losartan-potassium and Kidney-Tubular-Necrosis--Acute

Topics: Animals; Erythropoietin; Humans; Kidney Tubular Necrosis, Acute; Kidney Tubules

Aristolochic acid (AA) nephropathy, first reported as Chinese herbs nephropathy, is a rapidly progressive tubulointerstitial nephropathy that results in severe anemia, interstitial fibrosis and end-stage renal disease. Tubulointerstitial injury was studied in a mouse model of AA nephropathy to determine whether low-dose darbepoetin alpha (DPO) treatment prevents acute tubular necrosis and interstitial fibrosis.. AA was administered to C3H/He mice intraperitoneally and some mice were also treated with 0.1 microg/kg of DPO weekly starting on the day of AA administration or on day 28. At 28, 56 or 84 days, blood and urine samples were collected and mice were sacrificed for histological assessment of the kidneys.. AA-treated mice developed anemia, elevation of serum creatinine, severe tubular injury similar to acute tubular necrosis and progressive interstitial fibrosis. Although early treatment with low-dose DPO had minimal effects on the hematocrit, it significantly ameliorated acute tubular injury and interstitial inflammation through increasing the survival of tubular cells. As a result, it contributed to preservation of peritubular capillaries and reduction of interstitial fibrosis.. Low-dose DPO treatment conferred protection against acute tubular damage and attenuated interstitial fibrosis in a mouse model of AA nephropathy. Early administration of low-dose DPO may prevent the progression of acute tubular necrosis and the subsequent renal fibrosis in human AA nephropathy.

Topics: Animals; Apoptosis; Aristolochic Acids; Cell Proliferation; Darbepoetin alfa; Disease Models, Animal; Erythropoietin; Fibrosis; Kidney Tubular Necrosis, Acute; Kidney Tubules; Male; Mice; Mice, Inbred C3H

Erythropoietin (EPO) can induce a series of cytoprotective effects in many non-hematopoietic tissues through interaction with the erythropoietin receptor (EPOR), but whether EPO can prevent the overproduction of reactive oxygen species (ROS) and apoptosis in diabetes remains unclear. Here, we report that renal tubular cells possess EPOR and that EPO reduces high glucose-induced oxidative stress in renal tubular cells. Further, we found that EPO inhibited high glucose-induced renal tubular cell apoptosis and that this protective effect was dependent on reduction of Bax/caspase-3 expression as well as elevation of Bcl-2 expression. Our results suggest that EPO can inhibit high glucose-induced renal tubular cell apoptosis through direct effect on anti-oxidative stress and that EPOR may play a key role in this process.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Caspase Inhibitors; Cell Line; Erythropoietin; Flow Cytometry; Glucose; Kidney Tubular Necrosis, Acute; Kidney Tubules; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Rats; Reactive Oxygen Species; Receptors, Erythropoietin; RNA, Messenger

In this study, we have sought to establish the cellular origin and proliferative status of the renal parenchyma as it regenerates after damage induced by mercuric chloride, with or without erythropoietin treatments, that might alter the response.. Female mice were irradiated and male whole bone marrow was transplanted into them. Six weeks later recipient mice were assigned to one of four groups: control, mercuric chloride treated, erythropoietin treated and treated with mercuric chloride plus erythropoietin.. Tubular injury scores were high 3 days after mercuric chloride and had recovered partially after 14 days, in line with serum urea nitrogen levels. Confocal microscopy confirmed the tubular location of bone marrow-derived cells. A 'four-in-one' analytical technique (identifying cell origin, tubular phenotype, tubular basement membranes and S-phase status) revealed that tubular necrosis increased bone marrow derivation of renal tubular epithelium from a baseline of approximately 1.3% to approximately 4.0%. Erythropoietin increased the haematocrit, but no other effects were detected.. As 1 in 12 proximal tubular cells in S-phase was derived from bone marrow, we conclude that in the kidney, the presence of bone marrow-derived cells makes a minor but important regenerative contribution after tubular necrosis.

Topics: Adoptive Transfer; Animals; Blood Urea Nitrogen; Bone Marrow Cells; Cell Proliferation; DNA; Epithelial Cells; Epithelium; Erythropoietin; Female; Hematocrit; Hematopoiesis; Kidney Tubular Necrosis, Acute; Kidney Tubules; Male; Mercuric Chloride; Mice; Mice, Inbred C57BL; Recombinant Proteins; Regeneration; Thymidine; Time Factors

Administration of human recombinant erythropoietin (EPO) at time of acute ischemic renal injury (IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa (DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats (N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation (T0), or post-treated (6 h after the onset of reperfusion, T6) with EPO (5000 IU/kg), DPO (25 mug/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.08 +/- 0.03 mmol/l vs EPO-IRI 0.04 +/- 0.01 mmol/l, P = 0.01). Delayed administration of DPO or EPO (T6) also significantly abrogated subsequent renal dysfunction (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.06 +/- 0.01 mmol/l vs EPO-IRI 0.03 +/- 0.03 mmol/l, P = 0.01). There was also significantly decreased tissue injury (apoptosis, P < 0.05), decreased proapoptotic Bax, and increased regenerative capacity, especially in the outer stripe of the outer medulla, with DPO or EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult.

