Infiltrated macrophages contribute to recovery after ischemic injury but not to ischemic preconditioning in kidneys

BACKGROUND: Macrophages are associated with ischemia/reperfusion (I/R) injury; however, the role of macrophages that have infiltrated into tissues remains unclear. Therefore, we investigated whether infiltrated macrophages influence recovery after kidney I/R injury and affect the phenomenon of ischemic preconditioning, in which previous ischemia affords the kidney resistance to subsequent ischemia. METHODS: Mice were subjected to 30 min of bilateral renal ischemia on day 0, then intravenously administered either liposome-encapsulated dichloromethylene bisphosphonate (Cl2MBP; Lipo-clodronate, a remover of tissue macrophages) or PBS (Lipo-PBS) on day 6 and were then subjected to an additional 30 min of bilateral renal ischemia on day 8. RESULTS: Administration of lipoclodronate removed the infiltrated macrophages after I/R. The number of apoptotic and necrotic cells, as well as superoxide and peroxynitrite levels in kidneys from mice that received Lipo-clodronate, was significantly greater than those in kidneys from mice that were administered Lipo-PBS. Proliferating cell nuclear antigen (PCNA) expression was greater in kidneys from mice that were treated with Lipo-clodronate than in those from mice treated with Lipo-PBS. Thirty min of ischemic preconditioning protected the kidneys from 30 min of ischemia induced 8 days later. There was no difference in the plasma creatinine levels of mice treated with Lipo-clodronate or Lipo-PBS. CONCLUSIONS: Our results demonstrated that the infiltrated macrophages removed dead and dying cells and accelerated recovery after ischemia/reperfusion injury but did not make a critical contribution to ischemic preconditioning.     

mito-KATP通道在缺血后处理减轻大鼠肾缺血再灌注损伤中的作用

目的 评价线粒体ATP敏感性钾通道(mito-KATP通道)在缺血后处理减轻大鼠肾缺血再灌注损伤中的作用.方法 健康成年雄性SD大鼠35只,体重250～280 g,随机分为5组(n=7):假手术组(S组)仅分离双侧肾蒂,暴露45 min不夹闭;肾缺血再灌注组(I/R组)夹闭双侧肾蒂缺血45 min,再灌注6 h制备大鼠肾缺血再灌注模型;缺血后处理组(Ipo组)夹闭双侧肾蒂缺血45 min,再灌注10 s,缺血10 s,反复3次,再灌注6 h;mito-KATP通道阻断剂5-羟葵酸+I/R组(5-HD+I/R组)缺血前30 min腹腔注射5-HD 10 mg/kg,余处理同I/R组;缺血后处理+5-HD组(5-HD+Ipo组)缺血前30 min腹腔注射5-HD 10 mg/kg,余处理同Ipo组.于再灌注6 h时采集心脏血样,取肾并分离肾小管上皮细胞,测定血清Cr和BUN的浓度、肾小管上皮细胞线粒体膜电位、细胞内活性氧(ROS)含量和游离Ca2+浓度.结果 与S组比较,I/R组、Ipo组、5-HD+I/R组和5-HD+Ipo组血清Cr和BUN的浓度、肾小管上皮细胞内游离Ca2+浓度和ROS含量升高,线粒体膜电位降低(P＜0.05);与I/R组比较,Ipo组血清Cr和BUN的浓度、肾小管上皮细胞内游离Ca2+浓度和ROS含量降低,线粒体膜电位升高(P＜0.05),5-HD+I/R组和5-HD+Ipo组上述指标差异无统计学意义(P＞0.05);与Ipo组比较,5-HD+I/R组和5-HD+Ipo组血清Cr和BUN浓度、肾小管上皮细胞内游离Ca2+浓度和ROS含量升高,线粒体膜电位降低(P＜0.05).结论 mito-KATP通道的开放参与了缺血后处理减轻大鼠肾缺血再灌注损伤的过程.     

