Posttreatment with Aminoguanidine Attenuates Renal Ischemia/Reperfusion Injury in Rats

Acute renal failure secondary to ischemia/reperfusion (I/R) injury is associated with significant mortality and morbidity. Aminoguanidine (AG), an inducible nitric oxide synthase inhibitor with antioxidant properties, has been reported beneficial in renal I/R injury. The aim of the present study was to investigate the effect of AG on renal I/R injury and compare the effectiveness of different AG treatment modalities. Sprague-Dawley rats were randomly assigned to one of four groups. The control group (n?=?6) received sham operation. The I/R group (n?=?6), AG-I group (n?=?8), and AG-II group (n?=?8) received bilateral renal ischemia for 45 min followed by 24 hours of reperfusion. The AG-I group received AG (50 mg/kg) intraperitoneally four hours and 10 minutes before the induction of ischemia. The AG-II group received AG (50 mg/kg) intraperitoneally four hours and 10 minutes after the initiation of reperfusion. Serum urea and creatinine levels increased significantly in the I/R and AG-I groups compared to the control group. Kidney samples from rats in the I/R and AG-I groups revealed severe tubular damage at histopathological examination. Posttreatment with AG significantly reduced serum urea and creatinine levels and improved histopathological lesions compared with the I/R group. Although pretreatment with AG failed to protect kidneys against I/R injury in this experimental model, posttreatment with AG attenuated renal dysfunction and histopathological changes after I/R injury.     

Effects of Sodium Valproate on Renal Functions in Rats

In recent years, it has been reported that sodium valproate occasionally can cause renal tubular impairment. This study was designed to demonstrate the renal tubular and glomerular functions in rats given sodium valproate as monotherapy, as well as to determine any reversibility of dysfunctions. Female rats were randomly allocated to three groups: group 1 received sodium valproate 500 mg/kg/d intraperitoneal for six weeks; after the same injection period, group 2 was housed for another six weeks, after which laboratory investigations were completed; and group 3 served as a control group made up of 20 healthy rats living in same condition without any treatment. Serum ALT, total protein, uric acid, ALP, phosphorus, sodium levels, and urine Ca/cr ratio were significantly different between groups 1 and 3 (p?<?0.025), but this difference was not seen between groups 2 and 3. On the other hand, other parameters such as TRP, Ccr, NAG, and MDA were not significantly different among the three groups (?p?>?0.025) These results suggest that SV does not have a significant dose- or time-related side effect on renal functions. Minor biochemical dysfunctions related to long-term sodium valproate therapy is reversible, and the minimal renal fibrosis that showed histopathologically is not clinically important. The renal tissues of rats are known to show similar metabolic and histological patterns with human renal tissues. No renal dysfunction was expected in humans because there were no clinically statistically significant renal side effects in this study.     

人参二醇组皂甙减轻肾缺血再灌流性兔血清致伤肾小管细胞的作用及机制

目的：用培养的人肾小管细胞，观察人参二醇组皂甙(PDS)减轻急性缺血再灌流肾损伤性兔血清(SIR)对小管细胞的损伤作用，并探讨其机制。方法：用夹闭法致兔肾缺血并提取缺血血清和对照血清，测定血清中的MDA、NO含量和SOD活力。不同的培养基(普通培养基、对照血清、缺血血清以及缺血血清加PDS)分别与肾小管细胞共培养96h，生化法测定培养液或细胞中MDA和NO含量以及SOD、LDH、Na -K -ATP酶和Ca^2 —ATP酶活力。结果：(1)SIR中MDA和NO含量较SC的高，而SOD活力则降低；(2)SIR可使培养液中MDA含量、细胞内的NO含量、LDH活力显升高，使细胞内的SOD、Na -K -ATP酶和Ca^2 —ATP酶活力明显降低，而PCIS则可抑制SIR的这些效应的发挥。结论：PDS具有减轻急性肾缺血再灌流性兔血清致肾小管细胞损伤的作用。其机制可能同增强SOD活力、减轻氧自由基和NO等的细胞毒性作用、增强ATP酶活性以维持生物膜结构和功能的完整性等作用有关。     