Topics: Acute Kidney Injury; Animals; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Cell Division; Creatinine; Darbepoetin alfa; Disease Models, Animal; Erythropoietin; Immunohistochemistry; Injections, Intraperitoneal; Kidney Tubular Necrosis, Acute; Kidney Tubules, Proximal; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Regeneration; Reperfusion Injury; Time Factors

Erythropoietin (EPO) has recently been shown to exert important cytoprotective and anti-apoptotic effects in experimental brain injury and cisplatin-induced nephrotoxicity. The aim of the present study was to determine whether EPO administration is also renoprotective in both in vitro and in vivo models of ischaemic acute renal failure.. Primary cultures of human proximal tubule cells (PTCs) were exposed to either vehicle or EPO (6.25-400 IU/ml) in the presence of hypoxia (1% O(2)), normoxia (21% O(2)) or hypoxia followed by normoxia for up to 24 h. The end-points evaluated included cell apoptosis (morphology and in situ end labelling [ISEL], viability [lactate dehydrogenase (LDH release)], cell proliferation [proliferating cell nuclear antigen (PCNA)] and DNA synthesis (thymidine incorporation). The effects of EPO pre-treatment (5000 U/kg) on renal morphology and function were also studied in rat models of unilateral and bilateral ischaemia-reperfusion (IR) injury.. In the in vitro model, hypoxia (1% O(2)) induced a significant degree of PTC apoptosis, which was substantially reduced by co-incubation with EPO at 24 h (vehicle 2.5+/-0.5% vs 25 IU/ml EPO 1.8+/-0.4% vs 200 IU/ml EPO 0.9+/-0.2%, n = 9, P<0.05). At high concentrations (400 IU/ml), EPO also stimulated thymidine incorporation in cells exposed to hypoxia with or without subsequent normoxia. LDH release was not significantly affected. In the unilateral IR model, EPO pre-treatment significantly attenuated outer medullary thick ascending limb (TAL) apoptosis (EPO 2.2+/-1.0% of cells vs vehicle 6.5+/-2.2%, P<0.05, n = 5) and potentiated mitosis (EPO 1.1+/-0.3% vs vehicle 0.5+/-0.3%, respectively, P<0.05) within 24 h. EPO-treated rats exhibited enhanced PCNA staining within the proximal straight tubule (6.9+/-0.7% vs vehicle 2.4+/-0.5% vs sham 0.3+/-0.2%, P<0.05), proximal convoluted tubule (2.3+/-0.6% vs vehicle 1.1+/-0.3% vs sham 1.2+/-0.3%, P<0.05) and TAL (4.7+/-0.9% vs vehicle 0.6+/-0.3% vs sham 0.3+/-0.2%, P<0.05). The frequency of tubular profiles with luminal cast material was also reduced (32.0+/-1.6 vs vehicle 37.0+/-1.3%, P = 0.05). EPO-treated rats subjected to bilateral IR injury exhibited similar histological improvements to the unilateral IR injury model, as well as significantly lower peak plasma creatinine concentrations than their vehicle-treated controls (0.04+/-0.01 vs 0.21+/-0.08 mmol/l, respectively, P<0.05). EPO had no effect on renal function in sham-operated controls.. The results suggest that, in addition to its well-known erythropoietic effects, EPO inhibits apoptotic cell death, enhances tubular epithelial regeneration and promotes renal functional recovery in hypoxic or ischaemic acute renal injury.

Topics: Animals; Apoptosis; Biopsy, Needle; Cell Survival; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Immunohistochemistry; In Vitro Techniques; Kidney Function Tests; Kidney Tubular Necrosis, Acute; Kidney Tubules, Proximal; Male; Probability; Rats; Rats, Sprague-Dawley; Reference Values; Regeneration

The involvement of proximal kidney tubules in erythropoietin production and/or in its control has been a subject of controversy among researchers. The present study addresses the problem whether acute tubular impairment affects erythropoietin production and thus alters the basic hematological parameters. For this purpose rats with hypobaric hypoxia-stimulated (42.55 kPa) erythropoesis were studied and the rat model of gentamicin-induced (50 mg/kg daily for 15 days) tubular damage was employed. According to the study protocol 4 different groups of rats were used: control rats, rats exposed to hypobaric hypoxia, rats treated with gentamicin prior to hypoxic exposure and finally rats given a dose of 50 U human recombinant erythropoietin for 2 days following treatment with gentamicin. The evaluated hematological parameters included: hemoglobin and hematocrit levels, reticulocyte count and plasma creatinine concentration. Histological analysis of kidney sections was also used. INCSTAR (USA) immunoassay was employed to determine plasma erythropoietin level. Evidence (histological and laboratory-elevated plasma creatinine) of distinct tubular lesions was found in rats injected with gentamicin. Hemoglobin and hematocrit levels were decreased in rats treated with gentamicin but a rise in reticulocyte count was seen on day 3 after hypoxic exposure--39@1000 +/- 10 vs. 5@1000 +/- 1.3 on day 0 (p < 0.001). Reduced reticulocyte counts on day 0 were not seen only in rats injected with human recombinant erythropoietin--36.33@1000 (p < 0.01). Hypoxia-induced increase in plasma erythropoietin was inhibited in animals treated with gentamicin--15.3 mU/ml (on day 0). Both hypoxic exposure and erythropoietin administration were associated with a rise in plasma erythropoietin on day 0--40.5 +/- 4.4 mU/ml and 42.7 +/- 4.1 mU/ml respectively, which normalised on day 3. The results of the study support the hypothesis that the erythropoietin response in rats after stimulation is related to the functional condition of the proximal kidney tubules.