Role of CXC chemokine receptor 3 pathway in renal ischemic injury

Chemokines play a major role in the recruitment of leukocytes in inflammation and in the regulation of T helper 1 (Th1)/Th2 immune responses. These mechanisms have been recognized to be important in the pathogenesis of renal ischemia-reperfusion (I/R) injury. The interaction of the CXC chemokine receptor 3 (CXCR3) receptor with its ligands is a key pathogenic pathway in promoting inflammation and in enhancing Th1 immune responses. After the induction of ischemia in the mouse model of renal ischemia, an increase in intrarenal expression of CXCR3 and its ligands was observed. Compared with the wild-type (WT) mice, CXCR3-deficient mice (CXCR3-/-) had significantly lower serum creatinine levels, better survival rate, and significantly less acute tubular necrosis and cellular infiltrates. In the kidney, intracellular staining of infiltrating cells that were recovered from kidneys revealed a lower percentage of CD4+IFN-gamma+ cells in the CXCR3-/- mice compared with the WT mice. Furthermore, adoptive transfer of WT CD3+ cells into CXCR3-/- mice before induction of I/R injury abrogated the protection of CXCR3-/- mice from I/R injury. It is concluded that CXCR3 plays an important role in orchestrating the recruitment of Th1 cells to the ischemic kidney and in mediating I/R injury and therefore may serve as a novel target for the therapy of I/R injury.     

Hyperbaric oxygen therapy attenuates renal ischemia/reperfusion injury in rats

OBJECTIVE: Renal ischemia/reperfusion (I/R) injury occurs in both native and transplanted kidneys. Hyperbaric oxygen (HBO) has been shown to prevent I/R injury in different tissues. The aim of this study was to evaluate the effect of HBO on renal I/R injury in rats. MATERIALS AND METHODS: Sprague-Dawley rats were randomly assigned to one of three groups. The Control group (n = 6) received right nephrectomy. The I/R (n = 6) and I/R+HBO groups (n = 6) received 30 min left renal ischemia followed by 24 h of reperfusion after right nephrectomy. The I/R+HBO group (n = 6) received additional HBO therapy for 60 min at 2.5 absolute atmospheres starting at the initial 15th minute of reperfusion. RESULTS: In the I/R group, blood urea nitrogen (BUN) and creatinine levels increased significantly compared with the Control and I/R+HBO groups (p < 0.05). BUN and creatinine levels were similar in the Control and I/R+HBO groups. Kidney samples from I/R group rats revealed severe tubular damage and neutrophil infiltration at histopathological examination. The animals treated with HBO showed markedly improved lesions and less neutrophil infiltration compared with the I/R group (p < 0.05). CONCLUSIONS: HBO exhibited marked protection against I/R injury in this study as measured using BUN and creatinine levels and renal histopathology. However, further studies are needed to clarify the renoprotective effect of HBO on I/R injury.     

T cells as mediators in renal ischemia/reperfusion injury

Inflammation has been established to contribute substantially to the pathogenesis of ischemia/reperfusion (I/R) with a central role for particular cells, adhesion molecules, and cytokines. Until recently, most of the research trying to unravel the pathogenesis of I/R injury has been focused on the role of neutrophils. However, recent studies have brought evidence that T cells and macrophages are also important leukocyte mediators of renal and extrarenal (liver) I/R injury. In vivo depletion of CD4+ cells but not CD8+ cells in wild-type mice was protective in I/R of the kidney. A marked preservation of liver function was also found after I/R in T-cell deficient athymic mice. Blocking the b130/CD28 costimulatory pathway by CTLA-4 Ig (recombinant fusion protein) ameliorated renal dysfunction and decreased mononuclear cell infiltration in I/R of the kidney. b130-1 expression was found limited to the membrane of the endothelial cells of the ascending vasa recta, resulting in trapping of CD28-expressing CD4 T cells. This trapping of leukocytes results in the upstream congestion in the ascending arterial vasa recta, generating the since more than 150 years described medullary vascular congestion of the kidney soon after ischemic injury. It seems worthwhile to study a combination therapy using anti-inflammatory/anti-adhesion molecules in the early phase of I/R.     

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.     

