Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0920646 (renal ischemia)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathophysiology of ischemic acute renal failure is complex, and the role of leukocyte adhesion in this process is not well defined. A monoclonal antibody (mAb) against intracellular adhesion molecule 1 (anti-ICAM-1), administered at the time of bilateral renal ischemia in the rat, prevented both functional impairment and histologic changes of acute renal failure. Plasma creatinine measured (mg/dl) 24 hr after 30 min of ischemia was 0.61 +/- 0.05 in the anti-ICAM-1-treated animals compared with 2.4 +/- 0.14 (P < 0.0001) in the vehicle-treated ischemic group. Forty-eight hours after ischemia, creatinine values were 0.46 +/- 0.05 and 2.03 +/- 0.22 (P < 0.0001) in anti-ICAM-1 and vehicle-treated groups, respectively. A low dose of anti-ICAM-1 that was itself nonprotective, when given with partially protective doses of a mAb against lymphocyte function-associated antigen-1 (anti-LFA-1), acted synergistically to prevent renal failure. Anti-ICAM-1 mAb also protected the kidney when administered 0.5 or 2 hr but not 8 hr after restoration of blood flow and when the ischemic period was extended to 40 min. Ischemia-induced increases in tissue myeloperoxidase, a marker of neutrophil infiltration, were mitigated with anti-ICAM-1 treatment. Thus, anti-ICAM-1 mAb protected the kidney against ischemic renal failure, even when the antibody was administered after the ischemic period. These results suggest a critical role for leukocytes and adhesion molecules in the pathophysiology of ischemic injury and may have important therapeutic implications.
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PMID:Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury. 790 59

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.
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PMID:Antisense oligonucleotides for ICAM-1 attenuate reperfusion injury and renal failure in the rat. 884 Feb 75

Reperfusion after ischemia induces cytokines, chemoattractant chemokines, adhesion molecules, and nitric oxide (NO). The resultant neutrophil adherence and NO potentiates renal injury. alpha-Melanocyte-stimulating hormone (alpha-MSH) is a potent anti-inflammatory agent that inhibits neutrophil migration and production of neutrophil chemokines and NO. Since neutrophils and NO promote renal ischemic injury, we sought to determine if alpha-MSH inhibits renal injury in a model of bilateral renal ischemia. alpha-MSH significantly reduced ischemia-induced renal damage, measured by changes in renal histology and plasma blood urea nitrogen and creatinine in mice. alpha-MSH significantly decreased tubule necrosis, neutrophil plugging, and capillary congestion. Delay of alpha-MSH treatment for 6 h after ischemia also significantly inhibited renal damage. alpha-MSH also significantly inhibited ischemic damage in rats. To begin to determine the mechanism of action of alpha-MSH, we measured its effects on mediators of neutrophil trafficking and induction of the inducible isoform of NO synthase-II. alpha-MSH inhibited ischemia-induced increases in mRNA for the murine neutrophil chemokine KC/IL-8. alpha-MSH also inhibited induction of mRNA for the adhesion molecule ICAM-1, which is known to be critical in renal ischemic injury. alpha-MSH inhibited nitration of kidney proteins and induction of NO synthase-II. We conclude: (a) alpha-MSH protects against renal ischemia/reperfusion injury; and (b) it may act, in part, by inhibiting the maladaptive activation of genes that cause neutrophil activation and adhesion, and induction of NO synthase.
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PMID:Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats. 907 23

