Biomedical subjects

Muhammad M Yaqoob

Publications and source records attributed to Muhammad M Yaqoob.

At least 19 recordsLinked to original sources

PubMed2006

Long-term graft outcome with mycophenolate mofetil and azathioprine: A paired kidney analysis.

BACKGROUND: Randomized controlled trials and U.S. Registry data have demonstrated that mycophenolate mofetil (MMF) reduces acute rejection rates and improves graft survival. We undertook the first paired kidney analysis comparing the effects of MMF and azathioprine on graft outcome in the United Kingdom. METHODS: In all, 238 deceased donors from 1999 to 2002 who donated one kidney to a patient treated with MMF and the other kidney to a patient treated with azathioprine were identified from the national transplant database held by U.K. Transplant. Graft function and rates of change of graft function were compared using multiple linear regression analyses adjusting for covariates on an intention-to-treat basis. Incidence of acute rejection and delayed graft function were studied using logistic regression. Patient and graft survival censored for death were evaluated with Cox regression analyses. RESULTS: The MMF-treated patients exhibited a nonsignificant trend towards improved graft function but with increased rejection rates (44% versus 31%, P < 0.01). Treatment with MMF did not reduce delayed graft function rates. Univariate analysis showed that graft survival was inferior in MMF-treated patients (90% versus 95%, log-rank, P = 0.02) but in multivariate Cox regression models, MMF treatment was not a significant factor. Surprisingly, in the first year 32% of patients achieved daily doses of less than 2 g of MMF compared to 18% of patients who received less than 100 mg of azathioprine (P < 0.01). CONCLUSION: In this real-life study, there was no difference in patient or graft outcome between MMF and azathioprine treated groups despite increased rejection rates in patients receiving MMF therapy.

Azathioprine↗

PubMed2006

Erythropoietin and acute renal failure.

The hemopoietic growth factor erythropoietin (EPO) has been recognized to be a multifunctional cytokine that plays a key role in ischemic preconditioning in the brain and heart. The EPO receptor is expressed widely in the kidney, and we review the important findings from the use of EPO in experimental models of acute renal failure that show that EPO reduces tubular cell death and hence the dysfunction induced by ischemia reperfusion injury, and we explore how these observations may be translated into the clinical arena.

Acute Kidney Injury↗

PubMed2006

Increased L-arginine transport via system b0,+ in human proximal tubular cells exposed to albumin.

Albumin has complex effects on PTECs (proximal tubular epithelial cells) and is able to stimulate growth or injury depending on its bound moieties. Albumin itself is a mitogen, inducing proliferation through a number of pathways. In PTEC exposed to purified albumin, polyamines are required for entry into the cell cycle and are critical for proliferation. Polyamines are synthesized from L-ornithine (itself derived by the action of arginase on L-arginine), and the transport and availability of L-arginine may thus be important for subsequent polyamine-dependent proliferation. In the present study we investigated radiolabelled cationic amino-acid transport in cultured PTEC exposed to 20 mg/ml ultrapure recombinant human albumin, describing the specific kinetic characteristics of transport and the expression of transporters. L-[(3)H]Arginine transport capacity in human PTEC is increased after exposure for 24 h to human albumin, mediated by the broad-scope high-affinity system b(0,+) and, to a lesser extent, system y(+)L (but not system y(+)) transport. Increased transport is associated with increased b(0,+)-associated transporter expression. Inhibition of phosphoinositide 3-kinase, a key regulator of albumin endocytosis and signalling, inhibited proliferation, but had no effect on the observed increase in transport. PTEC proliferated in response to albumin. L-Lysine, a competitive inhibitor of L-arginine transport, had no effect on albumin-induced proliferation; however, arginine deprivation effectively reversed the albumin-induced proliferation observed. In conclusion, in PTEC exposed to albumin, increased L-arginine transport is mediated by increased transcription and activity of the apical b(0,+) transport system. This may make L-arginine available as a substrate for the downstream synthesis of polyamines, but is not critical for cell proliferation.

Albumins↗

PubMed2006

Insulin reduces the multiple organ injury and dysfunction caused by coadministration of lipopolysaccharide and peptidoglycan independently of blood glucose: role of glycogen synthase kinase-3beta inhibition.

