Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022672 (acute tubular necrosis)
 2,175 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal ischemia-reperfusion (I/R) injury was investigated in inducible nitric oxide synthase (iNOS) knockout mice. After a 26-min bilateral renal pedicle clamp, serum creatinine concentrations (in mg/dl) in wild-type mice after a 24-h reperfusion were 0.25 +/- 0.03 in sham-operated controls and 2.3 +/- 0.38 in ischemic mice (P < 0. 01); after 48 h, concentrations (in mg/dl) were 0.25 +/- 0.03 in controls and 2.0 +/- 0.18 in ischemic mice (P < 0.01). iNOS knockout mice demonstrated an attenuation of serum creatinine concentration after renal I/R injury. Serum creatinine concentrations (mg/dl) after a 24-h reperfusion were 2.3 +/- 0.22 in wild-type ischemic and 1.21 +/- 0.25 in iNOS knockout ischemic mice (P < 0.05); after 48 h, concentrations were 2.0 +/- 0.18 in wild-type ischemic and 0.96 +/- 0.25 in iNOS knockout ischemic mice (P < 0.01). Histological scoring of acute tubular necrosis in iNOS knockout mice was decreased compared with that in wild-type controls (0.88 +/- 0.2 vs. 3.3 +/- 0. 3, P < 0.05). iNOS protein in the renal cortex of wild-type mice subjected to renal I/R injury was undetectable up to 48 h. However, a strong upregulation of heat shock protein 72 expression was observed in renal cortex of iNOS knockout mice under basal conditions. In conclusion, kidneys of iNOS knockout mice were protected against ischemic acute renal failure. This protective effect may be related to a compensatory upregulation of heat shock protein 72.
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PMID:Attenuation of renal ischemia-reperfusion injury in inducible nitric oxide synthase knockout mice. 1048 22

It is not known whether a kidney with chronic structural and functional changes is more vulnerable to an acute renal insult, and whether its regeneration capacity after injury is altered. To study this question, Lewis rats were submitted 10 wk after 5/6 nephrectomy to an ischemic insult of 60 min (remnant kidney [RK] group). Functional and morphologic data of the RK group were compared with data obtained in 10-wk uninephrectomized (1K) and normal (2K) Lewis rats with unilateral and bilateral renal ischemia, respectively. The acute postischemic decrease in creatinine clearance was smallest in the RK group, followed by the 2K and 1K groups, respectively. At days 1 and 3, fewer proximal tubules in the outer stripe of the outer medulla of the RK and 2K groups had undergone acute tubular necrosis compared with the 1K group. The mean percentage of tubules with signs of regeneration was maximal at day 3 in the three experimental groups. At day 10, regeneration was almost complete in the three groups. The number of leukocytes (OX1+ cells) present in the RK before ischemia did not increase after ischemia/reperfusion injury (377 +/- 146 cells/mm2 at day 0) in contrast to the 1K and 2K groups. In the latter groups, the number of leukocytes had increased gradually, reaching a maximum at day 15 (1K: 960 +/- 308 cells/mm2) and day 10 (2K: 668 +/- 164 cells/mm2), respectively. In conclusion, this study has shown that an RK exhibiting chronic morphologic changes of interstitial fibrosis and tubular atrophy is protected against ischemia/reperfusion injury, and that its regeneration capacity is preserved. The reperfusion injury is not followed by further accumulation of leukocytes, which were already present in the RK before ischemia.
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PMID:Chronic reduction in renal mass in the rat attenuates ischemia/reperfusion injury and does not impair tubular regeneration. 1058 94