Renal Hemodynamics in AKI: In Search of New Treatment Targets

Novel therapeutic interventions are required to prevent or treat AKI. To expedite progress in this regard, a consensus conference held by the Acute Dialysis Quality Initiative was convened in April of 2014 to develop recommendations for research priorities and future directions. Here, we highlight the concepts related to renal hemodynamics in AKI that are likely to reveal new treatment targets on investigation. Overall, we must better understand the interactions between systemic, total renal, and glomerular hemodynamics, including the role of tubuloglomerular feedback. Furthermore, the net consequences of therapeutic maneuvers aimed at restoring glomerular filtration need to be examined in relation to the nature, magnitude, and duration of the insult. Additionally, microvascular blood flow heterogeneity in AKI is now recognized as a common occurrence; timely interventions to preserve the renal microcirculatory flow may interrupt the downward spiral of injury toward progressive kidney failure and should, therefore, be investigated. Finally, development of techniques that permit an integrative physiologic approach, including direct visualization of renal microvasculature and measurement of oxygen kinetics and mitochondrial function in intact tissue in all nephron segments, may provide new insights into how the kidney responds to various injurious stimuli and allow evaluation of new therapeutic strategies.     

去铁胺对缺血性急性肾衰竭大鼠的保护作用

目的：探讨去铁胺（DFO）对缺血性急性肾衰竭（iARF）大鼠的保护作用及其作用机制。方法：雄性Wistar大鼠，随机分成3组：假手术组、手术组、DFO＋手术组，每组各12只。用钳夹大鼠双侧肾蒂45min制成iARF动物模型，DFO＋手术组：缺血前24h给予DFO（200mg／kg）腹腔注射，其余处理同手术组。于缺血再灌注24h后检测血尿素氮（BUN）、肌酐（Scr）、超氧化物歧化酶（SOD）、丙二醛（MDA）的含量以及进行肾组织光镜形态学观察和采用免疫组织化学法测定低氧诱导因子-la（HIF-la）及血红素加氧酶（HO-1）蛋白的表达水平。结果：手术组BUN、Scr升高，SOD下降，MDA升高，HIF-1a、Ho-1中度提高，肾组织结构紊乱。DFO＋手术组除HIF-1a、HO-1含量大幅提高外，尚能显著逆转上述改变，两组间比较具有统计学意义（P〈0.01）。结论：DFO预处理可通过自由基清除和诱导HIF-1及下游基因HO-1过表达从而对iARF大鼠发挥保护作用。     

Renal plasma flow and glomerular filtration rate duringacute kidney injury in man

During acute kidney injury (AKI), lowered glomerular filtration rate (GFR) is believed to be consequent to reduced renal plasma flow (RPF). We aimed to systematically evaluate the evidence for such an association. Using specific search terms, we systematically interrogated the Pub Med electronic reference database for studies of human AKI where renal plasma or blood flow and GFR were measured; older articles were then identified by screening bibliographies of retrieved reports. We identified 22 articles describing 250 patients (203 native kidney, 47 in renal allograft). Of these studies, 8 articles (110 patients) estimated effective renal plasma flow (ERPF) by clearance techniques and 14 articles (140 patients) estimated true renal plasma flow (TRPF). Mean RPF was 272 mL/min (95% CI 213–331) and GFR 13.9 mL/min (9.9–17.9). Mean TRPF was significantly greater than mean ERPF (344 vs. 180, p = 0.004) despite lower mean GFR (8.8 vs. 20.4, p = 0.002). There was no significant association between RPF and GFR between studies. Eleven studies presented individual patient data (76 patients: 49 TRPF, 27 ERPF); here, individual patient ERPF was associated with GFR (r² = 0.52), but TRPF was not. During AKI in man, there is only a limited association between ERPF and GFR, and no detectable association between TRPF and GFR.     