缺血后处理对犬肾缺血再灌注损伤氧化应激反应的影响

目的：探讨缺血后处理对犬急性肾缺血再灌注损伤氧化应激反应的影响.方法：将15只成年雄性杂种狗分为3组,每组5只,即假手术组（S组）、缺血再灌注组（I/R组）、缺血后处理组（IPO组）.在肾缺血60min后立即给予再灌注30 s,再缺血30 s,循环3次,然后完全恢复灌注.术前及术后每天检测血清肌酐（Cr）浓度,检测肾组织超氧化物歧化酶（SOD）活性、丙二醛（MDA）含量、过氧化氢酶（CAT）、总抗氧化能力（TAC）.术后犬存活3天,杀死后取左肾标本,光镜下观察肾组织病理学改变.结果：IPO组与I/R组术后3天连续比较,血清Cr浓度有显着降低,差异有统计学意义（P〈0.05）;IPO组与I/R组比较,SOD、CAT、TAC活性升高,MDA浓度降低,病理损伤明显减轻,差异有统计学意义（P〈0.05）.结论：缺血后处理能减轻肾缺血再灌注损伤氧化应激反应,其机制与氧自由基清除有关.     

Ischemic acute renal failure following nephrectomy impairs long-term renal function

Uninephrectomy is associated with increased glomerular filtration rate in both the donated and the remaining contralateral kidney. The long-term effects of ischemic acute renal failure (ARF) following uninephrectomy are unknown. This study examined renal function, histology and proteinuria 52 weeks after an episode of reversible ischemic ARF. Ischemic ARF was induced in uninephrectomised mice by renal pedicle clamping. At 52 weeks inulin clearance (muL/min/g) was 7.2+/-0.2 in sham, 5.0+/-0.1 in uninephrectomy (P<0.01 vs. sham) and 3.9+/-0.1 in uninephrectomy + ischemia (P<0.01 vs. sham, P<0.05 vs. uninephrectomy). Thus, mice subjected to uninephrectomy alone demonstrated compensatory hyperfiltration following reduction in renal mass. This response was prevented by ischemic ARF. At 52 weeks there was no difference in urine protein/creatinine, mean arterial pressure or scores of glomerulosclerosis or interstitial fibrosis. In conclusion, ischemic ARF following uninephrectomy in mice impairs long-term renal function.     

The loss of renal dendritic cells and activation of host adaptive immunity are long-term effects of ischemia/reperfusion injury following syngeneic kidney transplantation

Ischemia/reperfusion injury associated with kidney transplantation induces profound acute injury, influences early graft function, and affects long-term graft outcomes. To determine whether renal dendritic cells play any role during initial innate ischemia/reperfusion injury and the subsequent development of adaptive immune responses, we studied the behavior and function of renal graft and host infiltrating dendritic cells during early and late phases of renal ischemia/reperfusion injury. Wild type to green fluorescent protein (GFP) transgenic rat kidney transplantation was performed with and without 24-h cold storage. Ischemia/reperfusion injury in cold-stored grafts resulted in histopathological changes of interstitial fibrosis and tubular atrophy by 10 weeks, accompanied by upregulation of mRNAs of mediators of interstitial fibrosis and inflammation. In normal rat kidneys, we identified two populations of renal dendritic cells, predominant CD103(-)CD11b/c(+) and minor CD103(+)CD11b/c(+) cells. After transplantation without cold storage, grafts maintained CD103(-) but not CD103(+) GFP-negative renal dendritic cells for 10 weeks. In contrast, both cell subsets disappeared from cold-stored grafts, which associated with a significant GFP-expressing host CD11b/c(+) cell infiltration that included CD103(+) dendritic cells with a TNF-α-producing phenotype. These changes in graft/host dendritic cell populations were associated with progressive infiltration of host CD4(+) T cells with effector/effector-memory phenotypes and IFN-γ secretion. Thus, renal graft ischemia/reperfusion injury caused graft dendritic cell loss and was associated with progressive host dendritic cell and T-cell recruitment. Renal-resident dendritic cells might function as a protective regulatory network.     

Effects of Pretreatment With Yisheng Injection on Renal Warm Ischemia/Reperfusion Injury in Mice

Introduction

Due to the organ supply shortage, the donor pool has been expanded to include non-heart-beating donors, where renal warm ischemia/reperfusion (I/R) injury is inevitable. This study was undertaken to determine whether Yisheng injection (YM) could attenuate renal warm I/R injury in mice.