OBJECTIVE: Insulin reduces morbidity and mortality among critically ill patients, but the molecular mechanisms of its effect remain unknown. Insulin is a well-known inhibitor of glycogen synthase kinase-3, which may play an important role in systemic inflammation and shock. Here we investigate the role of blood glucose and glycogen synthase kinase-3beta inhibition in the protective effect of insulin on the organ injury/dysfunction associated with excessive systemic inflammation. DESIGN: Prospective, randomized study. SETTING: University-based research laboratory. SUBJECTS: Eighty-five anesthetized Wistar rats. INTERVENTIONS: Rats received Escherichia coli lipopolysaccharide (1 mg/kg) and Staphylococcus aureus peptidoglycan (0.3 mg/kg) or vehicle intravenously. Insulin (1.4 units/kg intravenously) was administered in the absence or presence of continuous glucose administration (4.5 mg/kg/hr intravenously) either prophylactically or therapeutically. The potent and selective glycogen synthase kinase-3beta inhibitor TDZD-8 (1 mg/kg intravenously) or vehicle (10% dimethyl sulfoxide) was administered either prophylactically or therapeutically. MEASUREMENTS AND MAIN RESULTS: Coadministration of lipopolysaccharide and peptidoglycan resulted in increases in the serum levels of creatinine (indicator of renal dysfunction), alanine aminotransferase, and aspartate aminotransferase (indicators of liver injury) at 6 hrs. Insulin or TDZD-8 similarly attenuated the organ injury/dysfunction caused by lipopolysaccharide and peptidoglycan when given either prophylactically or therapeutically. Continuous glucose administration had no effect on blood glucose levels or organ injury/dysfunction at 6 hrs. Treatment with insulin or TDZD-8 reduced the plasma levels of the proinflammatory cytokine interleukin-1beta. In vitro, insulin or TDZD-8 caused similar reductions in the nuclear factor-kappaB p65 activity and similar increases in the phosphorylation of Ser9 of glycogen synthase kinase-3beta. CONCLUSIONS: Therapy with insulin or the potent and selective glycogen synthase kinase-3beta inhibitor TDZD-8 reduced the organ injury/dysfunction caused by lipopolysaccharide and peptidoglycan in the rat. We propose that the inhibitory effect of insulin on the activity of glycogen synthase kinase-3beta contributes to the protective effect of insulin against the organ injury/dysfunction caused by excessive systemic inflammation independently of any effects on blood glucose.

Analysis of Variance↗

PubMed2006

COX-2 in inflammation and resolution.

Aspirin and the other NSAIDs have popularized the notion of inhibiting prostaglandins as a common anti-inflammatory strategy based on the erroneous premise that all eicosanoids are, within the context of inflammation, generally detrimental. However, our fascination with aspirin and the emergence of COX-2 has shown a more affable side to lipid mediators based on our increasing interest in the endogenous control of acute inflammation and in factors that mediate its resolution. Epilipoxins, for instance, are produced from aspirin's acetylation of COX-2 and together with Resolvins and COX-2-derived prostaglandins of the D(2) and J(2) series represent an increasingly important family of immunoregulatory lipid mediators with strong implications for disease control and drug discovery.

Animals↗

PubMed2005

Ouabain-induced cell signaling.

When endogenous ouabain was first isolated from human plasma in 1991, many expressed doubts that such a compound could be endogenous to humans because of its unusual structure, its unknown synthesis, and its unidentified site of origin. Furthermore, the relevance of human ouabain was questioned because of its apparently low (< or =nmol/L) circulating concentration. Since then, much progress has been made on the origin and synthesis of endogenous ouabain, but perhaps the most significant finding is that nanomolar concentrations of ouabain can induce numerous signal transduction events in both primary and immortalized cultures of cells. Here we analyze the effects of low ouabain-induced signals including cell proliferation, calcium mobilization, cell cytotoxicity, apoptosis, mitogen-activated protein kinase (MAPK) activation and other signaling pathways. Furthermore, we consider how these low dose ouabain-induced events might enable a putative role for human endogenous ouabain to be assigned.

Animals↗

PubMed2005

Mechanisms of high glucose-induced apoptosis and its relationship to diabetic complications.

