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)

The proximal tubule undergoes hypertrophy in response to loss of functioning renal mass and hyperplasia following injury by ischemia or nephrotoxins. Both hypertrophic growth and cell proliferation are characterized by increases in the rate of protein synthesis. To investigate regulation of protein synthesis in mammalian proximal tubule cells, potential peptide mediators of proximal tubule growth, epidermal growth factor (EGF) and angiotensin II, were studied in cultured rabbit proximal tubule cells. Although only EGF stimulated DNA synthesis, both agonists stimulated protein synthesis. One potential regulatory mechanism of eukaryotic protein synthesis involves phosphorylation of ribosomal protein S6 by activation of a specific serine/threonine kinase (S6 kinase). Both EGF and angiotensin II stimulated S6 kinase activity and S6 phosphorylation. Phorbol 12-myristate 13-acetate was also found to activate S6 kinase, and 24 h of pretreatment to deplete protein kinase C inhibited subsequent S6 kinase activation by a high concentration (10(-6) M) of angiotensin II. To determine whether S6 kinase was also activated in the kidney in vivo, S6 kinase activity was examined after ablation of renal mass. Within 1 h after contralateral nephrectomy, S6 kinase activity increased in rat renal cortex. In summary, both EGF and angiotensin II stimulated protein synthesis and S6 kinase activity in cultured proximal tubule cells, and S6 kinase activity also increased in renal cortex after contralateral nephrectomy.
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PMID:Regulation of S6 kinase activity in renal proximal tubule. 163 37

Gastric mucosa is constantly exposed to various irritants, but it usually maintains its integrity owing to several lines of defense, including mucus-alkaline secretion, mucosal hydrophobicity, rich mucosal blood flow, stabilization of tissue lysosomes, maintenance of mucosal sulfhydryls, and rapid proliferation and renewal of mucosal cells. Prostaglandins (PG) inhibit experimental gastric mucosal damage and ulcerations induced by a wide variety of agents, hence PG have been proposed to contribute to the overall protective process by activation of various mucosal defence lines--particularly by prevention of vasocongestion, ischemia, and deep hemorrhagic necrosis. The relation between tissue PG generation and mucosal protection does not appear to be closely related, and probably only minute amounts of PG are required to maintain mucosal integrity. In contrast to PG, other products of arachidonate metabolism, such as TxA2, LTC4 or LTD4, and the related lipid, platelet-activating factor, appear to mediate mucosal damage mainly by the disturbance in mucosal microcirculation and tissue ischemia. Gastroprotection can be achieved by stimulation of mucosal biosynthesis of protective PG or by the inhibition of the release or action of the proulcerogenic arachidonate metabolites. Certain natural substances, such as sulfhydryls, epidermal growth factor, or polyamines, protect the mucosa via a PG-independent mechanism, probably by enhancing the tissue repair processes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of gastroprotection. 220 98

To determine the timing and location of renal cell regeneration after ischemic injury to the kidney and to assess whether exogenous epidermal growth factor (EGF) enhances this regenerative repair process to accelerate recovery of renal function, experiments were undertaken in rats undergoing 30 min of bilateral renal artery clamp ischemia followed by reperfusion for varying time intervals. Renal cell regeneration, as reflected by incorporation of radiolabeled thymidine within the kidney, began between 24 to 48 h and reached a peak at 72 h after renal ischemia. As demonstrated by histoautoradiography, renal thymidine incorporation was essentially confined to tubule cells. Morphometric analysis of histoautoradiograph sections of renal tissue demonstrated that the majority of labeled cells were found in renal cortex, but some labeled cells were also located in the inner stripe of the outer medulla, suggesting that injury to medullary thick ascending limbs also occurs in this ischemic model. Exogenous EGF administration produced increases in renal thymidine incorporation compared with non-treated animals at 24, 48, and 72 h after ischemic injury. This accelerated DNA replicative process was associated with significantly lower peak blood urea nitrogen (BUN) and serum creatinine levels, averaging 63 +/- 20 and 3.1 +/- 0.4 mg/dl in EGF-treated ischemic rats compared with 149 +/- 20 and 5.1 +/- 0.1 mg/dl, respectively, in nontreated ischemic rats, and was also associated with a return to near normal BUN and serum creatinine levels in EGF-treated animals approximately 4 d earlier than that observed in nontreated animals. This report is the first demonstration that EGF accelerates the repair process of a visceral organ after an injurious insult.
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PMID:Epidermal growth factor enhances renal tubule cell regeneration and repair and accelerates the recovery of renal function in postischemic acute renal failure. 259 59