Materials and Methods

Male C57BL/6 mice were divided into sham, ischemic, and YM-treated groups using 50 minutes of left kidney ischemia. Mice were humanely killed at 4 or 24 hours postreperfusion. We assayed the effects of YM on liver functional injury, neutrophil recruitment, and proinflammatory mediators after renal I/R injury.

Results

Renal I/R produced dramatic injuries in mouse kidneys. Administration of YM reduced liver function (urea nitrogen of untreated vs treated, 4.7 ± 0.6 vs 26.6 ± 1.5 mmol/L; P < .01) and histological injury (histological scores of untreated vs treated, 4.12 ± 0.14 vs 0.98 ± 0.07; P < .01). YM at doses of 5, 15, or 25 mg/kg reduced the serum levels of tumor necrosis factor-alpha (TNF-α) by about 32.9%, 55.1%, and 74.5%, respectively. Moreover, YM also suppressed the increase in messenger RNA (mRNA) and protein expressions of TNF-α and intercellular adhesion molecule-1 (ICAM-1), as well as abrogated neutrophil recruitment in a dose-dependent manner.

Conclusion

YM protects murine kidneys from warm I/R injury, probably via decreasing functional injury, reducing neutrophil infiltration, and suppressing the overexpression of proinflammatory mediators and adhesion molecules.     

Exogenous nitric oxide downregulates MIP-2 and MIP-1alpha chemokines and MAPK p44/42 after ischemia and reperfusion of the rat kidney.

The mechanisms by which nitric oxide (NO) exerts its protective effect in the ischemia/reperfusion (I/R) injury of the kidney have not been fully determined. The hypothesis of this study was based on the assumption that I/R upregulates some chemokines (MIP-2 and MIP-1alpha) as well as certain protein kinases (MAPK p44/42), and therefore we aimed in this work at recognizing if an exogenous NO donor would downregulate these effects in rat ischemic kidneys at the same time that it would offer functional protection as measured by serum creatinine. Sprague-Dawley rats were subjected to renal warm ischemia (75 min) and contralateral nephrectomy. Animals were divided into 3 groups (n = 8 per group): sham, ischemic control, and ischemic group treated with sodium nitroprusside (NaNP 5 mg/kg) given 15 min prior to reperfusion. Serum creatinine (SCr), serum chemokines (MIP-2 and MIP-1alpha), kidney tissue MAPK p44/42, kidney neutrophil infiltration determined by myeloperoxidase (MPO), and light histology were evaluated 4 h after reperfusion began. There were significant improvements in SCr and better histopathological features in the I/R-NaNP group compared with the I/R group. Similarly, the I/R-NaNP kidneys exhibited a downregulating effect of serum chemokines (MIP-2 and MIP-1alpha) and kidney tissue MAPK p44/42 that was not observed in the I/R group alone. The MPO levels were lower in the I/R-NaNP group compared with the I/R untreated group. We can conclude from these experiments that I/R of the rat kidney upregulated the production of MIP-2 and MIP-1alpha chemokines and the activation of MAPKp44/42. It also had a detrimental effect on the function and structure of the ischemic kidney. Exogenous NO had a temporal protective effect in organ function and histology and exerted a downregulating response in the production of MIP-2 and MIP-1alpha chemokines and the activation of MAPK p44/42 following I/R.     

Midkine antisense oligodeoxyribonucleotide inhibits renal damage induced by ischemic reperfusion

BACKGROUND: Midkine, a heparin-binding growth factor, is involved in the migration of inflammatory cells. The inflammatory cell migration to the tubulointerstitium of the kidney after ischemia/reperfusion (I/R) injury is attenuated in midkine gene-deficient mice, resulting in better preservation of the tubulointerstitium compared with wild-type mice. In the present investigation, we planned to evaluate the usefulness of antisense midkine for the therapy of ischemic renal failure. METHODS: Midkine antisense phosphorothioate oligodeoxyribonucleotide (ODN) at a dose of 1 mg/kg in saline was intravenously administered to mice 1 day before or after I/R. The kidneys were removed for examination 1, 2, 3, and 7 days after I/R. RESULTS: It was rapidly incorporated into proximal tubular epithelial cells, and inhibited midkine synthesis, leading to reduced migration of inflammatory cells to the injured epithelial layer. Consequently, the midkine antisense ODN-treated animals exhibited less severe renal damage than untreated or midkine sense ODN-treated animals 2 days after I/R as assessed by morphologic criteria and blood urea nitrogen (BUN) and serum creatinine levels. Midkine expression, BUN, and serum creatinine levels were not significantly different between injection of midkine antisense ODN before and after ischemic injury. CONCLUSION: These results indicate that intravenous injection of midkine antisense ODN is a candidate for a novel therapeutic strategy against acute tubulointerstitial injury induced by I/R injury.     

