Production and activation of hepatocyte growth factor in acute renal failure

Hepatocyte growth factor (HGF) facilitates the regeneration of injured kidney in acute renal failure (ARF). HGF is produced as a single-chain precursor by cells of mesenchymal origin and is converted to a biologically active, heterodimeric molecule by proteolytic processing. We studied HGF mRNA and protein levels in systemic organs of glycerol-induced ARF rats, a model of crush syndrome. HGF protein concentration of tissue homogenate was measured by ELISA. Both mRNA and protein levels were increased in liver and spleen at 24 hours after the glycerol injection whereas HGF protein level was decreased in the injured kidney. Expression of HGF receptor/c-met mRNA was elevated only in the kidney. These results suggest that HGF supplied in an endocrine manner may play an important role in the regenerating process following ARF. Next, we measured serum HGF concentration by ELISA in 8 ARF patients caused by crush syndrome and the molecular size of serum HGF was determined by immunoblotting. Although serum HGF levels elevated in all patients, the HGF levels did not associate with their prognoses. While a single-chain molecule was predominantly observed in sera from chronic renal failure patients and healthy subjects, the majority of serum HGF was a heterodimeric form in 7 ARF patients. In one patient who developed disseminated intravascular coagulation syndrome and had a poor prognosis, a single-chain molecule was predominant although the serum HGF concentration was equivalent. These data suggest that the activity of proteolytic processing may be also an important factor for the expression of the biological function of HGF.     

Pre- or post-treatment with hepatocyte growth factor prevents glycerol-induced acute renal failure

Hepatocyte growth factor (HGF) is known to have beneficial effects against damage in various organs, including liver, kidney and lung, in disease models. Previously, we reported that repeated administration of HGF ameliorates renal dysfunction and histological alteration of glycerol-injected rats, an animal model for severe acute renal failure (ARF). In the present study, we investigated in more detail the efficacy of pre- and post-treatment of HGF in this model. ARF was induced by intramuscular injection of glycerol into the hind limbs of male Wistar rats. The efficacy of pre-treatment was studied by intravenous injection of HGF (1 mg/kg) or vehicle 1 and 18 hours prior to glycerol injection. Pre-treatment of HGF dramatically protected glycerol-induced ARF rats against death, and prevented deterioration of biochemical parameters for renal function. We also analyzed expression of heme oxygenase-1 (HO-1), a cytoprotective protein, in kidney of HGF-injected rats. Intravenous administration of HGF enhanced renal expression of HO-1 mRNA from 1 to 3 hours after injection. Next, as a post-treatment study, HGF (1 mg/kg/3 hours) with dopamine was infused into glycerol-induced ARF rats 7 hours after glycerol injection. Intravenous infusion of HGF after ARF onset also ameliorated renal biochemical parameters. These results indicate that pre-treatment of HGF can improve ARF, and induction of HO-1 expression in kidney may be a cause of the protective effect. In addition, post-treatment of HGF with dopamine was also effective against the establishment of ARF.     

Ameliorative effect of hepatocyte growth factor on glycerol-induced acute renal failure with acute tubular necrosis

BACKGROUND/AIMS: Hepatocyte growth factor (HGF), a multi-potent growth factor, is known to promote regeneration of damaged renal epithelial cells. Glycerol injection into rats induces severe acute renal failure (ARF) with ischemia and tubular necrosis, a model which shares many features with human ARF or rhabdomyolysis. We investigated the efficacy of HGF in this glycerol-induced ARF rat model. METHODS: ARF was induced by intramuscular injection of glycerol into the hind limbs of male Wistar rats. HGF (0.25 mg/kg/shot) or vehicle was administered intravenously 1 h before and 1, 3, 5, 8, 24 and 36 h after glycerol injection. Biochemical parameters for serum and urine were measured and histological analyses of the kidneys were performed. We also analyzed endogenous HGF expression and phosphorylation of c-Met/HGF receptor in the kidneys of glycerol-induced ARF rats. RESULTS: Glycerol treatment caused severe ARF which invariably led to death of the rats. Repeated administration of HGF protected rats from death caused by severe ARF. Histological analyses revealed that HGF treatment reduced necrosis of tubular cells in the renal cortex. Serum/urine biochemical parameters also showed that renal dysfunction was improved by HGF administration. Intravenous administration of HGF enhanced phosphorylation of the c-Met/HGF receptor and mitogen-activated protein kinase in the kidney. In the vehicle-treated group the renal endogenous HGF concentration decreased and there was no change in c-Met/HGF receptor phosphorylation. CONCLUSION: These results indicate that HGF effectively accelerated the recovery of renal function and improved survival in glycerol-induced ARF rats.     