Levels of prepro epidermal growth factor (EGF) mRNA in renal cortical tissue and urinary EGF excretion have been determined during cisplatin and ischemia-induced acute renal failure in the rat. Northern analysis of polyadenylated RNAs of kidney cortical tissue showed diminished renal preproEGF mRNA in rats injected with cisplatin (5 mg/kg). The decrease in preproEGF mRNA occurred as early as 12 hours in the kidney and persisted for at least three days after cisplatin injection. The submandibular gland, a major site of EGF synthesis, contained normal levels of preproEGF mRNA. Transplatin, a non-nephrotoxic isomer of cisplatin, did not reduce renal preproEGF mRNA levels. Northern analysis of polyadenylated RNAs of kidney cortical tissue 24 hours after a 50 minute period of renal pedicle clamping also showed reduced preproEGF mRNA levels. By contrast, cisplatin increased renal c-fos mRNA. Urinary EGF excretion was also reduced after cisplatin and ischemia and the decrease in EGF excretion correlated significantly with the degree of renal failure. The data show that nephrotoxic and ischemic renal cell injury reduces preproEGF mRNA and urinary EGF excretion. Reduced preproEGF mRNA and diminished EGF excretion may be important in the functional and regenerative responses to renal injury.
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PMID:Reduced renal prepro-epidermal growth factor mRNA and decreased EGF excretion in ARF. 261 90

Renal tubular cells do not proliferate under normal intact conditions, whereas a marked regeneration is evident when tubular cells are injured by renal toxins or by ischemia. In case of compensatory renal growth too, hyperplasia of renal proximal tubular cells is observed. Various growth factors, including epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) seem to be involved in renal regeneration, however, the physiological role of these growth factors for the natural course of the renal regeneration have yet to be established. Hepatocyte growth factor (HGF), a potent mitogen for cultured renal tubular cells, may function as a renotropic factor, which enhances regeneration of the kidney. Once renal tubular cells are damaged by some agents, HGF mRNA, HGF activity and DNA synthesis of renal tubular cells are sequentially increased. Since both HGF mRMA and HGF protein are localized in renal interstitial cells, HGF seems to act on the tubular cells as a paracrine mediator. In addition to these results, HGF has multiple biological functions. This suggests that HGF possesses biological activities essential for renal regeneration.
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PMID:[Hypertrophy and hyperplasia of renal tubular interstitial cells--regulatory factors]. 756 25

Acute renal failure (ARF) is related to reversible tubular necrosis, usually caused by ischemia or toxic substances. Our knowledge of the pathophysiology of ARF stems from the study of animal models which reproduce either an ischemic or a toxic form of ARF. Classical studies using microdissection and micropuncture have characterized the salient mechanisms of ARF: vascular compromise with hypoperfusion and decrease in glomerular filtration rate, and tubular insult with cell necrosis and high intratubular pressure. More recent studies have emphasized the cellular and molecular events occurring during the course of ARF, including changes in cytoskeleton and matrix proteins, apoptosis and the role of Heat Shock Proteins. Endothelin and growth factors such as epidermal growth factor or hepatocyte growth factor seem to be important mediators in the regeneration phase of ARF. In various animal models, EGF, HGF or antagonists of endothelin receptors have a protective effect on renal function. These findings may be of clinical relevance, and suggest future therapeutic approaches in the treatment of ARF.
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PMID:[Experimental models of acute kidney failure]. 756 87

Nerve growth factor (NGF), which has been shown to act as a morphological and neurochemical differentiating factor in PC12 cells, also protects PC12 cells from the toxicity of serum withdrawal and ischemia. By using a previously established in vitro model of ischemia, which incorporates the combination of anoxia with glucose deprivation (Boniece and Wagner: J Neurosci 13:4220-4228, 1993), we have been able to study the signal transduction pathways upon which NGF-induced survival is dependent. Here we demonstrate that inhibitors of the N-kinase and NGF-induced neuritogenesis, 6-thioguanine and 2-aminopurine, prevent the protective effects of NGF, while they have little, if any, effect on the protection conferred by epidermal growth factor (EGF) or dbcAMP. This suggests that only NGF acts by a mechanism that depends strongly on the N-kinase. Furthermore, the methyltransferase inhibitor 5'-deoxy-5'-methylthioadenosine (MTA), which also inhibits NGF-induced neuritogenesis, inhibits the protective effect of NGF but not the protective effects of EGF or dbcAMP. Thus, the neuroprotective effect of NGF requires some of the same signal transduction steps used by NGF to promote differentiation and neurite formation. Furthermore, we found that exposure of PC12 cells to retinoic acid, which promotes the differentiation and inhibits the growth of PC12 cells, also improves cell survival during ischemia. In addition, a combination of NGF and retinoic acid was more effective than either agent alone. It is likely that these two agents confer protection by independent pathways.
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PMID:NGF protects PC12 cells against ischemia by a mechanism that requires the N-kinase. 771 16

