Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ischemia-induced acute renal failure (ARF) is a disorder with high morbidity and mortality. ARF is characterized by a regeneration phase, yet its molecular basis is still under study. Changes in gene expression have been reported in ARF, and some of these genes are specific for nephrogenic processes. We tested the hypothesis that the regeneration process developed after ischemia-induced ARF can be characterized by the reexpression of important regulatory proteins of kidney development. The distribution pattern and levels of nephrogenic proteins in rat kidneys after ischemia were studied by immunohistochemistry and immunoblot analysis. Ischemic damage was assessed by conventional morphology, serum creatinine, and the apoptotic markers terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and caspase 3. The hypoxia levels induced by ischemia were assessed by specific markers: hypoxia induced factor (HIF)-1alpha and 2-pimonidazole. In kidneys with ARF, an important initial damage was observed through periodic acid Schiff staining, by the induction of damage markers alpha-smooth muscle actin (alpha-SMA) and macrophages (ED-1) and by apoptosis induction. In agreement with diminishing renal damage at the initial reparation phase, the expression of the mesenchymal proteins vimentin, neural cell adhesion molecules (Ncam), and the epithelial markers, Pax-2, Noggin, and basic fibroblast growth factor was observed; after, in a second phase, the tubular markers bone morphogen protein 7, Engrailed, and Lim-1, as well as the transcription factors Smad and p-Smad, were observed. Additionally, the endothelial markers VEGF and Tie-2 were induced at the initial and middle stages of regeneration phase, respectively. The expression of these proteins was restricted in time and space, as well as spatially and temporally. Because all of these proteins are important in maintaining a functional kidney, these results suggest that during the regeneration process after induced hypoxia, these nephrogenic proteins can be reexpressed in a similar fashion to that observed during development, thus restoring mature kidney function.
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PMID:Ischemic acute renal failure induces the expression of a wide range of nephrogenic proteins. 1628 88

During renal injury, activation of p38 mitogen-activated protein kinase (MAPK) in proximal tubular cells plays an important role in the inflammatory events that eventually lead to renal fibrosis. We hypothesized that local inhibition of p38 within these cells may be an interesting approach for the treatment of renal fibrosis. To effectuate this, we developed a renal-specific conjugate of the p38 inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] and the carrier lysozyme. First, we demonstrated that SB202190 inhibited the expression of albumin-induced proinflammatory (monocyte chemoattractant protein-1) and transforming growth factor (TGF)-beta1-induced profibrotic (procollagen-Ialpha1) genes over 50% in renal tubular cells (normal rat kidney-52E). Next, we conjugated SB202190 via a carbamate linkage to lysozyme. However, this conjugate rapidly released the drug upon incubation in serum. Therefore, we applied a new platinum(II)-based linker approach, the so-called universal linkage system (ULS), which forms a coordinative bond with SB202190. The SB202190-ULS-lysozyme remained stable in serum but released the drug in kidney homogenates. SB202190-ULS-lysozyme accumulated efficiently in renal tubular cells and provided a local drug reservoir during a period of 3 days after a single intravenous injection. Treatment with SB202190-ULS-lysozyme inhibited TGF-beta1-induced gene expression for procollagen-Ialpha1 by 64% in HK-2 cells. Lastly, we evaluated the efficacy of a single dose of the conjugate in the unilateral renal ischemia-reperfusion rat model. A reduction of intrarenal p38 phosphorylation and alpha-smooth muscle actin protein expression was observed 4 days after the ischemia-reperfusion injury. In conclusion, we have developed a novel strategy for local delivery of the p38 MAPK inhibitor SB202190, which may be of use in the treatment of renal fibrosis.
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PMID:Intracellular delivery of the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] in renal tubular cells: a novel strategy to treat renal fibrosis. 1680 61