肾衰Ⅱ号方对5/6肾切除大鼠肾血流量和肾内氧耗影响及其作用机制

目的：观察肾衰Ⅱ号方对于5/6（A/I）肾切除慢性肾衰竭大鼠模型的肾血流量和肾内氧耗影响及其作用机制。方法：采用经典5/6（Ablation/Infarction,A/I）肾切除慢性肾衰竭（CRF）模型法制作CRF动物模型,随机分为模型组（B组）、肾衰组（肾衰Ⅱ号方）（C组）、西药组（氯沙坦钾合蒙诺）（D组）,每组15只,另设假手术组（A组）15只。给予相应干预,60d后检测肌酐、尿素氮等生化指标,测定肾内血流量,计算残余肾内氧耗。结果：（1）造模后与A组相比,模型组尾动脉收缩压明显升高（P〈0.01）,舒张压升高（P〈0.05）。（2）干预结束后,与B组相比,C、D组的尿素氮、血肌酐下降（P〈0.05）,内生肌酐清除率上升（P〈0.05）,左肾静脉压升高（P〈0.05）,肾血流量升高（P〈0.05）,肾内氧耗明显降低（P〈0.01）,血红蛋白值上升（P〈0.05）,体重增加（P〈0.05）,左肾与体重比值下降（P〈0.05）;C组与D组比较,肾血流量、肾内氧耗组间差异有统计学差异（P〈0.05）,肾衰Ⅱ号方在提高肾血流量、降低肾内氧耗方面优于氯沙坦钾合蒙诺。干预前后比较,C组和D组治疗前后各组血肌酐、尿素氮的差异有统计学意义（P〈0.05）,肾衰Ⅱ号方在降血肌酐、尿素氮方面好于氯沙坦钾合蒙诺,在改善内生肌酐清除率方面两组治疗内生肌酐清除率的差异无统计学意义（P〉0.05）。结论：肾衰Ⅱ号方可以提高残余肾组织的肾血流量,降低肾内氧耗,改善肾功能,可能通过能量代谢变化延缓慢性肾脏病进程。     

Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury

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Garlic Extract Ameliorates Renal and Cardiopulmonary Injury in the Rats with Chronic Renal Failure

Abstract

Chronic renal failure (CRF) is associated with oxidative stress that promotes production of reactive oxygen species and cytokine release. We aimed to investigate the possible protective and antioxidant effects of aqueous garlic extract (AGE) in a rat model of CRF. Male Sprague-Dawley rats were randomly assigned as either CRF group with 5/6 reduction in the renal mass or sham-operated control group. CRF group received either saline or AGE (250 mg/kg/day/1 mL) orally for 3 weeks. At the end of the 3 weeks, rats were decapitated and trunk blood was collected. Creatinine, blood urea nitrogen (BUN) and lactate dehydrogenase (LDH) activity, and TNF-α and IL-1β levels were measured in the serum samples, while malondialdehyde (MDA), glutathione (GSH) levels, and myeloperoxidase (MPO) activity were determined in the kidney, lung, and heart samples. CRF caused significant decreases in tissue GSH, which were accompanied with significant increases in MDA levels and MPO activities, while the circulating levels of the LDH activity, creatinine, BUN, TNF-α, and IL-1β were elevated. AGE treatment alleviated CRF-induced oxidative changes in the injured tissues, while CRF-induced elevations in the blood levels of the pro-inflammatory cytokines and LDH were reduced. In conclusion, CRF-induced oxidative tissue injury occurs via the activation of pro-inflammatory mediators and by neutrophil infiltration into tissues and that the protective effects of garlic on CRF-induced injury can be attributed to its ability to inhibit neutrophil infiltration and pro-inflammatory mediators. These findings suggest that garlic, as a supplementary to diet, may have a potential therapeutic use in delimitating the systemic oxidant effects of CRF on remote organs.     

Hyperbaric Oxygen Therapy Alleviates Oxidative Stress and Tissue Injury in Renal Ischemia/Reperfusion Injury in Rats

Hyperbaric oxygen (HBO) therapy has been shown to attenuate renal ischemia/reperfusion (I/R) injury in rats, when applied in the early reperfusion period. The aim of this study was to elucidate possible beneficial effects of HBO therapy on renal I/R injury, when applied 24 h after ischemia. Rats were randomized into three groups: (1) control group (n = 20), (2) I/R group (n = 20), and (3) I/R + HBO group (n = 20). Renal I/R injury was created by interrupting renal blood flow for 30 min with a non-traumatic vascular clamp. HBO therapy was administered 24 h after I/R injury and continued for 5 days. At the end of the study, rats were sacrificed under anesthesia, blood was drawn, and right kidneys were harvested for analysis. Renal I/R injury increased serum and tissue malondialdehyde (MDA) levels and reduced superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. HBO therapy attenuated MDA levels by increasing SOD and GPx activities. HBO therapy also prevented neutrophil infiltration and tissue injury in kidneys. Taken together, HBO therapy has been found to be effective in the delayed period of I/R injury.     