Serum hepatocyte growth factor levels in patients with renal diseases.

The serum levels of hepatocyte growth factor (HGF) were determined in patients with various renal diseases. In patients with acute-phase acute renal failure (ARF) and chronic tubulointerstitial nephritis (chronic TIN), the serum HGF levels were 0.55 +/- 0.24 and 0.44 +/- 0.37 ng/ml (mean +/- SD), respectively, and were significantly higher than that in the control group (0.12 +/- 0.12 ng/ml). The serum HGF level tended to be high also in patients with active-phase steroid-sensitive nephrotic syndrome (SSNS). The serum levels of HGF were not elevated in patients with IgA nephropathy (IgAN), Henoch-Sch?nlein purpura nephritis (HSPN), membranoproliferative glomerulonephritis (MPGN), poststreptococcal acute glomerulonephritis (PSAGN), unilateral renal atrophy, unilateral nephrectomy, or proximal tubular dysfunction. These observations suggest that glomerular disorders cause no apparent elevation of the serum HGF level, and that elevation of the serum HGF level may be associated with tubulointerstitial damage in renal diseases.     

Serum HGF levels in acute renal rejection after living related renal transplantation

Hepatocyte growth factor (HGF), a long sought-after hepatotrophic factor, has recently been shown to act as a renotrophic factor in regeneration of the kidney. We investigated serum HGF levels in 16 renal transplant patients. In patients with acute rejection, the serum HGF level was markedly increased (over 1 ng/ml), and its elevation was accompanied by an increase in serum creatinine and blood urea nitrogen (BUN). In contrast, serum HGF levels were continuously low in patients without rejection. We conclude that serum HGF may become a clinically useful marker for the assessment of acute renal rejection.     

Prevention of acute ischemic renal failure by targeted delivery of growth factors to the proximal tubule in transgenic mice: the efficacy of parathyroid hormone-related protein and hepatocyte growth factor

Treatment of acute renal failure (ARF) would be enhanced by identification of factors that accelerate renal recovery from injury. Parathyroid hormone-related protein (PTHrP) and hepatocyte growth factor (HGF) have been shown to stimulate proliferation in proximal nephron-derived cells. For studying the pathophysiologic roles and therapeutic potential of these two factors in ARF, transgenic mice overexpressing PTHrP or HGF in the proximal tubule under the direction of the gamma-glutamyl transpeptidase-I promoter were developed. These mice display (1) abundant expression of the respective transgenes in the kidney; (2) similar PTH type I receptor and HGF receptor (c-met) expression levels in the proximal tubule compared with control littermates; and (3) normal renal morphology, function, and tubule cell proliferation under basal conditions. However, in contrast to control mice, when acute ischemic renal injury was induced, renal function rapidly and dramatically recovered in HGF-overexpressing mice. In addition, 48 h after ischemia, HGF-overexpressing transgenic mice displayed a fourfold increase in tubule cell proliferation and a threefold decrease in apoptotic tubule cell death compared with control mice. In contrast, PTHrP-overexpressing mice responded to either ischemic or folic acid-induced renal damage similarly to control mice. These studies demonstrate that overexpression of PTHrP in the proximal nephron of mice does not seem to provide protection against acute renal injury. In marked contrast, HGF overexpression results in dramatic protection from ischemia-induced ARF, without inducing any apparent alteration in the physiology of the kidney under normal conditions. These studies suggest that HGF, when targeted specifically to the proximal tubule, may have therapeutic potential in providing protection against ischemia-induced renal failure.     