Cellular responses to high glucose are numerous and varied but ultimately result in functional changes and, often, cell death. High glucose induces oxidative and nitrosative stress in many cell types causing the generation of species such as superoxide, nitric oxide and peroxynitrite and their derivatives. The role of these species in high glucose-mediated apoptotic cell death is relevant to the complications of diabetes such as neuropathy, nephropathy and cardiovascular disease. High glucose causes activation of several proteins involved in apoptotic cell death, including members of the caspase and Bcl-2 families. These events and the relationship between high glucose-induced oxidative stress and apoptosis are discussed here with reference to additional regulators of apoptosis such as the mitogen-activated protein kinases (MAPKs) and cell-cycle regulators.

Animals↗

PubMed2005

GSK-3beta inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat.

OBJECTIVE: Serine-threonine protein kinase glycogen synthase kinase (GSK)-3 is involved in regulation of many cell functions, but its role in regulation of inflammatory response is unknown. Here we investigate the effects of GSK-3beta inhibition on organ injury/dysfunction caused by lipopolysaccharide or coadministration of lipopolysaccharide and peptidoglycan in the rat. DESIGN: Prospective, randomized study. SETTING: University-based research laboratory. SUBJECTS: Ninety-nine anesthetized male Wistar rats. INTERVENTIONS: Study 1: Rats received either intravenous Escherichia coli lipopolysaccharide (6 mg/kg) or vehicle (1 mL/kg; saline). Study 2: Rats received either intravenous E. coli lipopolysaccharide (1 mg/kg) and Staphylococcus aureus peptidoglycan (0.3 mg/kg) or vehicle. The potent and selective GSK-3beta inhibitors TDZD-8 (1 mg/kg intravenously), SB216763 (0.6 mg/kg intravenously), and SB415286 (1 mg/kg intravenously) or vehicle (10% dimethyl sulfoxide) was administered 30 mins before lipopolysaccharide or lipopolysaccharide and peptidoglycan. MEASUREMENTS AND MAIN RESULTS: Endotoxemia resulted in increases in the serum levels of creatinine (indicator of renal dysfunction), aspartate aminotransferase, alanine aminotransferase (markers for hepatocellular injury), lipase (indicator of pancreatic injury), and creatine kinase (indicator of neuromuscular injury). Coadministration of lipopolysaccharide and peptidoglycan resulted in hepatocellular injury and renal dysfunction. All GSK-3beta inhibitors attenuated the organ injury/dysfunction caused by lipopolysaccharide or lipopolysaccharide and peptidoglycan. GSK-3beta inhibition reduced the Ser536 phosphorylation of nuclear factor-kappaB subunit p65 and the messenger RNA expression of nuclear factor-kappaB-dependent proinflammatory mediators but had no effect on the nuclear factor-kappaB/DNA binding activity in the lung. GSK-3beta inhibition reduced the increase in nuclear factor-kappaB p65 activity caused by interleukin-1 in human embryonic kidney cells in vitro. CONCLUSIONS: The potent and selective GSK-3beta inhibitors TDZD-8, SB216763, and SB415286 reduced the organ injury/dysfunction caused by lipopolysaccharide or lipopolysaccharide and peptidoglycan in the rat. We propose that GSK-3beta inhibition may be useful in the therapy of the organ injury/dysfunction associated with sepsis, shock, and other diseases associated with local or systemic inflammation.

Alanine Transaminase↗

PubMed2005

Albumin stimulates cell growth, l-arginine transport, and metabolism to polyamines in human proximal tubular cells.

BACKGROUND: Pure albumin stimulates proximal tubular epithelial cell (PTEC) proliferation, and may have a role in homeostasis in health, as well as in disrupted PTEC turnover in proteinuric nephropathies. We investigated a role for arginine and its metabolites, the polyamines, in this process, given the ability of polyamines to trigger proliferation in other mammalian cells. METHODS: [(3)H]-L-arginine uptake was examined after incubation with 20 mg/mL recombinant human serum albumin (rHSA) in HK-2 PTEC monolayers. Nitric oxide synthase (NOS) and arginase activity was measured; NOS, arginase, and ornithine decarboxylase (ODC) expression was identified by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Polyamine synthesis and intracellular amino acid concentrations were compared using high-performance liquid chromatography, and cell growth measured by [(3)H]-thymidine incorporation. RESULTS: In HK-2 PTEC exposed to 20 mg/mL rHSA for 24 hours, cell proliferation as determined by [(3)H]-thymidine incorporation was increased. In parallel, L-arginine transport capacity was increased in a dose- and time-dependent manner. This effect was specific to rHSA, and was not seen with transferrin or immunoglobulin G. The intracellular concentration of L-arginine remained unchanged, although L-ornithine was increased with rHSA incubation. rHSA up-regulated type II arginase mRNA, and increased arginase activity, although no difference in nitric oxide synthase expression or activity was seen. ODC mRNA was increased, as were intracellular polyamine concentrations. alpha-Difluoromethylornithine (DFMO), an ODC inhibitor, reduced intracellular polyamine concentrations and rHSA-induced cell proliferation to control levels. CONCLUSION: The arginine-ornithine-polyamine pathway appears enhanced in PTEC incubated with rHSA and is involved in cellular proliferation; this may offer novel approaches to understanding progressive proteinuric nephropathies.