The purpose of this study was to characterize the time course of renal ischemia-reperfusion injury in the rat. Male Sprague-Dawley rats were subjected to bilateral renal clamping for 45 min. At reestablishment of blood flow, the rats were divided into nine groups (representing 0, 0.5, 1, 2, 4, 6, 9, and 24 h, and 1 week post-ischemia). At each time point, blood samples were taken for analysis of blood urea nitrogen (BUN) and creatinine, and both kidneys were harvested for histopathology and myeloperoxidase activity (MPO) assays. An intracellular adhesion molecular (ICAM-1) monoclonal antibody (IMAb) was tested in a separate group of animals (1 mg/rat) to confirm that it may provide renal protection previously reported by Kelly et al. (1994). Following renal ischemia, significant increases in serum BUN and creatinine were observed compared to levels in normal animals. Serum BUN and creatinine increased 2, 4, and 6 h post-ischemia leading to peak elevations 24 h post-ischemia. Values returned to normal at the 1 week time point. MPO activity was slightly increased 2 and 4 h following ischemia, with peak elevations occurring at the 6-h and 9-h time points. Histopathologic examination of kidneys revealed that the most severe damage occurred at the 24-h time point, which correlated with the peak elevations in serum BUN and creatinine. Evidence of renal injury was still evident histologically 1 week following ischemia, although renal function tests (BUN and creatinine) had returned to normal. In summary, renal injury following ischemia may be demonstrated as early as 4 h post-ischemia as judged by changes in renal function, MPO levels, and renal histopathology. However, based upon renal function tests and histology, peak injury is observed approximately 24 h following ischemia. The ICAM-1 monoclonal antibody, ICAM-Ab, provided some renal protection against ischemia-reperfusion injury in this study as measured by serum creatinine, BUN and renal histopathology. However, in contrast to the results reported by Kelly et al., the magnitude of the protective effects was not as dramatic in the present study, and furthermore, no reductions in renal MPO activity were observed.
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PMID:Characterization of renal ischemia-reperfusion injury in rats. 908 82

The role of neutrophils in acute renal failure is controversial. Acute renal failure can clearly occur in the absence of neutrophils. However, recent studies using specific neutrophil markers indicate that neutrophils accumulate in postischemic kidneys. Moreover, reperfusion of ischemic kidneys with neutrophils worsens ischemic injury and causes kidney neutrophil retention. Neutrophil retention is dependent on the state of neutrophil activation and the duration of renal ischemia. This interaction could account for the high frequency of acute renal failure in conditions associated with prolonged prerenal asotemia and neutrophil priming such as the adult respiratory distress syndrome, or sepsis. Neutrophil retention is mediated by interaction of neutrophil integrins and endothelial cell ICAM-1 because maneuvers reducing the expression and/or function of these adhesion molecules is protective in experimental models of ischemia. Nitric oxide is a key modulator of neutrophil worsening of ischemic injury because maneuvers that decrease nitric oxide production worsen and those which increase nitric oxide protect ischemic kidneys from neutrophil effects. The clinical significance of neutrophils may relate to the observation that bioincompatible membranes activate complement, and retard recovery from acute renal failure. In conclusion, neutrophils are an important contributor to ischemic acute renal failure. It remains to be determined whether decreasing neutrophil function accelerates recovery in acute renal failure.
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PMID:The role of neutrophils in acute renal failure. 975 2