The complex pathogenesis of ischemia reperfusion injury (IRI) includes endothelial expression of adhesion molecules, leukocyte recruitment and activation, reactive oxygen species production, and apoptotic and necrotic cell death. A role for complement in IRI of different organs, including kidney, has been proposed on the basis of results of experiments that used pharmacologic inhibitors as well as animals that were deficient in individual complement proteins. Here, renal IRI in mice was examined. Animals that were deficient in C3 had partial protection from IRI induced by 27.5 min of bilateral renal ischemia, followed by 20 h of reperfusion (blood urea nitrogen [BUN] values, 46.6 +/- 6.9 and 68.4 +/- 7.9 mg/dl in C3 -/- and C3 +/+ mice; n = 7 and 8, respectively; P = 0.033). Given the reduction in IRI in C3 -/- mice, it was investigated, by use of the rodent C3 convertase inhibitor CR1-related gene/protein y-Ig (Crry-Ig), whether exogenous administration of a complement inhibitor could lessen renal injury. Despite the use of Crry-Ig in high doses, there was no significant reduction of injury induced by 20 to 30 min of ischemia followed by up to 30 h of reperfusion. Histologic examination revealed acute tubular necrosis and neutrophilic infiltration, both of which correlated significantly with BUN values (P < 0.001). Of interest, C3 deposition around renal tubules was significantly less in animals with IRI, compared with that in unmanipulated controls (P < 0.001). In Crry-Ig-treated animals, C3 deposition was inversely proportional to BUN values (r = -0.63; P < 0.001), which presumably indicates that severe vascular IRI allowed access of the 160 kD Crry-Ig to the interstitium. Thus, renal IRI in mice may have a partial complement dependence, yet pharmacologic inhibition of the complement system does not seem to be effective, likely because of the presence of other mediator systems that operate in parallel.
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PMID:Inhibiting the complement system does not reduce injury in renal ischemia reperfusion. 1142 67

Ischemia-reperfusion injury (IRI) is a complex and incompletely understood process involving a cascade of events that culminates in apoptotic and/or necrotic cell death. Natural IgM antibodies and complement have been implicated in the pathogenesis of IRI in a variety of organ systems as have T lymphocytes in renal IRI. To investigate the role of Ig and T lymphocytes in renal IRI, recombination-activating gene (RAG)-1-deficient mice were studied. RAG-1(-/-) mice were not protected from acute renal failure induced by 27.5 min of bilateral renal ischemia and subsequent reperfusion [serum urea nitrogen levels 30 h after reperfusion, 155.2 +/- 5.6 and 152.8 +/- 11.4 mg/dl in RAG-1(-/-) and wild-type mice, respectively; n = 13 each]. Histological examination showed acute tubular necrosis and neutrophilic infiltration with no significant differences between groups. In contrast with other organ systems, Igs were not found in kidneys at time points ranging from 1 min to 30 h after ischemia. Thus Igs and mature T lymphocytes do not appear to play a significant role in the pathogenesis of IRI in the kidney.
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PMID:Injury in renal ischemia-reperfusion is independent from immunoglobulins and T lymphocytes. 1178 50

The straight segment (S3) of the proximal tubule is predominantly damaged during renal ischemia-reflow, whereas medullary thick ascending limbs (mTALs) are principally affected in other models of hypoxic acute tubular necrosis (ATN). Since the latter injury pattern largely depends on the extent of reabsorptive activity during hypoxic stress, we hypothesized that proximal tubular damage might attenuate downstream mTAL injury by means of diminished distal solute delivery for reabsorption. In isolated rat kidneys perfused for 90 min with oxygenated Krebs-Henseleit solution, mTAL necrosis developed in 75 +/- 3% of tubules in the mid-inner stripe of the outer medulla. By contrast, S3 segments in the outer stripe were minimally affected, with tubular fragmentation involving some 5 +/- 2% of tubules. In kidneys subjected in vivo to proximal tubular injury and subsequently used for isolated perfusion studies, the injury pattern was inverted: following 20 and 30 min ischemia and reflow for 24 h, S3 fragmentation rose to 18 +/- 16% and 72 +/- 13%, while mTAL damage was reduced to 33 +/- 10 and 24 +/- 8%, respectively. In kidneys subjected in vivo to D-serine S3 necrosis rose to 100%, while mTAL damage fell to 1 +/- 1% (p < 0.001). Substantial S3 tubular collapse (involving approximately 30% of tubules) and inner stripe interstitial hemorrhage were also noted, exclusively in kidneys subjected to ischemia-reflow. Proximal tubular necrosis alone or in combination with collapse inversely correlated with mTAL necrosis (R = -0.51 and -0.72, respectively, p < 0.003). This cogent inverse association might imply that disruption of the proximal nephron attenuates downstream mTAL necrosis by a reduction of distal tubular reabsorptive workload.
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PMID:Proximal tubular injury attenuates outer medullary hypoxic damage: studies in perfused rat kidneys. 1209 29