Arginase↗

PubMed2005

The selective PPARgamma antagonist GW9662 reverses the protection of LPS in a model of renal ischemia-reperfusion.

BACKGROUND: We have recently reported that pretreatment of rats with endotoxin (lipopolysaccharide, LPS) and selective agonists of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) protect the kidney against ischemia/reperfusion (I/R) injury. Here we investigate the hypothesis that the renoprotective effects of LPS may be due to an enhanced formation of endogenous ligands of PPARgamma, rather than an up-regulation of PPARgamma expression. METHODS: Rats were pretreated with LPS (1 mg/kg, IP, 24 hours prior to ischemia) in the absence (control) or presence of the selective PPARgamma antagonist GW9662 (1 mg/kg, IP, 24 and 12 hours prior to ischemia). Twenty-four hours after injection of LPS, rats were subjected to 60 minutes of bilateral renal ischemia, followed by 6 hours of reperfusion. Serum and urinary indicators of renal injury and dysfunction were measured, specifically serum creatinine, aspartate aminotransferase, and gamma-glutamyl-transferase, creatinine clearance, urine flow, and fractional excretion of sodium. Kidney PPARgamma1 mRNA levels were determined by reverse transcriptase-polymerase chain reaction. RESULTS: Pretreatment with LPS significantly attenuated all markers of renal injury and dysfunction caused by I/R. Most notably, GW9662 abolished the protective effects of LPS. Additionally, I/R caused an up-regulation of kidney PPARgamma1 mRNA levels compared to sham animals, which were unchanged in rats pretreated with LPS. CONCLUSION: We document here for the first time that endogenous ligands of PPARgamma may contribute to the protection against renal I/R injury afforded by LPS pretreatment in the rat.

Anilides↗

PubMed2005

Caspase and calpain function in cell death: bridging the gap between apoptosis and necrosis.

Calpain and caspase are families of cysteine proteases that have important roles in the initiation, regulation and execution of cell death. The function of both groups of proteases in the progression of apoptotic and necrotic pathways is presented here in the context of a concise overview of regulated cell death. Many of the morphological differences between apoptotic and necrotic processes are thought to be as a consequence of the action of cysteine proteases. Recent studies suggest that caspase and calpain cascades are tightly interrelated and an appreciation of how these proteases cross-talk should enable a greater understanding of how the boundaries between apoptotic and necrotic cell death have become blurred. Furthermore, an assessment of the contribution that caspase and calpain make to human physiology and pathology is provided, with a description of how these proteases can be detected and quantified. Lastly, an evaluation is made of how caspase and calpain activation might be exploited diagnostically.

Apoptosis↗

PubMed2004

Coronary artery calcification measured with electron-beam computerized tomography correlates poorly with coronary artery angiography in dialysis patients.

BACKGROUND: Coronary artery calcification measured by electron-beam computerized tomography (EBCT) correlates with plaque burden and vessel stenosis and is predictive of future cardiac events in the general population. Uremic vascular calcification is common and widespread, tends to be medial as well as intimal, and may not relate solely to atherosclerotic lesions. Despite this difference and in the absence of any direct evidence in uremic patients, it is generally implied that coronary artery calcification equates to occlusive atherosclerosis. METHODS: We set out to compare the predictive value of coronary artery calcification assessed by EBCT with contemporaneous coronary angiography. We studied 18 patients with end-stage renal disease undergoing maintenance dialysis. Seventy-two coronary vessels were analyzed for angiographic evidence of stenotic disease and correlated with individual vessel calcification score. RESULTS: There was no significant correlation between degree of vessel stenosis and calcification score for individual vessels in patients with a positive calcium scan. Specificity was 48% and the positive predictive value was 53%. However, a calcification score <20 strongly correlated with the absence of significant luminal narrowing, and a 0 calcification score had a negative predictive value of 87.5%. CONCLUSION: Coronary artery calcification measured by EBCT is not an accurate marker of the degree of vessel stenosis in coronary artery disease in uremic patients and should not be used as a single screening test for atherosclerotic coronary disease.