The reversibility of ischemic renal injury is dependent on epithelial cell regeneration and repopulation of the nephron. Renal cells produce and respond to many growth factors. In the rat, epidermal growth factor (EGF) is mitogenic for tubular cells and accelerates renal recovery after ischemia. We used a pig renal autotransplant model to evaluate the effect of exogenous EGF on renal recovery in a large animal more analogous to man. Group 1 animals underwent left autotransplant after 120 minutes of warm ischemia and received either a single intra-arterial dose of recombinant human EGF (EGF, 10(-7) M.) (N = 11) or vehicle alone (N = 6). Group 2 animals underwent left autotransplant after 72 hours of cold preservation with Collins' solution and received a similar intra-arterial dose plus a subcutaneous dose of EGF (0.5 ml. of 10(-3) M.) (N = 8) or vehicle alone (N = 6). Contralateral nephrectomy was performed in all animals. Daily creatinine measurements revealed no beneficial effect from EGF on recovery of renal function in Group 1 or 2 animals. Studies of EGF on pig proximal tubular cells demonstrated in vitro mitogenesis; autoradiography with 125I-EGF revealed binding of EGF throughout the kidney. Immunohistochemistry showed significant tubular cell proliferation in response to ischemic injury, without further enhancement from EGF. Thus, although exogenous EGF bound to pig kidney cells and stimulated cell proliferation, we were unable to demonstrate a clinically significant acceleration of recovery from ischemic injury.
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PMID:Exogenous epidermal growth factor fails to accelerate functional recovery in the autotransplanted ischemic pig kidney. 810 11

The time course for the increases in soluble renal epidermal growth factor (EGF) after ischemia has been established. These elevated levels of EGF have been compared with the degree of tissue injury as well as the extent of cell proliferation in the recovering tissue. Levels of soluble immunoreactive EGF (irEGF) in control animals were 9.74 +/- 1.1 ng/g wet wt (n = 4-8 for all values) and rose to 83.9 +/- 30 ng/g within 12 h after injury. Soluble irEGF content peaked at 88.8 +/- 15 ng/g at 24 h postinjury and returned to control values by 72 h. We previously reported that trypsin digestion of crude renal membranes (CRM) generates rat EGF that is indistinguishable from that isolated from the submandibular gland. Initial levels of trypsin-releasable membrane-associated irEGF were 439 +/- 26 ng/g. These levels fell to 46.6 +/- 9.6 ng/g at 48 h after injury. The total renal EGF demonstrated an 80% decline 48 h after injury but returned to 50% of the initial values after 72 h representing significant new synthesis of EGF-containing proteins between 48 and 72 h postinjury. Immunohistochemical staining of kidney paraffin sections for EGF immunoreactivity demonstrated staining intensities that paralleled the amount of irEGF in the trypsin-digested CRM fraction, suggesting that the membrane-associated irEGF is the predominant form detected by this technique. Regenerative hyperplasia subsequent to tubular insult was monitored by immunostaining nuclei of S phase cells after pulse labeling with the thymidine analogue 5-bromo-2'-deoxyuridine. Cell proliferation was particularly prominent in the outer stripe of outer medulla of kidneys exposed to ischemia and reached a maximum (19-fold higher than the baseline value) 48 h after reperfusion. Renal cell turnover returned to control values by day 7. The observation that the peak in soluble EGF levels (24 h) precedes the peak in tubular regeneration (48 h) by 24 h is consistent with the hypothesis that EGF is one of the mitogenic signals triggering regenerative hyperplasia after renal injury.
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PMID:Endogenous EGF as a potential renotrophic factor in ischemia-induced acute renal failure. 821 2

We have established an in vitro model of ischemia incorporating the combination of anoxia with glucose deprivation, which is toxic to PC12 cells. In this model, nerve growth factor (NGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) improve PC12 cell survival. K252a, a specific inhibitor of NGF-induced trk p140 autophosphorylation, did not alter the neuroprotection provided by EGF or bFGF, yet it completely abolished the protection provided by NGF. Activation of protein kinase A (PKA) with dibutyryl-cAMP also protected during ischemia, although it was not additive with the effect provided by growth factors. Furthermore, growth factors protected a PKA-deficient mutant as effectively as the parental cell line; thus, activation of PKA is protective against ischemia but is not necessary for the action of peptide growth factors. Neither the stimulation of protein kinase C (PKC) with acute phorbol ester treatment nor the downregulation of PKC with chronic high-dose phorbol ester treatment resulted in an altered response to growth factors in either the PC12 wild type or PKA-deficient mutant. Thus, protection by peptide growth factors depends on neither PKA nor PKC. Furthermore, downregulation of PKC alone was protective, indicating that PKC may contribute to toxicity. Interestingly, treatment with the kinase inhibitor H-7 was neuroprotective and may have enhanced the neuroprotective effect of NGF. In contrast, staurosporine, a broadly acting kinase inhibitor, inhibited the neuroprotective effect of NGF, but not of EGF or FGF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Growth factors protect PC12 cells against ischemia by a mechanism that is independent of PKA, PKC, and protein synthesis. 841 Jan 84


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