Recovery from acute renal failure (ARF) requires the replacement of injured cells with new cells that restore tubule epithelial integrity. We described recently the expression of a wide range of nephrogenic proteins in tubular cells after ARF induced by ischemia-reperfusion (I/R) (Villanueva S, Cespedes C, and Vio CP. Am J Physiol Regul Integr Comp Physiol 290: R861-R870, 2006). These markers, namely, Vimentin, neural cell adhesion molecules (Ncam), basic fibroblast growth factor (bFGF), paired homeobox-2 (Pax-2), bone morphogene protein-7 (BMP-7), Noggin, Lim-1, Engrailed, Smad, phospho-Smad, hypoxia-induced factor-1alpha (HIF-1alpha), VEGF, and Tie-2, are expressed in a time frame similar to that observed in normal kidney development. bFGF participates in early kidney development as a morphogen involved in mesenchyme/epithelial transition, and it is reexpressed in the recovery phase of ARF. To test the hypothesis that bFGF can accelerate the regeneration after renal damage, we used recombinant bFGF and studied the expression pattern of the above described morphogens in ARF. Male Sprague-Dawley rats were subjected to 30 min of renal ischemic injury and were injected with bFGF 30 microg/kg followed by reperfusion. Rats were killed and the expression of nephrogenic proteins were analyzed by immunohistochemistry and Western blot analysis. In the animals subjected to I/R treated with bFGF, we observed a 12- to 24-h earlier and more abundant reexpression of the proteins Ncam, bFGF, Pax-2, BMP-7, Noggin, Lim-1, Engrailed, VEGF, and Tie-2 than the I/R untreated rats. In addition, we observed a reduction in renal damage markers ED-1 and alpha-smooth muscle actin. These results indicate that bFGF can participate in the regeneration process and suggest that the treatment with bFGF can induce an earlier regeneration process after ischemic acute renal failure.
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PMID:bFGF induces an earlier expression of nephrogenic proteins after ischemic acute renal failure. 1687 59

We previously described a mouse model of fibrotic ischemia/reperfusion cardiomyopathy (I/RC) arising from daily, brief coronary occlusion. One characteristic of I/RC was the prolonged elevation of monocyte chemoattractant protein 1 (MCP-1), which was obligate to its phenotype and may contribute to the uptake of bloodborne cells. Here we describe in I/RC hearts a population of small spindle-shaped fibroblasts that were highly proliferative and expressed collagen I and alpha-smooth muscle actin (myofibroblast markers), CD34 (a precursor marker), and CD45 (a hematopoietic marker). These cells represented 3% of all nonmyocyte live cells. To confirm the cells' bone marrow origin, chimeric mice were created by the rescue of irradiated C57BL/6 mice with marrow from ROSA26, a congenic line expressing lacZ. I/RC resulted in a large population of spindle-shaped fibroblasts containing lacZ. We postulated that the fibroblast precursors represented a developmental path for a subset of monocytes, whose phenotype we have shown to be influenced by serum amyloid P (SAP). Thus, we administered SAP in vivo, which markedly reduced the number of proliferative spindle-shaped fibroblasts and completely prevented I/RC-induced fibrosis and global ventricular dysfunction. By contrast, SAP did not suppress the inflammation or chemokine expression seen in I/RC. SAP, a member of the pentraxin family, binds to Fcgamma receptors and modifies the pathophysiological function of monocytes. Our data suggest that SAP interferes with assumption of a fibroblast phenotype in a subset of monocytes and that SAP may be an important regulator in the linkage between inflammation and nonadaptive fibrosis in the heart.
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PMID:Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice. 1711 86

Bone marrow-derived cells (BMDC) have been proposed to exert beneficial effects after renal ischemia/reperfusion injury (IRI) by engraftment in the tubular epithelium. However, BMDC can give rise to myofibroblasts and may contribute to fibrosis. BMDC contribution to the renal interstitial myofibroblast population in relation to fibrotic changes after IRI in rats was investigated. A model of unilateral renal IRI (45 min of ischemia) was used in F344 rats that were reconstituted with R26-human placental alkaline phosphatase transgenic BM to quantify BMDC contribution to the renal interstitial myofibroblast population over time. After IRI, transient increases in collagen III transcription and interstitial protein deposition were observed, peaking on days 7 and 28, respectively. Interstitial infiltrates of BMDC and myofibroblasts reached a maximum on day 7 and gradually decreased afterward. Over time, an average of 32% of all interstitial alpha-smooth muscle actin-positive myofibroblasts coexpressed R26-human placental alkaline phosphatase and, therefore, were derived from the BM. BMD myofibroblasts produced procollagen I protein and therefore were functional. The postischemic kidney environment was profibrotic, as demonstrated by increased transcription of TGF-beta and decreased transcription of bone morphogenic protein-7. TGF-beta protein was present predominantly in interstitial myofibroblasts but not in BMD myofibroblasts. In conclusion, functional BMD myofibroblasts infiltrate in the postischemic renal interstitium and are involved in extracellular matrix production.
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PMID:Bone marrow-derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after ischemia/reperfusion in rats. 1718 82