汶川地震伤致挤压综合征合并肾功能衰竭患者的救治

目的 回顾性分析汶川地震挤压综合征(CS)的治疗结果,为指导类似灾难性事件中挤压伤、cs的救治提供理论依据和指导.方法 2008年5月12口汶川地震后所致49例合并急性肾脏功能衰竭(ARF)的cS患者,致伤原因均为地震中被重物砸伤;受挤压时间4～102 h,平均24.7 h.男27例,女22例;年龄6.8～76.0岁,平均31.8岁.平均累计肢体1.5肢.49例存在ARF,血Cr平均365.6μmol/L(169～842 μmol/L),CK平均64 022 U/L(34 571～76 836 U/L),均出现肌红蛋白尿,39例合并有高钾血症(血钾5.23～6.38 mmoL/L).所有患者均予持续肾脏替代疗法(CRRT)治疗,补液、利尿、碱化尿液和纠正电解质紊乱、输血、改善低蛋白血症、预防或治疗创面感染治,扩创换药、扩创缝合.结果 CRRT治疗49例,肾脏功能在11～37 d恢复.高钾血症均在入院后当天纠正.CK在人院后13～45 d恢复正常.无1例死亡.骨筋膜间室切开减压30例52肢,截肢35例45肢.5例因感染、肢体坏死行二次截肢手术.24例创而经换药、扩创或植皮愈合,8处创面(4例)因感染、组织坏死或创面过大等原因未愈合,均为长时间(>20 d)接受CRRT治疗患者,并合并有其他系统、器官损伤.结论 及时明确诊断、积极有效的早期局部和全身治疗,是成功治疗CS,降低并发症发生率和病死率的关键.CS时创面愈合与长时间CRRT治疗之间的协调,是目前部分尚存创而患者治疗的难点.     

Hepatocyte growth factor protects functional and histological disorders of HgCl(2)-induced acute renal failure mice

Hepatocyte growth factor (HGF) enhances proliferation of renal epithelial cells as well as hepatocytes. HGF accelerates recovery from acute renal failure (ARF) in animal models. However, pharmacological profiles of HGF including its action mechanism has not been studied in detail. An HgCl(2)-induced ARF mouse was used in this study to evaluate the efficacy of HGF. Single administrations of recombinant human HGF or vehicle were given to ARF mice 30 min after HgCl(2) injection. Renal function was monitored by measuring serum creatinine, blood urea nitrogen and creatinine clearance. In the ARF mice, there was a deterioration of renal function biochemical parameters and histological evidence of renal damage including acute tubular necrosis of proximal tubules. These were both significantly ameliorated by a single HGF administration. The effect of HGF was noticeable in the early phase of ARF (1 day after onset) when there was no histological evidence of increased labeling indexes in renal tubular epithelial cells. Western blot analysis of the c-Met/HGF receptor showed that tyrosine phosphorylation was enhanced immediately after HGF administration indicating direct activation of renal epithelial cells. HGF prevented increase of apoptotic nuclei with DNA fragmentation in renal epithelial cells which suggests cytoprotective activity of HGF on renal epithelial cells in the ARF mice.     

肾皮质大部分切除与肾缺血再灌注损伤对大鼠肾干、祖细胞的影响及其对肾损伤预后的意义

目的 比较肾皮质大部分切除与肾缺血再灌注损伤对大鼠肾干、祖细胞的影响,探讨肾干、祖细胞在肾脏损伤修复中的意义及急性肾衰竭（AFR）和慢性肾衰竭（CRF）预后不同的可能机制。 方法 肾动脉结扎再灌注和5/6肾皮质切除术（假手术为对照）分别制作SD大鼠ARF和CRF模型,定期监测血肌酐、尿素氮及24 h尿蛋白量。于设定时间采集肾脏标本,HE染色检查病理改变,免疫荧光检测肾鲍曼囊区CD24、CD133及肾小球podocin表达;RT-PCR检测大鼠肾皮质区podocin mRNA表达和肾组织转化生长因子β1（TGF-β1）、Notch2、肝细胞生长因子（HGF）、成骨蛋白7（BMP7）和Pax-2 mRNA表达。分析5/6肾皮质切除术后Pax-2 mRNA表达量与podocin mRNA表达量及肾小球硬化指数（GSI）的相关性。 结果 两种模型大鼠分别出现急、慢性肾衰竭的典型肾脏病理及功能变化。CRF组随时间延长肾小球硬化指数逐渐升高,于术后第14、30、60、90天分别为（2.34±0.28）%、（25.12±5.67）%、（89.42±12.28）%和（171.23±32.28）%。与假手术组比较,ARF组不同时间点大鼠鲍曼囊区CD24+CD133+表达细胞分布无显著变化,而CRF组大鼠鲍曼囊区CD24+CD133+表达细胞逐渐减弱;ARF组肾小球podocin表达有短暂减少后迅速恢复,而CRF组肾小球podocin表达则进行性减少。与假手术组相比,ARF组HGF、BMP7 mRNA表达升高（P ＜ 0.05）,而CRF组TGF-β1、Notch2 mRNA表达升高（P ＜ 0.05）,Pax-2和podocin mRNA表达均进行性减少（P ＜ 0.05）。后两者呈正相关（r = 0.872）,且均与GSI呈负相关（r = -0.906、-0.872,均P ＜ 0.05）。 结论 肾脏缺血再灌注损伤对大鼠肾干、祖细胞无明显损伤,足细胞修复迅速,肾脏结构及功能完全恢复。肾皮质大部分切除引起大鼠肾干、祖细胞所处环境中生长抑制因子水平上调,促生长因子降低,导致肾干、祖细胞逐渐减损,足细胞修复缺陷,肾小球硬化及肾功能进行性衰竭。两种肾损伤对肾脏干、祖细胞的不同影响及由此产生肾脏再生修复功能的差异可能是其预后不同的主要机制。     

