巨噬细胞在肾脏损伤中的作用

巨噬细胞是一种能够分泌炎性介质、杀灭细胞内病原体的细胞,最近证实其在组织修复和保持组织完整性上发挥了重要作用。不同活化状态的巨噬细胞表现出不同的功能,在肾脏疾病中,它既介导损伤,也可能促进修复。通过免疫调节改变巨噬细胞功能是肾脏疾病治疗的一个机遇。     

巨噬细胞在肾脏损伤中的作用

巨噬细胞是一种能够分泌炎性介质、杀灭细胞内病原体的细胞，最近证实其在组织修复和保持组织完整性上发挥了重要作用。不同活化状态的巨噬细胞表现出不同的功能，在肾脏疾病中，它既介导损伤，也可能促进修复。通过免疫调节改变巨噬细胞功能是肾脏疾病治疗的一个机遇。     

巨噬细胞活化与肾脏疾病

正巨噬细胞来源于单核细胞,单核细胞穿过血管内皮,进入各组织器官,就分化成为组织特异性的巨噬细胞。巨噬细胞有两种常见的活化方式,分别对应M1型和M2型。巨噬细胞在干扰素-γ(IFN-γ)、脂多糖(LPS)、C反应蛋白(CRP)或与其他细胞因子(如TNF)协同诱导下活化为M1型巨噬细胞,其特征主要表现为产生多种促炎症细胞因子,如白细胞介素-1(IL-1)、白细胞介素-18(IL-18)、白细胞介素-23(IL-23)、     

巨噬细胞在急性肾脏损伤中作用的研究进展

多种病因均可导致急性肾损伤,先天性免疫和适应性免疫参与了急性肾损伤的损伤和修复过程,巨噬细胞是其中的关键免疫细胞。正常肾脏驻留有巨噬细胞,当肾脏发生损伤时肾组织中浸润的巨噬细胞急剧增加,并在不同刺激下分化为不同的亚型,即经典活化型巨噬细胞M1型和替代活化型巨噬细胞M2型,并表现出特定的细胞特性和功能。本文着重描述巨噬细胞在缺血再灌注肾损伤(IRI)、脓毒症急性肾损伤、横纹肌溶解引起的急性肾损伤中的作用,阐释肾损伤局部微环境调控巨噬细胞表型,了解调控巨噬细胞表型和功能的因素,探讨巨噬细胞用于肾损伤治疗的潜在可能性,为开发新的肾损伤策略方法提供新思路。     

气腹与肾脏损伤

动物及临床实验均显示气腹可使肾脏血流量减少 ,气腹压力越高 ,这种变化越大 ,由此可引起肾小球滤过率下降、尿量减少、血清血肌苷和尿素氮水平升高等表现。这与气腹导致的肾脏血液流变学改变 ,以及神经内分泌因子、体位变化和气体种类等有关 ,同时缺血再灌注损伤可能是一个不容忽视的因素。提示气腹可导致肾脏功能的改变 ,这种影响是由多重机制参与的并在一定压力范围和持续时间内是可逆的。过高的气腹压或对于肾功能不全的肾脏可能造成更为明显的损害。     

不同活化状态的巨噬细胞对雪旺细胞增殖、分泌神经生长因子功能的影响

目的 观察不同活化状态的巨噬细胞对雪旺细胞(SCs)生理功能的影响.方法 分离、培养成年SD大鼠巨噬细胞,利用髓鞘组织(20μg/well)使其激活;从新生1d SD大鼠坐骨神经内分离SCs(1×106个/ml)并培养于Transwell下室.共培养组:激活状态的巨噬细胞加入到Transwell上室;对照组1:Transwell上室内加入未激活的巨噬细胞;对照组2:Transwell上室内加入不含细胞的培养基.通过细胞计数、3H-TdR掺入法检测SCs增殖情况,Western blot检测SCs表达神经生长因子(NGF)水平.结果 共培养组从新生大鼠内获取4.16×106个SCs,明显高于对照组1(3.83×106)和对照组2(3.19×106)(P<0.05);3H-TdR结果显示细胞增殖水平(0.2766±0.0079)明显强于对照组1(0.2268±0.0084)和对照组2(0.1929±0.0031)(P<0.05);WB结果显示NGF表达水平明显高于对照组(P<0.05). 结论巨噬细胞对SCs的影响受其活化状态的影响,激活状态的巨噬细胞可以明显促进SCs增殖,增强其表达NGF的能力.     