Topics: Anemia; Animals; Disease Models, Animal; Erythropoiesis; Erythropoietin; Gentamicins; Hematologic Tests; Hypoxia; Kidney Tubular Necrosis, Acute; Kidney Tubules, Proximal; Male; Rats; Rats, Wistar; Recombinant Proteins

Topics: Adult; Anemia; Erythropoietin; Humans; Kidney Tubular Necrosis, Acute; Male; Spider Bites

The effects of recombinant human erythropoietin (r-HuEPO) on haematological parameters were studied in rats in which uraemia and anaemia had been induced by gentamicin, an aminoglycoside antibiotic and a nephrotoxic agent. After the occurrence of slight polycythaemia, the red blood cell count, haematocrit and haemoglobin concentration decreased by 20-30% compared with those of the control (saline-injected) rats. At the end of gentamicin treatment, the endogenous serum EPO level had decreased to about 40% compared with that of control rats. Gentamicin-treated rats showed marked elevation of blood urea nitrogen, extensive tubular necrosis in the kidney and haemosiderin deposition in the spleen. In the osmotic fragility test, the fragility of erythrocytes significantly increased compared with that of control rats. These findings indicate that the anaemia induced by gentamicin is due not only to a deficiency of EPO but also to an enhancement of fragility of erythrocytes in an azotaemic environment. The administration of r-HuEPO during anaemia markedly increased red blood cell count, haematocrit and haemoglobin concentration. It is suggested that a gentamicin-treated rat is a useful and convenient anaemic model and r-HuEPO is useful for treatment of anaemia in acute renal failure.

Topics: Anemia; Animals; Blood Volume; Erythropoietin; Gentamicins; Hematocrit; Kidney Tubular Necrosis, Acute; Male; Osmotic Fragility; Radioimmunoassay; Rats; Rats, Inbred Strains; Recombinant Proteins; Spleen; Uremia

Serum erythropoietin (EPO) concentrations were markedly depressed relative to the degree of anaemia in 10 patients with acute tubular necrosis, and remained low long after restoration of excretory renal function as estimated by glomerular filtration rate. Evidence is presented that the low serum EPO level is due to defective synthesis and not to increased catabolism. It is suggested that the predominantly are generatory anaemia found in prolonged cases of acute tubular necrosis, and the slow restoration of red cell mass during recovery, are due to the deficient synthesis of EPO. A positive erythropoietic response in a therapeutic trial with recombinant human erythropoietin (rhEPO) appears to support this hypothesis.

Topics: Acute Kidney Injury; Adult; Aged; Anemia; Creatinine; Erythropoietin; Female; Half-Life; Hemoglobins; Humans; Kidney Tubular Necrosis, Acute; Male; Middle Aged; Recombinant Proteins

The role of the kidney tubules in the renal formation of erythropoietin is incompletely understood. Therefore, the capability to produce erythropoietin in response to hypoxia was studied in rats with tubular lesions. Nephron damage was induced in two different ways. First, rats were treated with the nephrotoxic aminoglycoside gentamicin (67.5 mg/kg and day) for 14 days. The animals were then subjected to simulated altitude (6,800 m) for 6 h. The resulting plasma erythropoietin concentration was significantly lower (0.5 IU/ml) than in saline treated control rats exposed to hypoxia (1.0 IU/ml). Second, unilateral hydronephrosis was induced by ureteral ligation. The contralateral kidney was removed immediately before the animals were exposed to simulated altitude for 6 h. The plasma erythropoietin concentration in the ureter-ligated rats did not increase above the value (0.3 IU/ml) in hypoxia exposed anephric rats. These results indicate that the production of erythropoietin is reduced following tubular injury. Tubule cells may directly produce the hormone or interfere with the O2-sensing mechanisms controlling its synthesis. The latter hypothesis would seem to be supported by our failure to demonstrate in vitro erythropoietin production by the two established kidney tubule cell lines, LLC-PK1 and PK-15.

Topics: Altitude; Animals; Cell Line; Erythropoietin; Gentamicins; Hydronephrosis; Hypoxia; Kidney Tubular Necrosis, Acute; Kidney Tubules; Male; Rats; Rats, Inbred Strains