Ischemia-reperfusion is closely associated with tissue damage in various organs, including kidney. Despite clinical investigations, useful therapy for renal ischemia-reperfusion injury is not available so far. This study evaluated therapeutic effects of gene therapy expressing an amino-terminal deletion mutant of MCP-1 called 7ND to inhibit monocyte chemoattractant protein (MCP)-1/CCR2 signaling in vivo on renal ischemia-reperfusion injury. 7ND gene was transferred into the femoral muscle of Balb/c mice. Renal artery and vein of the left kidney were occluded with a vascular clamp for 60 min. A large number of infiltrated cells were observed, as was marked acute tubular necrosis in outer medulla after renal ischemia-reperfusion injury in control mice, while these lesions were significantly decreased in 7ND gene-transfected mice. Macrophages in the interstitial region, most of which were CCR2-positive, were markedly decreased in 7ND gene-transfected mice after reperfusion. Although macrophages infiltrated around MCP-1-positive cells in control mice, the smaller number of F4/80-positive cells could infiltrate into the neighbor of MCP-1-positive cells in 7ND-treated mice. These results provide evidence that gene therapy by 7ND is potentially a powerful therapeutic approach to inhibit MCP-1/CCR2 signaling, resulting in rescue from renal ischemia-reperfusion injury.
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PMID:Gene therapy expressing amino-terminal truncated monocyte chemoattractant protein-1 prevents renal ischemia-reperfusion injury. 1266 Mar 47

The paradigm for recovery of the renal tubule from acute tubular necrosis is that surviving cells from the areas bordering the injury must migrate into the regions of tubular denudation and proliferate to re-establish the normal tubular epithelium. However, therapies aimed at stimulating these events have failed to alter the course of acute renal failure in human trials. In the present study, we demonstrate that Lin-Sca-1+ cells from the adult mouse bone marrow are mobilized into the circulation by transient renal ischemia and home specifically to injured regions of the renal tubule. There they differentiate into renal tubular epithelial cells and appear to constitute the majority of the cells present in the previously necrotic tubules. Loss of stem cells following bone marrow ablation results in a greater rise in blood urea nitrogen after renal ischemia, while stem cell infusion after bone marrow ablation reverses this effect. Thus, therapies aimed at enhancing the mobilization, propagation, and/or delivery of bone marrow stem cells to the kidney hold potential as entirely new approaches for the treatment of acute tubular necrosis.
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PMID:Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. 1282 56