Ischemia/Reperfusion-Induced Renal Failure in Rats as a Model for Evaluating Cell Therapies

Chronic renal failure is a devastating disease that leads to a multitude of complications. Cell therapy has emerged as a potential treatment modality for renal failure. However, efficacy testing on systemic renal function has been challenging due to the limited availability of reliable models that are fully characterized. In this study, we investigated the possibility of using renal ischemia/reperfusion (I/R) injury as a viable model for testing cell therapies. We examined functional and pathological changes in rat kidneys that were exposed to different ischemia times. Male Lewis rats were divided into five groups. Renal failure was induced by clamping both renal pedicles for combinations of 60, 75, and 90 min, followed by reperfusion. Age-matched healthy rats served as controls. Blood was collected at regular intervals for serum chemistry, and kidneys were harvested at the same intervals for histomorphological assessment. Serum creatinine levels of the animals with I/R injury increased significantly after 3 days and returned to normal levels at 4 weeks. Histologically, kidney tissue showed progressive glomerular and tubular deterioration with varying degrees of fibrosis. Animals exposed to 75- and 90-min ischemia combination times consistently generated more severe injury than the 60-min ischemia period. However, these groups resulted in a high mortality rate. A model in which one kidney is exposed to a shorter ischemia time (60 or 90 min) resulted in sustained renal damage with a lower mortality rate. This study shows that kidneys exposed to I/R result in renal tissue damage as well as decreased renal function. This model can be used to study both the short-term and longer-term effects of kidney disease by varying the length of the ischemic time. In particular, the use of longer ischemic times (75 and 90 min) could be used to study new therapies for acute renal disease, whereas shorter ischemic times (60 min) could be used to study therapies for chronic renal insufficiency.     

Effects of Delayed Rapamycin Treatment on Renal Fibrosis and Inflammation in Experimental Ischemia Reperfusion Injury

Ischemia reperfusion injury (IRI) has long-term sequelae on kidney allograft function. Early initiation of rapamycin can retard surgical wound healing and recovery from IRI. In contrast, rapamycin may paradoxically retard long-term fibrotic effects of kidney IRI. We, therefore, hypothesized that delayed initiation of rapamycin after kidney ischemia, started after the initial week of wound healing, would decrease the long-term inflammation and fibrosis caused by IRI. C57BL/6 male mice were subjected to either 45 or 60 minutes of unilateral kidney ischemia or a sham operation. Mice were given rapamycin (subcutaneous, 1.5 mg/kg/d) or vehicle starting at 1 week after IRI surgery for 3 weeks. Urine albumin excretion, kidney histology, and kidney cytokine proteins were examined at 4 weeks after surgery. The 3-week treatment course of rapamycin significantly reduced body weight gain in all 3 groups and reduced postischemic kidney weight in both the 45- and 60-minute ischemia groups, but unexpectedly increased urine albumin excretion in all rapamycin-treated sham or IRI mice compared with vehicle-treated mice. Rapamycin treatment showed minimal effects on postischemic kidney fibrosis with variable effects on various cytokine/chemokine protein expressions, namely, decreasing interleukin (IL)-1α, IL-6, tumor necrosis factor (TNF)-α, and regulated on activation normal T cell expressed and secreted (RANTES) while increasing IL-4, keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP-1α), and IL-10 in the ischemic kidney. These data demonstrated that rapamycin reduced mouse body weight and ischemic kidney weight, while increasing urinary albumin excretion. Delayed initiation of rapamycin after IRI had a minimal effect on renal fibrosis and mixed effects on proinflammatory mediator production. These data do not support delayed initiation of rapamycin after IRI to attenuate IRI-induced progressive fibrosis and inflammation, and They raise further caution regarding rapamycin and albuminuria.     