地震挤压综合征血液透析患者营养状态分析

目的评估地震致挤压综合征血液透析患者营养状态,为临床提供治疗依据。方法收集我院2008年5月12日后收治的汶川地震所致挤压综合征接受血液透析的患者24例,用比色法测量相关生化指标进行营养评估。结果所有患者血尿素氮、血肌酐、血白介素-6、C反应蛋白均升高;95．8％的患者血清白蛋白减低,100%的患者血清铁及转铁蛋白饱和度降低,87．5％的患者血清前白蛋白降低,92．9％的患者转铁蛋白降低,56．3％的患者总胆固醇降低。结论地震所致挤压综合征透析患者均存在营养不良,应对地震急性挤压伤透析患者加强营养支持治疗。     

肝细胞生长因子负性调控细胞转分化在肾间质纤维化中的作用

目的 研究肝细胞生长因子(HGF)对单侧输尿管梗阻(UUO)大鼠肾间质纤维化的保护作用及其可能机制｡方法 大鼠随机分为UUO组､HGF治疗组和假手术组｡用实时荧光定量RT-PCR､Western杂交和免疫组化检测术后大鼠肾组织结缔组织生长因子(CTGF)和骨形成蛋白7(BMP7)表达量｡免疫组化检测大鼠肾组织TGF-β1､FN及α-SMA表达｡结果 与假手术组相比,UUO组及HGF治疗组CTGF mRNA､TGF-β1､α-SMA､FN､CTGF蛋白表达均增高,且UUO组明显高于治疗组;UUO组及HGF治疗组BMP7 mRNA和蛋白表达均减少,且UUO组显著低于治疗组｡结论 HGF能减轻肾间质纤维化,负性调控肾小管上皮细胞-肌成纤维细胞转分化,调节CTGF及BMP7表达可能是其作用途径｡     

VCAM-1, ICAM-1, and E-selectin in IgA nephropathy and Schönlein-Henoch syndrome: differences between tissue expression and serum concentration

The tissue expressions of vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) and endothelial leukocyte adhesion molecule 1 (E-selectin-1) were investigated in biopsy specimens from 28 patients with different stages of IgA nephropathy (IgAN) and 20 patients with acute renal failure (ARF) or chronic renal diseases (amyloidosis, Alport's glomerulopathy) by immunohistochemistry. The results were compared with the serum levels of the three adhesion molecules. VCAM-1 expression was significantly increased on parietal/tubular epithelial cells in IgAN and ARF. Significantly elevated circulating VCAM-1 levels were measured in IgAN and amyloidosis, but did not correlate with renal function (creatinine clearance). Significantly increased glomerular endothelial/epithelial ICAM-1 expression was found in IgAN and ARF. Intense mesangial ICAM-1 expression was found in mild stages of IgAN and in Sch?nlein-Henoch syndrome. Circulating ICAM-1 was not significantly elevated in IgAN and different renal diseases. VCAM-1 and ICAM-1 expressions of interstitial infiltrating cells were significantly higher in severe than in mild IgAN and associated with an increased infiltration of inflammatory leukocytes. Patients with IgAN and different renal diseases had decreased mesangial and almost absent interstitial E-selectin expression as compared with controls. The circulating E-selectin levels were significantly elevated in ARF. In conclusion, the tissue expression of adhesion molecules in IgAN reflects a continuous inflammatory renal activity. However, only increased circulating VCAM-1 serum levels correlated significantly with the histological state of renal inflammation and could be used as a disease marker.     