Calcinosis↗

PubMed2004

Pretransplantation levels of C-reactive protein predict all-cause and cardiovascular mortality, but not graft outcome, in kidney transplant recipients.

BACKGROUND: Chronic inflammation, the common pathway that leads to cardiovascular disease and chronic allograft nephropathy after transplantation, is prevalent in patients with end-stage renal failure. We set out to investigate the hypothesis that enhanced pretransplantation C-reactive protein (CRP) levels and Chlamydia seropositivity, both markers of an altered immune response, would predict graft failure and mortality in patients receiving renal replacement therapy. METHODS: A retrospective study of 115 patients, based on CRP levels in pretransplantation serum (group 1, 0 to 5 mg/L; group 2, 5 to 10 mg/L; group 3, >10 mg/L), were investigated for the following end points: transplant rejection, graft failure, and all-cause and cardiovascular mortality. RESULTS: There were no correlations between CRP levels or Chlamydia seropositivity with respect to rejection rates or graft failure. Furthermore, there was no relationship between Chlamydia seropositivity and survival. All-cause and cardiovascular mortality were significantly greater in patients with CRP levels greater than 10 mg/L and 5 to 10 mg/L compared with those with CRP levels less than 5 mg/L. All-cause mortality rates were 5% in the 0-to-5-mg/L group, 20% in the 5-to-10-mg/L group, and 44% in the greater-than-10-mg/L group. With regard to cardiovascular mortality, death rates were 0% in the 0-to-5-mg/L group, 10% in the 5-to-10-mg/L group, and 22% in the greater-than-10-mg/L group. Univariate analysis of cardiovascular mortality and covariates showed a significant relationship with age (relative risk [RR], 1.07; P < 0.05), diabetes (RR, 5.6; P < 0.05), aspirin intake (RR, 0.2; P < 0.05), antihypertensive therapy (RR, 0.02; P < 0.05), and CRP level (RR, 11; P < 0.05), but CRP level remained the only significant predictor (RR, 1.19; P < 0.05) on multivariate analysis. CONCLUSION: Pretransplantation CRP level is independently associated with all-cause and cardiovascular mortality in our cohort of transplant recipients and may be a useful predictive marker in the follow-up of posttransplantation patients.

Adult↗

PubMed2004

Toluene and p-xylene induced LLC-PK1 apoptosis.

Occupational exposure to organic solvents was found to be associated with development and progression of tubulo-interstitial fibrosis and chronic renal failure. However, the cellular mechanism by which this occurs remains elusive. This study was conducted to evaluate the mode of cell death in proximal tubular cells exposed to organic solvents. LLC-PK1 cell line cytotoxicity due to exposure to 1 mM of either p-xylene or toluene was compared to untreated control by cell viability, LDH release, and DNA fragmentation. Cells were exposed to solvents for 96 hrs. Toluene and p-xylene reduced cell viability and increased DNA fragmentation. LDH release was unchanged. These data indicates that long-term exposure to organic solvents is associated with proximal tubule cell apoptosis, which may be the mechanism of progressive renal fibrosis and renal failure in patients with high solvent exposure.

Animals↗

PubMed2004

Role of cytochrome P4502E1 activation in proximal tubular cell injury induced by hydrogen peroxide.