Protective effect of insulin on ischemic renal injury in diabetes mellitus

BACKGROUND: An exceptional susceptibility to unilateral renal ischemia/reperfusion (I/R) injury resulting in inflammation, fibrosis, atrophy of the kidney, and end-stage renal disease (ESRD) has been demonstrated in the diabetic rat. The aim of this study was to examine whether insulin treatment would reduce I/R injury in diabetic kidneys. METHODS: Diabetes mellitus (DM) was induced in male Wistar rats by streptozotocin. I/R was achieved by clamping the left renal artery for 30 minutes. Treatment with long acting insulin was started 7 to 14 days before or one day after I/R. Short acting insulin was administrated 2 to 6 hours before the injury. Apoptosis was evaluated six hours after ischemia with the TUNEL-method. Four weeks after the clamping inulin clearance was measured and kidneys were removed for histopathological evaluation. RESULTS: In DM animals renal I/R caused massive induction of apoptosis in the renal medulla after six hours as well as inflammation, fibrosis, renal atrophy and anuria within four weeks. Treatment with long acting insulin before I/R resulted in decreased cell death and an almost complete protection of both renal function and histomorphology. Treatment with short acting insulin before I/R also decreased the loss of renal function. In contrast, insulin treatment after I/R did not protect the kidney from damage. CONCLUSIONS: This study shows that insulin treatment with a subsequent improved metabolic control before renal I/R protected kidneys from ESRD.     

缺血预处理联合后处理对大鼠肾缺血再灌注损伤的影响

目的 评价缺血预处理联合后处理对大鼠肾缺血再灌注损伤的影响.方法 健康雄性SD大鼠30只,体重250～280 g,随机分为5组(n=6):假手术组(S组)、缺血再灌注组(I/R组)、缺血预处理组(IP组)、缺血后处理组(IPo组)和缺血预处理联合后处理组(IP+IPo组).S组仅开腹,游离双侧肾脏,分离双侧肾蒂但不夹闭.采用夹闭双侧肾蒂45 min、再灌注6 h的方法 制备肾缺血再灌注模型.IP组夹闭双侧肾蒂5 min,再灌注5 min,反复3次,余操作同I/R组;IPo组夹闭双侧肾蒂45 min后,再灌注10 8,缺血10 s,反复3次,再灌注6 h.于再灌注6 h时,经心脏抽血后迅速处死大鼠取肾,测定血清肌酐(Cr)和尿素氮(BUN)的浓度;采用硫代巴比妥酸法测定肾组织丙二醛(MDA)含量,采用黄嘌呤氧化酶法测定肾组织超氧化物歧化酶(SOD)活性;光镜下观察肾组织病理学结果 ;TUNEL法检测肾组织凋亡细胞,计算凋亡指数(AJ).结果 与S组比较,其余各组血清Cr和BUN的浓度升高,肾组织SOD活性降低,MDA含量和AI升高(P<0.05);与I/R组比较,IP组、IPo组和IP+IPo组血清Cr和BUN的浓度降低,肾组织SOD活性升高,MDA含量和AJ降低(P<0.05),肾损伤减轻;与IP组和IPo组比较,IP+IPo组肾组织SOD活性升高,AI降低(P<0.05),肾损伤减轻.结论 缺血预处理联合后处理可减轻大鼠肾缺血再灌注损伤,较单独应用时效果好.     

Inhibition of 20-HETE synthesis and action protects the kidney from ischemia/reperfusion injury

20-Hydroxyeicosatetraenoic acid (20-HETE) production is increased in ischemic kidney tissue and may contribute to ischemia/reperfusion (I/R) injury by mediating vasoconstriction and inflammation. To test this hypothesis, uninephrectomized male Lewis rats were exposed to warm ischemia following pretreatment with either an inhibitor of 20-HETE synthesis (HET0016), an antagonist (20-hydroxyeicosa-6(Z),15(Z)-dienoic acid), an agonist (20-hydroxyeicosa-5(Z),14(Z)-dienoic acid), or vehicle via the renal artery and the kidneys were examined 2 days after reperfusion. Pretreatment with either the inhibitor or the antagonist attenuated I/R-induced renal dysfunction as shown by improved creatinine clearance and decreased plasma urea levels, compared to controls. The inhibitor and antagonist also markedly reduced tubular lesion scores, inflammatory cell infiltration, and tubular epithelial cell apoptosis. Administering the antagonist accelerated the recovery of medullary perfusion, as well as renal medullary and cortical re-oxygenation, during the early reperfusion phase. In contrast, the agonist did not improve renal injury and reversed the beneficial effect of the inhibitor. Thus, 20-HETE generation and its action mediated kidney injury due to I/R. Whether or not these effects are clinically important will need to be tested in appropriate human studies.     