Effects of Initiation of Continuous Renal Replacement Therapy on Hemodynamics in a Pediatric Animal Model

There are no studies analyzing the initial hemodynamic impact of continuous renal replacement therapy (CRRT) in children. We have performed a prospective observational study in 34 immature Maryland pigs to analyze the initial hemodynamic changes during venovenous CRRT. The heart rate, blood pressure, central venous pressure (CVP), pulmonary arterial occlusion pressure (PAOP), pulmonary capillary wedge pressure, temperature, and cardiac output (CO), simultaneously by pulmonary arterial thermodilution and femoral arterial thermodilution, were measured at 30-min intervals during 2 h. Venovenous CRRT induced an initial significant diminution of volemic hemodynamic parameters (intrathoracic blood volume, global end-diastolic volume, stroke volume index, PAOP, and CVP). Simultaneously, a significant increase in systemic vascular resistance index and left ventricular contractility, and a decrease in CO, was observed. We conclude that CRRT in a pediatric animal model induces initial hypovolemia, and a systemic cardiovascular response with vasoconstriction and increase in ventricular contractility.     

MicroRNA-687 Induced by Hypoxia-Inducible Factor-1 Targets Phosphatase and Tensin Homolog in Renal Ischemia-Reperfusion Injury

Ischemia-reperfusion injury contributes to tissue damage and organ failure in clinical settings, but the underlying mechanism remains elusive and effective therapies are still lacking. Here, we identified microRNA 687 (miR-687) as a key regulator and therapeutic target in renal ischemia-reperfusion injury. We show that miR-687 is markedly upregulated in the kidney during renal ischemia-reperfusion in mice and in cultured kidney cells during hypoxia. MiR-687 induction under these conditions was mediated by hypoxia-inducible factor-1 (HIF-1). Upon induction in vitro, miR-687 repressed the expression of phosphatase and tensin homolog (PTEN) and facilitated cell cycle progression and apoptosis. Blockade of miR-687 preserved PTEN expression and attenuated cell cycle activation and renal apoptosis, resulting in protection against kidney injury in mice. Collectively, these results unveil a novel HIF-1/miR-687/PTEN signaling pathway in ischemia-reperfusion injury that may be targeted for therapy.     

The Effect of Seventy-Two-Hour Continuous Infusion of Long-Acting Natriuretic Peptide on Acute Ischemic Renal Failure in the Rat

Objectives. Atrial natriuretic peptide (ANP_1-28) protects the kidneys against acute renal failure in animals; however, its use in humans has been disappointing. Long-acting natriuretic peptide (LANP_1-30) has natriuretic and diuretic actions similar to ANP_1-28, but it has a longer half-life and a different receptor site. Therefore, this study's aim was to determine if LANP_1-30 has better renal protection than ANP_1-28, which may make it useful in the treatment of acute renal failure. Subjects/Methods. Three groups of male Sprague-Dawley rats were used, each with a body weight between 250-300 gm. Group 1 (ischemia only, n = 6) had a right nephrectomy followed by 30 minutes of left renal pedicle clamping. Group 2 (LANP Peptide treated, n = 7) had renal ischemia similar to Group 1, followed by an intraperitoneal bolus of 10 μg of LANP_1-30 and the placement of mini-osmotic pumps delivering LANP_1-30 at a rate of 1μg/hr for 72 hours. Group 3 (controls, n = 6) was used to measure the baseline creatinine level and had no renal ischemia or surgery. Results. Seventy-two hours post-renal ischemia, the weight loss in the ischemia group was similar to the peptide treated group (7.65 ± 1.14% and 10.03 ± 0.9% body weight loss, respectively, p?=?0.126). The ischemia group had significantly higher creatinine levels compared to the controls (66.3 ± 5.3 versus 30.1 ± 0.9 μmol/L, p?=?0.002). The peptide-treated group had higher creatinine (174.1 ± 77.8 versus 66.3 ± 5.3 μmol/L, p?=?0.035) and LANP_1-30 levels (673.14 ± 69.64 versus 45.83 ± 8.45 pg/mL, p?=?0.001) than the ischemia group. Conclusion. Prolonged use of LANP_1-30 has no renal protective effect.     

Renal perfusion,oxygenation, and sympathetic nerve activity during volatile or intravenous general anaesthesia in sheep

Background

Global and intra-renal perfusion and oxygenation may be affected by the choice of anaesthetic. We compared the effects of isoflurane with those of propofol and fentanyl on renal blood flow (RBF) and intra-renal perfusion and oxygenation, and assessed how these were associated with renal sympathetic nerve activity (RSNA).