Examined were CCR2-deficient mice to clarify the contribution of macrophages via monocyte chemoattractant protein 1 (MCP-1 or CCL2)/CCR2 signaling to the pathogenesis of renal ischemia-reperfusion injury. Also evaluated was the therapeutic effects via the inhibition of MCP-1/CCR2 signaling with propagermanium (3-oxygermylpropionic acid polymer) and RS-504393. Renal artery and vein of the left kidney were occluded with a vascular clamp for 60 min. A large number of infiltrated cells and marked acute tubular necrosis in outer medulla after renal ischemia-reperfusion injury was observed. Ischemia-reperfusion induced the expression of MCP-1 mRNA and protein in injured kidneys, followed by CCR2-positive macrophages in interstitium in wild-type mice. The expression of MCP-1 was decreased in CCR2-deficient mice compared with wild-type mice. The number of interstitial infiltrated macrophages was markedly smaller in the CCR2-deficient mice after ischemia-reperfusion. CCR2-deficient mice decreased the number of interstitial inducible nitric oxide synthase-positive cells after ischemia-reperfusion. The area of tubular necrosis in CCR2-deficient mice was significantly lower than that of wild-type mice after ischemia-reperfusion. In addition, CCR2-deficient mice diminished KC, macrophage inflammatory protein 2, epithelial cell-derived neutrophil-activating peptide 78, and neutrophil-activating peptide 2 expression compared with wild-type mice accompanied with the reduction of interstitial granulocyte infiltration. Similarly, propagermanium and RS-504393 reduced the number of interstitial infiltrated cells and tubular necrosis up to 96 h after ischemia-reperfusion injury. These results revealed that MCP-1 via CCR2 signaling plays a key role in the pathogenesis of renal ischemia-reperfusion injury through infiltration and activation of macrophages, and it offers a therapeutic target for ischemia-reperfusion.
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PMID:CCR2 signaling contributes to ischemia-reperfusion injury in kidney. 1451 28

This study evaluated the effect of fenoldopam, a selective dopamine (DA1) agonist, on renal blood flow and renal tubular function following renal ischemia induced by suprarenal aortic cross-clamping. Twenty anesthetized research pigs received either fenoldopam (10 micro g/kg/min; n = 10) or saline ( n = 10) beginning 20 min before suprarenal aortic cross-clamping and continuing for 20 min after clamp release, for a total infusion time of 160 min (120-min cross-clamp). Recordings of renal blood flow, mean arterial pressure, and heart rate were taken at baseline, during cross-clamping, and immediately postclamp. Ischemic renal injury was evaluated by serum creatinine and by histologic grading of acute tubular necrosis. Treatment with fenoldopam increased renal blood flow in comparison to that in the control group ( p = 0.03). The mean creatinine increase from baseline at 6 hr and 18 hr after cross-clamp removal for the fenoldopam-treated group was significantly less than that in the control group ( p < 0.001). On histologic evaluation, the mean score for the degree of tubular necrosis was significantly higher in the control group ( p = 0.02), indicating less derangement of tubular morphology in the fenoldopam group. This study demonstrated that the intraoperative use of a continuous infusion of fenoldopam during suprarenal aortic cross-clamping results in increased renal blood flow, less postoperative rise in creatinine, and better preservation of tubular histology in the pig model.
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PMID:The effects of intraoperative fenoldopam on renal blood flow and tubular function following suprarenal aortic cross-clamping. 1456 32

Vimentin, an intermediate filament protein mainly expressed in mesenchyma-derived cells, is reexpressed in renal tubular epithelial cells under many pathological conditions, characterized by intense cell proliferation. Whether vimentin reexpression is only a marker of cell dedifferentiation or is instrumental in the maintenance of cell structure and/or function is still unknown. Here, we used vimentin knockout mice (Vim(-/-)) and an experimental model of acute renal injury (30-min bilateral renal ischemia) to explore the role of vimentin. Bilateral renal ischemia induced an initial phase of acute tubular necrosis that did not require vimentin and was similar, in terms of morphological and functional changes, in Vim(+/+) and Vim(-/-) mice. However, vimentin was essential to favor Na-glucose cotransporter 1 localization to brush-border membranes and to restore Na-glucose cotransport activity in regenerating tubular cells. We show that the effect of vimentin inactivation is specific and results in persistent glucosuria. We propose that vimentin is part of a structural network that favors carrier localization to plasma membranes to restore transport activity in injured kidneys.
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PMID:Recovery of Na-glucose cotransport activity after renal ischemia is impaired in mice lacking vimentin. 1523 51


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