Several studies have shown that erythropoietin (EPO) can protect the kidneys from ischemia-reperfusion injury and can raise the hemoglobin (Hb) concentration. Recently, the EPO molecule modified by carbamylation (CEPO) has been identified and was demonstrated to be able to protect several organs without increasing the Hb concentration. We hypothesized that treatment with CEPO would protect the kidneys from tubular apoptosis and inhibit subsequent tubulointerstitial injury without erythropoiesis. The therapeutic effect of CEPO was evaluated using a rat ischemia-reperfusion injury model. Saline-treated kidneys exhibited increased tubular apoptosis with interstitial expression of alpha-smooth muscle actin (alpha-SMA), while EPO treatment inhibited tubular apoptosis and alpha-SMA expression to some extent. On the other hand, CEPO-treated kidneys showed minimal tubular apoptosis with limited expression of alpha-SMA. Moreover, CEPO significantly promoted tubular epithelial cell proliferation without erythropoiesis. In conclusion, we identified a new therapeutic approach using CEPO to protect kidneys from ischemia-reperfusion injury.
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PMID:Carbamylated erythropoietin protects the kidneys from ischemia-reperfusion injury without stimulating erythropoiesis. 1719 38

Granulocyte colony-stimulating factor (G-CSF) is known to mobilize bone marrow stem cells into the peripheral circulation. This study was designed to investigate whether G-CSF by itself or in combination with hepatocyte growth factor (HGF) can promote vasculogenesis and angiogenesis in murine hind limb ischemia. Hind limb ischemia was induced in BALB/c nude or C57/BL6 mice that received bone marrow transplantation from green fluorescent protein (GFP)-transgenic mice. In the HGF group, hHGF expression plasmid was injected into the ischemic muscles. In the G-CSF group, G-CSF was administered subcutaneously for 10 days. The G-CSF+HGF group was concomitantly treated with G-CSF and HGF, and the control group received no treatment. All effects were confirmed at 4 weeks. The G-CSF+HGF group had a higher laser Doppler blood perfusion index, higher microvessel density, and a lower incidence of hind limb necrosis than the other groups. Confocal laser microscopy revealed that a number of GFP-positive cells infiltrated to the vasculature of the ischemic area. Some of the GFP positive cells were clearly co-immunostained with alpha-smooth muscle actin as well as von Willebrand factor. G-CSF-mobilized stem cells co-expressed CD49d and CD34, which would have promoted their adhesion to cells in the ischemic muscle that expressed HGF-induced vascular cell adhesion molecule-1. The combination of G-CSF and HGF had a significant synergistic effect, suggesting that the combination of mobilization of stem cells from bone marrow to peripheral circulation and their recruitment to the ischemic area might potentiate angiogenesis and vasculogenesis.
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PMID:G-CSF and HGF: combination of vasculogenesis and angiogenesis synergistically improves recovery in murine hind limb ischemia. 1722 29

Acute renal failure (ARF) is a clinical syndrome characterized by deterioration of renal function over a period of hours or days. The principal causes of ARF are ischemic and toxic insults that can induce tissue hypoxia. Transcriptional responses to hypoxia can be inflammatory or adaptive with the participation of the hypoxia-inducible factor 1alpha and the expression of specific genes related to oxidative stress. The production of peroxynitrites and protein nitrotyrosylation are sequelae of oxidative stress. In several clinical and experimental conditions, inflammatory responses have been related to cyclooxygenase (COX)-2, suggesting that its activation might play an important role in the pathogenesis and progression of nephropathies such as ARF. In the kidney, renin and bradykinin participate on the regulation of COX-2 synthesis. With the hypothesis that in ARF there is an increase in the expression of agents involved in adaptive and inflammatory responses, the distribution pattern and abundance of COX-2, its regulators renin, kallikrein, bradykinin B2 receptor, and oxidative stress elements, heme oxygenase-1 (HO-1), erythropoietin (EPO), inducible nitric oxide synthase (iNOS), and nitrotyrosylated residues were studied by immunohistochemistry and immunoblot analysis in rat kidneys after bilateral ischemia. In kidneys with ARF, important initial damage was demonstrated by periodic acid-Schiff staining and by the induction of the damage markers alpha-smooth muscle actin and ED-1. Coincident with the major damage, an increase in the abundance of EPO, HO-1, and iNOS and an increase in renin and bradykinin B2 receptor were observed. Despite the B2 receptor induction, we observed an important decrease in COX-2 in the ischemic-reperfused kidney. These results suggest that COX-2 does not participate in inflammatory responses induced by hypoxia.
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PMID:Effect of ischemic acute renal damage on the expression of COX-2 and oxidative stress-related elements in rat kidney. 1724 95