RIFLE Criteria and Hepatic Function in the Assessment of Acute Renal Failure in Liver Transplantation

Renal dysfunction in cirrhotic patients is primary related to disturbances of circulatory function, triggered by portal hypertension with chronic intrarenal vasoconstriction and hypoperfusion. Pretransplant renal function is an important factor implicated in the development of acute renal failure (ARF) after liver transplantation (OLT), but other factors mostly related to liver function seem to influence the development of ARF.The Acute Dialysis Quality Initiative workgroup developed the RIFLE classification to define ARF. We sought to evaluate the incidence of ARF among patients undergoing OLT, to evaluate the association of ARF with pre-OLT renal and hepatic functions, and to evaluate the influence of ARF on chronic kidney disease (CKD) at 1 month post-OLT.Clinical, renal, hepatic function, and donor risk index data of 24 patients who underwent deceased donor OLT were collected before transplantation, in the perioperative period and in the first month post-OLT. ARF occurred in 37.5% of patients with 56% developing the R grade and 44% the I grade; no patient showed the F grade.An association was observed between ARF and a higher Model for End-Stage Liver Disease (MELD) score and between ARF and a reduced pre-OLT serum albumin. No association was noted between ARF and other pre-OLT parameters. In cirrhotic patients serum creatinine is a bias for renal function assessment and the Modification of Diet in Renal Disease formula overestimates GFR. Post-OLT CKD was present in 6.7% of patients without ARF and in 44.4% of patients with ARF. The R grade developed more frequently among patients with viral cirrhosis.The association of ARF with MELD and hypoalbuminemia may be the result of a close relationship between renal and hepatic functions among cirrhotic patients. Post-OLT CKD may be the result of unrecognized, preexisting CKD and/or the effects of not fully resolved acute damage to an injured kidney.     

Early detection of acute renal failure by serum cystatin C

BACKGROUND: Acute renal failure (ARF) is associated with high mortality. Presently, no specific therapy for ARF exists. Therefore, early detection of ARF is critical to prevent its progression. However, serum creatinine, the standard marker to detect ARF, demonstrates major limitations. We prospectively evaluated whether serum cystatin C detected ARF earlier than serum creatinine. METHODS: In 85 patients at high risk to develop ARF, serum creatinine and cystatin C were determined daily. ARF was defined according to the Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, and ESRD (RIFLE) classification when creatinine increased by >/=50% (R-criteria), by >/=100% (I-criteria), or by >/=200% (F-criteria). In analogy, ARF was detected when cystatin C increased by >/=50%, by >/=100%, or by >/=200%. RESULTS: Forty-four patients developed ARF and 41 served as controls. In ARF by R-, I-, and F-criteria, the increase of cystatin C significantly preceded that of creatinine. Specifically, serum cystatin C increased already by >/=50% 1.5 +/- 0.6 days earlier compared to creatinine. Serum cystatin C demonstrated a high diagnostic value to detect ARF as indicated by area under the curve of the ROC analysis of 0.82 and 0.97 on the two days before the R-criteria was fulfilled by creatinine. Cystatin C detected ARF according to the R-criteria with a sensitivity of 55% and 82% on these days, respectively. Cystatin C also performed excellently, detecting ARF defined by the I- and F-criteria two days prior to creatinine, and moderately well predicting renal replacement therapy in the further course of ARF. Additionally, low T(3)- or T(3)/T(4) syndrome, glucocorticoid deficiency and excess did not affect cystatin C levels, adding to its usefulness in critically ill patients with ARF. CONCLUSION: Serum cystatin C is a useful detection marker of ARF, and may detect ARF one to two days earlier than creatinine.     