Lipoxins are endogenous lipoxygenase-derived eicosanoids, generated during inflammatory, hypersensitivity, and vascular events, that display vasodilatory, antiinflammatory, and pro-resolution activity. Here, we evaluated the efficacy of 15-epi-16-(para-fluorophenoxy)-lipoxin A(4)-methyl ester (15-epi-16-(FPhO)-LXA(4)-Me), a stable synthetic analogue of aspirin-triggered 15-epi-lipoxin A(4) in ischemic acute renal failure (ARF) in NIH Swiss mice. ARF was induced by 30-min crossclamping of renal pedicles and was associated with elevated serum creatinine, morphologic injury, polymorphonuclear leukocyte (PMN) recruitment, and increased mRNA levels for adhesion molecules (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]), chemokines (growth regulated oncogene-1 [GRO1]), and cytokines (interleukin-1beta [IL-1beta] and IL-6) after 24-h reperfusion. A single bolus of 15-epi-16-(FPhO)-LXA(4)-Me afforded striking functional (mean +/- SEM creatinine in mg/dl: sham-operated, 0.77 +/- 0.04; ARF + vehicle, 2.49 +/- 0.19; ARF + 15-epi-16-(FPhO)-LXA(4)-Me, 0.75 +/- 0.12; P < 0.001) and morphologic protection and reduced PMN infiltration. Treatment with 15-epi-16-(FPhO)-LXA(4)-Me was also associated with lower IL-1beta, IL-6, and GRO1 mRNA levels, whereas ICAM-1 and VCAM-1 mRNA levels were unchanged. Compatible with these results, LXA(4) blunted chemoattractant-stimulated PMN migration across HK-2 renal epithelial cell monolayers in vitro, but it did not inhibit cytokine-induced HK-2 ICAM-1 expression or adhesiveness for PMN. Interestingly 15-epi-16-(FPhO)-LXA(4)-Me-treated animals also displayed increased renal mRNA levels for suppressors of cytokine signaling-1 (SOCS-1) and SOCS-2, but not CIS-1, endogenous inhibitors of cytokine-elicited Jak/Stat-signaling pathways. These results indicate that 15-epi-16-(FPhO)-LXA(4)-Me is protective in renal ischemia reperfusion injury in vivo, at least partially by modulating cytokine and chemokine expression and PMN recruitment, and provides a rationale for further exploration of the efficacy of LXA(4) structural analogues in ischemic ARF and other renal diseases.
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PMID:15-Epi-16-(para-fluorophenoxy)-lipoxin A(4)-methyl ester, a synthetic analogue of 15-epi-lipoxin A(4), is protective in experimental ischemic acute renal failure. 1203 96

Recent data support a modulatory role for CD4 T cells in experimental renal ischemia-reperfusion injury (IRI). CD4 T cells can functionally differentiate to either a Th1 (IFN-gamma producing) or the counterbalancing Th2 (IL-4) phenotype. The enzymes signal transducers and activators of transcription (STAT) 4 and STAT6 regulate Th1 or Th2 differentiation and cytokine production, respectively. We therefore hypothesized that mice that were STAT4 deficient would be protected from renal IRI and that STAT6-deficient mice would have a more severe course. Intracellular cytokine staining of splenocytes from STAT4-/- or STAT6-/- exhibited distinct IFN-gamma and IL-4 cytokine expression profiles. STAT6-/- had markedly worse renal function and tubular injury postischemia compared with wild type. STAT4-/- had only mildly improved function. Renal phagocyte infiltration and ICAM-1 upregulation were similar in STAT4-/-, STAT6-/-, and wild type. To evaluate if the mechanism of the marked worsening in the STAT6-/- mice could be due to IL-4 deficiency, IL-4-deficient mice were studied and had similar postischemic phenotype to STAT6-/- mice. These data demonstrate that the STAT6 pathway has a major protective role in renal IRI. IL-4 deficiency is a likely mechanism underlying the STAT6 effect. A "yin-yang" role for inflammation is emerging in renal IRI, similar to recent observations in atherosclerosis.
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PMID:Contrasting roles for STAT4 and STAT6 signal transduction pathways in murine renal ischemia-reperfusion injury. 1270 97