Liver fibrosis is produced by myofibroblasts of different origins. In culture models, rat myofibroblasts derived from hepatic stellate cells (HSCs) and from periductal portal mesenchymal cells, show distinct proliferative and immunophenotypic evolutive profiles, in particular regarding desmin microfilament (overexpressed vs shut-down, respectively). Here, we examined the contributions of both cell types, in two rat models of cholestatic injury, arterial liver ischemia and bile duct ligation (BDL). Serum and (immuno)histochemical hepatic analyses were performed at different time points (2 days, 1, 2 and 6 weeks) after injury induction. Cholestatic liver injury, as attested by serum biochemical tests, was moderate/resolutive in ischemia vs severe and sustained in BDL. Spatio-temporal and morphometric analyses of cytokeratin-19 and Sirius red stainings showed that in both models, fibrosis accumulated around reactive bile ductules, with a significant correlation between the progression rates of fibrosis and of the ductular reaction (both higher in BDL). After 6 weeks, fibrosis was stabilized and did not exceed F2 (METAVIR) in arterial ischemia, whereas micronodular cirrhosis (F4) was established in BDL. Immuno-analyses of alpha-smooth muscle actin and desmin expression profiles showed that intralobular HSCs underwent early phenotypic changes marked by desmin overexpression in both models and that the accumulation of fibrosis coincided with that of alpha-SMA-labeled myofibroblasts around portal/septal ductular structures. With the exception of desmin-positive myofibroblasts located at the portal/septal-lobular interface at early stages, and of myofibroblastic HSCs detected together with fine lobular septa in BDL cirrhotic liver, the vast majority of myofibroblasts were desmin-negative. These findings suggest that both in resolutive and sustained cholestatic injury, fibrosis is produced by myofibroblasts that derive predominantly from portal/periportal mesenchymal cells. While HSCs massively undergo phenotypic changes marked by desmin overexpression, a minority fully converts into matrix-producing myofibroblasts, at sites, which however may be important in the healing process that circumscribes wounded hepatocytes.
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PMID:Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries. 1726 5

Recovery from acute renal failure (ARF) requires the replacement of injured cells by new cells that are able to restore tubule epithelial integrity. We have recently described the expression of nephrogenic proteins [Vimentin, neural cell adhesion molecule, basic fibroblast growth factor (bFGF), Pax-2, bone morphogen protein-7, Noggin, Smad 1-5-8, p-Smad, hypoxia-inducible factor-1alpha, vascular endothelial growth factor], in a time frame similar to that observed in kidney development, after ischemic ARF induced in an ischemia-reperfusion (I/R) model. Furthermore, we show that bFGF, a morphogen involved in mesenchyme/epithelial transition in kidney development, induces a reexpression of morphogenic proteins in an earlier time frame and accelerates the recovery process after renal damage. Herein, we confirm that renal morphogenes are modulated by bFGF and hypothesized that a decrease in bFGF receptor 2 (bFGFR2) levels by the use of antisense oligonucleotides diminishes the expression of morphogenes. Male Sprague-Dawley rats submitted to ischemic injury were injected with 112 microg/kg bFGFR2 antisense oligonucleotide (bFGFR2-ASO) followed by reperfusion. Rats were killed, and the expression of nephrogenic proteins and renal marker damage was analyzed by immunohistochemistry and immunoblot. Animals subjected to I/R treated with bFGFR2-ASO showed a significant reduction in morphogen levels (P < 0.05). In addition, we observed an increase in markers of renal damage: macrophages (ED-1) and interstitial alpha-smooth muscle actin. These results confirm that bFGF participates in the recovery process and that treatment with bFGFR2-ASO induces an altered expression of morphogen proteins.
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PMID:Inhibition of bFGF-receptor type 2 increases kidney damage and suppresses nephrogenic protein expression after ischemic acute renal failure. 1818 69


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