肾移植术后肝细胞生长因子的动态监测及临床意义

目的:探讨肝细胞生长因子(HGF)在急性排斥反应的早期诊断、鉴别诊断中的意义。方法:采用双抗体夹心酶联免疫吸附法,对50例肾移植受者血清HGF水平在手术前后进行动态监测。观察肾移植术后发生急性排斥反应(AR)、急性肾小管坏死(ATN)、环孢素(CsA)中毒时血清HGF的变化。结果:术前组HGF水平与对照组相比有统计学意义(P<0.05)。稳定组术后前3天HGF下降明显,2周左右降至对照组水平。AR组在典型症状出现及血Cr升高前1~3d,HGF即有升高,且峰值出现在抗排斥治疗的当天。经甲基泼尼松龙冲击后AR逆转者HGF迅速下降。ATN组HGF升高,与AR组相比有统计学意义(P<0.05)。CsA中毒组HGF水平升高,与AR相比有统计学意义(P<0.05),但与ATN组相比无统计学意义(P>0.05)。结论:动态监测HGF可能作为急性排斥反应的早期诊断敏感指标,并且对ATN、CsA中毒的鉴别诊断也具有一定临床应用价值。     

Predictive factors for acute renal failure in crush injuries in the Sichuan earthquake

IntroductionThe Sichuan earthquake caused a large number of crush injuries and many of them developed acute renal failure (ARF). A retrospective study was performed on victims with crush injuries of West China Hospital to investigate the predictive factors for acute renal failure (ARF) in crush injuries.Patients and methodsMedical records of injured victims treated in West China Hospital within the first week after the Sichuan earthquake were retrospectively reviewed and 101 patients with crush injury were enrolled in the study. We divided them into an ARF group and a non-ARF group. The clinical data of included patients were extracted and analysed.ResultsPatients with ARF accounted for 42% of the included population. Patients younger than 20 made up the biggest age category (45%), and the entrapped time under the debris (22 [IQR 3.5–38] h) was longer than previous reports. In univariate analysis, male gender, multiple crush injuries, medical comorbidities, surgical interventions and infections were more frequent in patients with ARF than in those without ARF. Mean arterial pressure was higher in the ARF group. Besides, the risk of ARF was increased by creatine kinase >14,494.5 IU/L most significantly, followed by time under the rubble >4 h, aspartate transaminase >453.5 IU/L, albumin <27.15 g/L and white blood cell >11.8 × 10⁹/L. In multivariate analysis, male gender, time under the rubble, multiple crush injuries, surgical interventions, infections and creatine kinase level were independently associated with ARF in crush injuries.ConclusionsThe entrapped time under the debris, multiple crush injuries, male gender, infections, and creatine kinase level are predictive factors for ARF in crush injuries.     

Endothelial dysfunction in acute renal failure: role of circulating and tissue endothelin-1

The kidney is an important target and source of the potent vasoconstrictor and mitogen endothelin-1 (ET-1). However, its exact role in acute renal failure (ARF) remains to be determined. ARF was induced in male Wistar-Kyoto rats (n = 7) in a 2-kidney, 2-clip model of 30-min clamping. Twenty-four hours after clamp release, contractions to angiotensin I (Angl) and II, ET-1, and big ET-1 were studied in isolated aortic and renal artery rings. Endothelium-dependent and -independent relaxations were assessed by acetylcholine and sodium nitroprusside. ET-1 clearance, tissue uptake, plasma levels, and vascular and kidney content were investigated. In addition, ET(A) and Et(B) receptor mRNA expression was determined. Sham-operated animals served as controls (n = 7). In ARF, ET-1 plasma levels and tissue content of the renal artery, the aorta, and the kidney markedly increased (P<0.01). Plasma half-life of radiolabeled 125I-ET-1 was markedly prolonged, whereas 125I-ET-1 tissue uptake decreased in the kidney in ARF. Contractions to AngI and AngII were blunted (P<0.05) and those to KCl were unchanged, whereas vascular responses to big ET-1 and ET-1 were enhanced in the renal artery and also in the aorta in ARF (P<0.05 to 0.001). Correspondingly, ET(A) and Et(B) receptor mRNA expression significantly increased in both vascular beds. In addition, endothelium-dependent relaxation to acetylcholine was diminished and inversely correlated with vascular ET-1 protein levels in the renal artery (r = -0.827, P<0.001) and the aorta (r = -0.812, P<0.001). In conclusion, the present study demonstrates that increase of circulating and tissue ET-1 protein levels and ET(A) and Et(B) receptor gene expression occurs, which induces endothelial dysfunction and enhanced vasoconstriction in different vascular beds in ARF.     

