K1C rats. Thus, Ang I conversion in the rat hindlimb is linear over a wide range of substrate concentrations and occurs at a fixed relationship. Nevertheless, increased ACE gene expression and ACE activity in the vessel wall lead to an increase in the conversion of Ang I to Ang II. We conclude that local ACE gene expression and ACE activity can influence the local rate of Ang II production.

Angiotensin I↗
PubMed1996

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

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.

Acute Kidney Injury↗
PubMedDate not supplied

Diapedesis of leukocytes: antisense oligonucleotides for rescue.

Ischemia-reperfusion injury is an acute inflammatory process during which leukocytes are intimately involved. In this review, we summarize the current data on the leukocyte cell adhesion cascade in ischemia-reperfusion injury, focus upon studies which have demonstrated specific cell adhesion molecule interactions which mediate the leukocyte involvement in ischemia-reperfusion injury, and suggest future avenues of therapeutic interventions. The increased adhesion between activated vascular endothelium and peripheral blood leukocytes is central to the structural and the functional impairment in ischemia-reperfusion injury. Several families of adhesion molecules, namely the selectins, the intercellular adhesion molecules (ICAMs), and the integrins expressed either on the endothelium or on the leukocytes, are involved the cascade of events. Sequential and overlapping cellular interactions between the members of the three gene families of adhesion receptors result in adhesion of the leukocytes to the endothelium and extravasation at the site of ischemia. The functional importance of ICAM-1 and its beta2 integrin ligands in ischemia-reperfusion of the kidney has been demonstrated by monoclonal antibody blockade studies, in knockout mice and by treatment with antisense oligodeoxynulceotides (ODN). We have shown that antisense ODN for ICAM-1 protected the kidney against ischemic renal failure. In addition, in transplanted kidneys, ICAM-1 inhibition by antisense ODN ameliorates ischemia-reperfusion injury and prevents delayed graft function. Recent developments in antisense ODN technology make this a promising therapeutic approach, and antisense ODN treatment of donors or donor organs for ICAM-1 may be useful for the prevention of reperfusion injury in human renal transplantation and could influence acute and chronic graft function.

Animals↗