Trasylol (aprotinin) decreases kidney Interleukin-1beta (IL-1beta) and IL-6 levels following renal ischemia and reperfusion injury

Introduction. Acute renal failure (ARF) may be an ominous complication of circulatory arrest in cardiac surgical patients. Aprotinin is used as a therapeutic adjunct to preserving hemostasis by inhibiting protease-mediated fibrinolysis. Aprotinin has been shown to possess anti-inflammatory properties, which may be renal protective. However, it is unknown whether aprotinin decreases renal proinflammatory cytokine production following I/R. Indeed, other agents which have reduced renal IL-1beta and IL-6 have protected renal function in this setting. We hypothesized that aprotinin would decrease renal IL-1beta and IL-6 production following I/R. Methods. Adult male rats were subjected to unilateral I/R with varying lengths of both ischemia and reperfusion, with and without clinically relevant dosing and administration of aprotinin prior to the insult (clinically aprotinin is given prior to circulatory arrest). At various time points, the kidneys were harvested and the tissue homogenates were assayed for IL-1beta and IL-6 (ELISA). All experiments were approved by the Indiana University Animal Care and Use Committee (IACUC). Results. One-hour ischemia and 2 h of reperfusion significantly increased renal tissue IL-1beta and IL-6 levels (P < 0.05 versus sham, ANOVA with Bonferroni/Dunn). Aprotinin significantly (P < 0.05) decreased renal IL-1beta and IL-6 levels at this time point. Aprotinin also significantly decreased renal IL-1beta at the 1 h ischemia/4 h reperfusion time point. At no point did aprotinin increase production of either cytokine. Conclusions. Aprotinin decreases renal proinflammatory cytokine production following I/R. Further study will be needed to determine if aprotinin decreases renal tubular apoptosis and acute renal failure following such conditions. If so, aprotinin may be useful as an adjunct to preserving renal function following diverse planned ischemic events.     

Stimulation of carnitine palmitoyltransferase 1 improves renal function and attenuates tissue damage after ischemia/reperfusion

BackgroundRenal injury as a result of ischemia/reperfusion (I/R) is a major clinical problem with a high mortality rate and a lack of therapeutic treatment. During I/R, cellular homeostasis is disrupted owing to energy depletion, leading to cell death. Fatty acid β-oxidation is the major metabolic pathway for generating adenosine triphosphate (ATP) in the kidneys, which is governed by carnitine palmitoyltransferase 1 (CPT1). C75 is a synthetic compound that up-regulates CPT1 activity. Thus, we hypothesized that C75 treatment could increase energy production and alleviate renal I/R injury.MethodsWe subjected male adult rats to renal I/R by bilateral renal pedicle clamping with microvascular clips for 60 min, followed by administration of 8% dimethyl sulfoxide (vehicle) or C75 (3 mg/kg body weight), with 5 animals/group. We collected blood and renal tissues 24 h after reperfusion and subjected them to various measurements and histological examination.ResultsC75 treatment restored the loss of CPT1 activity and intracellular ATP levels in the kidneys after I/R. Administration of C75 significantly lowered serum creatinine, blood urea nitrogen, aspartate aminotransferase, and lactate dehydrogenase levels elevated by I/R. C75 treatment preserved morphological features of the kidneys with a significant improvement in the damage score. In addition, C75 treatment inhibited the increase of TNF-α levels in serum and kidneys, and lowered myeloperoxidase activity in the kidneys after I/R.ConclusionsStimulation of CPT1 activity by C75 recovered ATP depletion, improved renal function, attenuated tissue injury, and inhibited proinflammatory cytokine production and neutrophil infiltration after renal I/R injury. Therefore, enhancing the metabolism pathways for energy production may provide a novel modality to treat renal I/R injury.