The study of oliguric and polyuric acute renal failure

A simple laboratory model for acute renal failure (ARF) induced by warm ischemia was studied in an attempt to elucidate the mechanisms for oliguria. It was observed that unilateral warm ischemic injury with contralateral nephrectomy or bilateral warm ischemic injury resulted in a high output (polyuric) form of ARF. In contrast, when unilateral warm ischemic injury was induced and the contracolateral kidney was left intact, low output (oliguric) ARF was observed in the injured kidney. Ligation of the ureter of the normal contralateral kidney reversed the oliguric state. Replacement of the urine output by the normal kidney with Ringer's lactate solution failed to reverse the low output state in the injured kidney. Reinfusion of the urine itself from the intact contralateral kidney, while increasing urine output, did not entirely alleviate the oliguric phenomenon in the injured kidney during a 24-hr period during which the animals underwent volume expansion. Although the basis for the oliguria in the injured kidney when functioning renal tissue remains is unclear, indirect evidence suggests that the excretion of a diuretic factor in urine by the normal kidney contributes to the oliguria observed in the injured kidney.     

Interleukin-6 stimulates tubular regeneration in rats with glycerol-induced acute renal failure

Interleukin-6 stimulates tubular regeneration in rats with glycerol-induced acute renal failure. BACKGROUND: Interleukin 6 (IL-6) is a pleiotropic cytokine released after endotoxemia, trauma and organ injury. IL-6 may act in cellular proliferation activating transduction signals and Ras/Map cascade or the HGF/c-met axis. We tested the effect of IL-6 in the regeneration of tubular epithelia after acute tubular necrosis (ATN) in rats. METHODS: Rats with glycerol-induced acute renal failure (Gly-ARF) were treated with IL-6 200 microg/kg/day. Functional, histological and immunohistochemical tests were done 24 and 72 h after Gly-ARF to localise mitotic cells (BrdU). The renal expression of c-met (Western-Blot) and circulating levels of HGF (ELISA) were also determined. RESULTS: Rats with Gly-ARF had reduced creatinine clearance that was not influenced by IL-6. The histological appearance of ATN was also unaffected by IL-6. The IL-6 treated rats showed a significant increase in tubular cell proliferation in cortex and medulla, as well as in the expression of c-met protein in the renal cortex, compared to untreated Gly-ARF rats. The plasma HGF concentration was equally elevated in treated and untreated Gly-ARF rats. DISCUSSION: IL-6 stimulates tubular regeneration after Gly-ARF and increases the expression of c-met in the renal cortex. Gly-ARF rats have high circulating levels of HGF that is targeted to act in the injured kidneys by the IL-6 overexpressed renal c-met.     

Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute [corrected] renal failure

The effect of acute renal failure (ARF) induced by ischemia/reperfusion (I/R) of rat kidney on the expression of organic anion transporters (OATs) was examined. The level of serum indoxyl sulfate (IS), a uremic toxin and substrate of OATs in renal tubules, shows a marked increase with the progression of ARF. However, this increase was significantly attenuated by ingestion of cobalt. The level of mRNA and protein of both rOAT1 and rOAT3 were markedly depressed in the ischemic kidney. The uptake of p-aminohippuric acid (PAH) and estrone sulfate (ES) by renal slices of ischemic rats was significantly reduced compared to control rats. Renal slices taken from ischemic rats treated with cobalt displayed significantly elevated levels of ES uptake. Cobalt intake did not affect PAH uptake, indicating the functional restoration of rOAT3 but not rOAT1. The expression of Na(+)/K(+)-ATPase was markedly depressed in the ischemic kidney, suggesting that the inward Na(+) gradient in renal tubular cells had collapsed, thereby reducing the outward gradient of alpha-ketoglutarate, a driving force of both rOATs. The decreased expression of Na(+)/K(+)-ATPase was significantly restored by cobalt treatment. Our results suggest that the downregulation of renal rOAT1 and rOAT3 could be responsible for the increase in serum IS level of ischemic rats. Cobalt treatment has a significant protective effect on ischemia-induced ARF, being accompanied by the restoration of rOAT3 and/or Na(+)/K(+)-ATPase function.