BACKGROUND: There is now good evidence to suggest that cytochrome P450 (CYP450) may act as an iron-donating catalyst for the production of hydroxyl ion (OH*), which contributes to proximal tubular cell injury. However, it remains unclear which isoform of CYP450 is involved in this process. Cytochrome P4502E1 (CYP2E1) is a highly labile isoform which is not only involved in free radical generation, but has also been shown to be a source of iron in cisplatin-induced renal injury. This study investigates the role of CYP2E1 in the proximal tubular cell injury induced by hydrogen peroxide (H2O2). METHODS: Porcine proximal tubular cells (LLC-PK1) were incubated with H2O2 (1 mM) for 4 h in the presence or absence of 0.1 mM of two CYP2E1 inhibitors; diallyl sulfide (DAS), or disulfiram (DSF), desferrioxamine (DFO) (0.1-0.4 mM), or catalase (CT) (78, 150, 300 U/mL). Cell death was determined by measuring LDH release. CYP2E1 activity was determined by p-nitrophenol hydroxylation after 2 h incubation with H2O2. RESULTS: Exposure of LLC-PKI to H2O2 significantly increased cell death. CT, DFO, DAS and DSF significantly reduced H2O2-mediated cell death. Incubation with H2O2 increased CYP2EI activation in time- and dose-dependent manner, which was significantly reduced by CT, DFO, DAS and DSF. CONCLUSION: We propose that CYP2E1 activation occurs possibly due to OH* and contributes to H2O2-mediated LLC-PK1 cell necrosis by acting as a source of iron and perpetuating the generation of OH* via the Fenton reaction. Inhibition of CYP2E1 may be a novel approach for the prevention of tubular injury caused by oxidative stress.

Allyl Compounds↗

PubMed2004

Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion.

Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X(L) and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.

Animals↗

PubMed2004

Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia.

Here we investigate the effects of erythropoietin (EPO) on the tissue/organ injury caused by hemorrhagic shock (HS), endotoxic shock, and regional myocardial ischemia and reperfusion in anesthetized rats. Male Wistar rats were anesthetized with thiopental sodium (85 mg/kg i.p.) and subjected to hemorrhagic shock (HS; i.e., mean arterial blood pressure reduced to 45 mmHg for 90 min, followed by resuscitation with shed blood for 4 h), endotoxemia (for 6 h), or left anterior descending coronary artery occlusion (25 min) and reperfusion (2 h). HS and endotoxemia resulted in renal dysfunction and liver injury. Administration of EPO (300 IU/kg i.v., n = 10) before resuscitation abolished the renal dysfunction and liver injury in hemorrhagic, but not endotoxic, shock. HS also resulted in significant increases in the kidney of the activities of caspases 3, 8, and 9. This increase in caspase activity was not seen in HS rats treated with EPO. In cultured human proximal tubule cells, EPO concentration-dependently reduced the cell death and increase in caspase-3 activity caused by either ATP depletion (simulated ischemia) or hydrogen peroxide (oxidative stress). In the heart, administration of EPO (300 IU/kg i.v., n = 10) before reperfusion also caused a significant reduction in infarct size. In cultured rat cardiac myoblasts (H9C2 cells), EPO also reduced the increase in DNA fragmentation caused by either serum deprivation (simulated ischemia) or hydrogen peroxide (oxidative stress). We propose that the acute administration of EPO on reperfusion and/or resuscitation will reduce the tissue injury caused by ischemia-reperfusion of the heart (and other organs) and hemorrhagic shock.

Animals↗

PubMed2004

Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo.

BACKGROUND: Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells and is known to be up-regulated during states of hypoxia. Here we investigate the effects of renal ischemia/reperfusion (I/R) on the degree of renal dysfunction and injury with recombinant human EPO in mice when given as either a 3-day pretreatment, or upon reperfusion of the kidney. METHODS: Mice were treated with EPO (1000 IU/kg/day subcutaneously) for 3 days, or treated with EPO (1000 IU/kg subcutaneously) upon reperfusion, and subsequently subjected to bilateral renal artery occlusion (30 minutes) and reperfusion (24 hours). At the end of experiments, the following indicators and markers of renal injury and dysfunction were measured: plasma urea, creatinine, and aspartate aminotransferase (AST), tissue myeloperoxidase (MPO) activity [for polymorphonuclear leukocyte (PMN) infiltration], and tissue malonaldehyde (MDA) levels (for tissue lipid peroxidation). Kidneys were used for histologic evaluation of renal injury. RESULTS: EPO was able to significantly attenuate the renal dysfunction and injury associated with I/R, as well as the tissue injury. The increase in renal MPO activity and, hence, the degree of PMN infiltration were also significantly reduced in EPO-treated mice. In addition, lipid peroxidation as a result of renal I/R injury was also attenuated in EPO-treated mice. CONCLUSION: The protection afforded by the pretreatment regime of EPO was greater than that of administering EPO as a single bolus upon reperfusion. We propose that different mechanisms underlie the protective effects seen with EPO when given as either a daily pretreatment or as a single bolus, which need to be further investigated.

Animals↗