Local anesthetics are widely used during the perioperative period, even in patients with preexisting renal disease. However, local anesthetics have been shown to cause cell death in multiple cell lines, including human kidney proximal tubule cells. We questioned whether local anesthetics potentiate renal dysfunction after ischemia-reperfusion (I/R) injury in vivo. Rats were implanted with subcutaneous miniosmotic pumps that continuously delivered lidocaine (2 mg.kg-1.h-1), bupivacaine (0.4 mg.kg-1.h-1), tetracaine (1 mg.kg-1.h-1), or saline vehicle, and 6 h later the rats were subjected to 30 min of renal ischemia or to sham operation. Renal function was assessed by measurement of plasma creatinine at 24 and 48 h after renal I/R injury in the presence or absence of chronic infusions of local anesthetics and correlated to histological changes indicative of necrosis. The degree of renal apoptosis was assessed by three methods: 1) DNA fragmentation detected by terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling staining, 2) DNA laddering detected after agarose gel electrophoresis, and 3) morphological identification of apoptotic tubules at the corticomedullary junction. We also measured the expression of the proinflammatory markers ICAM-1 and TNF-alpha. Continuous local anesthetic infusion with renal I/R injury resulted in an increased magnitude and duration of renal dysfunction compared with the saline-infused I/R group. Additionally, both apoptotic and necrotic renal cell death as well as inflammatory changes were significantly potentiated in local anesthetic-treated rat kidneys. Local anesthetic infusion alone without I/R injury had no effect on renal function. We conclude that local anesthetics potentiated renal injury after I/R by increasing necrosis, apoptosis, and inflammation.
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PMID:Local anesthetics worsen renal function after ischemia-reperfusion injury in rats. 1451 92

Controversy exists regarding the effect of A1 adenosine receptor (AR) activation in the kidney during ischemia and reperfusion (I/R) injury. We sought to further characterize the role of A1 ARs in modulating renal function after I/R renal injury using both pharmacological and gene deletion approaches in mice. A1 AR knockout mice (A1KO) or their wild-type littermate controls (A1WT) were subjected to 30 min of renal ischemia. Some A1WT mice were subjected to 30 min of renal ischemia with or without pretreatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) or 2-chrolo-cyclopentyladenosine (CCPA), selective A1 AR antagonist and agonist, respectively. Plasma creatinine and renal histology were compared 24 h after renal injury. A1KO mice exhibited significantly higher creatinines and worsened renal histology compared with A1WT controls following renal I/R injury. A1WT mice pretreated with the A1 AR antagonist or agonist demonstrated significantly worsened or improved renal function, respectively, after I/R injury. In addition, A1WT mice pretreated with DPCPX or CCPA showed significantly increased or reduced markers of renal inflammation, respectively (renal myeloperoxidase activity, renal tubular neutrophil infiltration, ICAM-1, TNF-alpha, and IL-1beta mRNA expression), while demonstrating no differences in indicators of apoptosis. In conclusion, we demonstrate that endogenous or exogenous preischemic activation of A1 ARs protects against renal I/R injury in vivo via mechanisms leading to decreased necrosis and inflammation.
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PMID:A1 adenosine receptor knockout mice exhibit increased renal injury following ischemia and reperfusion. 1460 29

Tetracyclines exhibit significant anti-inflammatory properties in a variety of rheumatologic and dermatologic conditions. They have also been shown to inhibit apoptosis in certain neurodegenerative disorders. Because ischemic renal injury is characterized by both apoptosis and inflammation, we investigated the therapeutic potential of tetracyclines in a rat model of renal ischemia-reperfusion. Male Sprague-Dawley rats underwent bilateral renal artery clamp for 30 min followed by reperfusion and received either minocycline or saline for 36 h before ischemia. Minocycline reduced tubular cell apoptosis 24 h after ischemia as determined by terminal transferase-mediated dUTP nick end-labeling staining and nuclear morphology. It also decreased cytochrome c release into the cytoplasm and reduced upregulation of p53 and Bax after ischemia. The minocycline-treated group showed a significant reduction in tubular injury and cast formation. In addition, minocycline reduced the number of infiltrating leukocytes, decreased leukocyte chemotaxis both in vitro and ex vivo, and downregulated the expression of ICAM-1. Serum creatinine 24-h postischemia was significantly reduced in the minocycline-treated group. We conclude that minocycline has potent antiapoptotic and anti-inflammatory properties and protects renal function in this model of ischemia-reperfusion. Tetracyclines are among the safest and best-studied antibiotics. They are thus attractive candidates for the therapy of human ischemic acute renal failure.
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PMID:Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal injury. 1517 83


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