Effects of air-jet stress on renal blood flow in spontaneously hypertensive rats

Background Stressful psychological stimuli produce an increase in renal sympathetic nerve activity (RSNA) and a decrease in renal blood flow. Very few direct analyses of the relationship between RSNA and renal blood flow during the application of psychological stimuli have been conducted by recording these 2 measurements simultaneously in the same individual animals. Methods We simultaneously measured RSNA and renal blood flow as a Doppler shift in conscious, unrestrained, spontaneously hypertensive rats. The rats were stressed by directing a continuous air jet at their faces for 20 seconds. Results Air-jet stimulus increased RSNA 81%±15% (mean±standard error of the mean, n=10), mean arterial pressure (21±3 mm Hg), and renal vascular resistance (37%±6%), and decreased renal blood flow (−15%±2%). The percentage change in RSNA correlated positively with the change in mean arterial pressure (r=0.934,P<0.001) and percentage change in renal vascular resistance (r=0.912), and negatively with the percentage change in renal blood flow (r=−0.804). The denervation of renal nerves prevented renal blood flow from decreasing in response to air-jet stress. Conclusions A reduction in renal blood flow in response to short-term air-jet stress is elicited mainly by neural mechanisms in spontaneously hypertensive rats. Enhancement of RSNA by air-jet stimulus exerts a potent constricting effect on the renal vascular bed, resulting in a reduction in renal blood flow.     

Neural effects of natural behavior on renal blood flow in spontaneously hypertensive rats

Background In states of stress and exercise, renal blood flow is shown to be depressed, mainly through neural mechanisms. Little is known, however, about the effects of natural or spontaneous behaviors on renal blood flow and renal sympathetic nerve activity. Methods We simultaneously measured renal sympathetic nerve activity and renal blood flow as a Doppler shift during grooming and exploring behaviors in spontaneously hypertensive rats. We also tested the effects of vasodilating drugs on changes in renal blood flow. Results Grooming behavior (n=21) increased renal sympathetic nerve activity, mean arterial pressure, and decreased renal blood flow. Percentage changes in renal sympathetic nerve activity correlated negatively with percentage changes in renal blood flow. Exploring with rearing (n=14) induced similar but larger changes in these variables. Denervation of renal nerves suppressed a reduction in renal blood flow during these behaviors. After intravenous injection of manidipine (a calcium channel blocker) or CV-11974 (an angiotensin II receptor antagonist), the behavior-induced reduction in renal blood flow was significantly smaller than that found before treatment, despite similar increases in renal sympathetic nerve activity. Conclusion Natural behaviors decrease renal blood flow in relation to the enhancement of renal sympathetic nerve activity, which is similar to the responses of the animals to stressful psychologic stimuli. Vasodilating drugs can attenuate the reduction in renal blood flow.     

Combination of Renal Biomarkers Predicts Acute Kidney Injury in Critically Ill Adults

Objective: Most studies so far have focused on the performance of individual biomarkers to detect early acute kidney injury (AKI) in the adult intensive care unit (ICU) patients; however, they have not determined the predictive ability of their combinations. The aim of this study was to compare the predictive abilities of plasma neutrophil gelatinase-associated lipocalin (pNGAL), urine neutrophil gelatinase-associated lipocalin (uNGAL), plasma cystatin C (pCysC), serum creatinine (sCr), and their combinations in detecting AKI in an adult general ICU population. Methods: A total of 100 consecutive ICU patients were included in the analysis. AKI was defined according to RIFLE criteria. Biomarker predictive abilities were evaluated by area under the curve (AUC), net reclassi?cation improvement (NRI), and integrated discrimination improvement (IDI). Results: AKI occurred in 36% of patients 7 days post-admission. All three novel biomarkers as well as sCr had moderate predictive abilities for AKI occurrence. The most efficient combinations (pNGAL + sCr and pNGAL + uNGAL + sCr) were selected to participate in the subsequent analyses. Both combinations, when added to a reference clinical model, increased its AUC significantly (0.858, p = 0.04). Their NRI (0.78, p = 0.0002) was equal to that of pNGAL, but higher than that of the other three biomarkers, whereas their IDI was higher than that of any individual biomarker (0.23, p = 0.0001). Both combinations had better specificities, positive likelihood ratios, and positive predictive values than those of any individual biomarker. Conclusion: The biomarker combinations had better predictive characteristics compared with those of each biomarker alone.