巨噬细胞的浸润、活化与新月体性肾小球肾炎

新月体性肾小球肾炎是肾小球肾炎中最严重的一种,巨噬细胞参与介导了新月体的形成,在新月体性肾小球肾炎的病程进展发挥重要作用。本文就巨噬细胞浸润的促进因子、巨噬细胞活化的主要途径、巨噬细胞活化后产生的主要损伤因子等因素与新月体性肾小球肾炎发病机制的关系进行综述。     

胰腺疾病与肾脏损伤

重症急性胰腺炎（severeacutepancreatitis,SAP）常并发多器官功能障碍（multipleorgandysfunctionsyndrome,MODS）。有资料显示,胰外器官损伤中肾功能障碍（胰性肾病）发生率约14％～439／6,仅次于肺功能障碍,一旦发展至急性肾衰竭（acuterenalfailure,ARF）后,其死亡率可高达71％～849／6。因此,认识胰腺疾病与肾脏损伤有着十分重要的临床意义。     

细胞凋亡与肾脏损伤

细胞凋亡是一种特殊的可调控的细胞死亡形式，在生理和病理条件下都可以发生。急慢性肾脏损伤中，均可发现细胞凋亡现象．本文阐述了细胞凋亡在急、慢性肾损伤中的作用及机理。     

内质网应激与肾脏损伤

内质网( endoplasmic reticulum,ER)是真核细胞中一种重要的亚细胞器,其主要功能包括调节蛋白质的合成、折叠、运输及修饰.内质网功能易受环境损害的影响,例如缺氧、低糖、氧化应激和遗传突变都将导致内质网腔内蛋白质折叠异常.这些未折叠蛋门以及错误折叠蛋白的积聚引起内质网一系列功能的紊乱,称为内质网应激[1].内质网应激与多种疾病相关,如阿尔茨海默症、帕金森病、亨廷顿病、缺血再灌注损伤、糖尿病及动脉粥样硬化等.越来越多的证据提示,内质网应激在肾脏病理生理过程中亦发挥重要作用[2].本文就内质网应激与肾脏疾病的研究进展作一综述.一、内质网应激与未折叠蛋白反应发生内质网应激的细胞为能够恢复正确的蛋白折叠、阻止未折叠蛋白以及错误折叠蛋白的积聚,激活一项较为保守的适应性反应,称为未折叠蛋白反应( UPR).     

Distinct macrophage phenotypes contribute to kidney injury and repair

The ischemically injured kidney undergoes tubular cell necrosis and apoptosis, accompanied by an interstitial inflammatory cell infiltrate. In this study, we show that iNos-positive proinflammatory (M1) macrophages are recruited into the kidney in the first 48 hours after ischemia/reperfusion injury, whereas arginase 1- and mannose receptor-positive, noninflammatory (M2) macrophages predominate at later time points. Furthermore, depletion of macrophages before ischemia/reperfusion diminishes kidney injury, whereas depletion at 3 to 5 days after injury slows tubular cell proliferation and repair. Infusion of Ifnγ-stimulated, bone marrow-derived macrophages into macrophage-depleted mice at the time of kidney reperfusion restored injury to the level seen without macrophage depletion, suggesting that proinflammatory macrophages worsen kidney damage. In contrast, the appearance of macrophages with the M2 phenotype correlated with the proliferative phase of kidney repair. In vitro studies showed that IFNγ-stimulated, proinflammatory macrophages begin to express markers of M2 macrophages when cocultured with renal tubular cells. Moreover, IL-4-stimulated macrophages with an M2 phenotype, but not IFNγ-stimulated proinflammatory macrophages, promoted renal tubular cell proliferation. Finally, tracking fluorescently labeled, IFNγ-stimulated macrophages that were injected after injury showed that inflammatory macrophages can switch to an M2 phenotype in the kidney at the onset of kidney repair. Taken together, these studies show that macrophages undergo a switch from a proinflammatory to a trophic phenotype that supports the transition from tubule injury to tubule repair.     

Monocyte chemoattractant protein-1 and macrophage infiltration in hypertensive kidney injury

BACKGROUND: We investigated whether monocyte chemoattractant protein-1 (MCP-1) is expressed in hypertensive nephrosclerosis, and tested the effect of angiotensin II type 1 receptor blockade on MCP-1 expression and macrophage (MPhi) infiltration. METHODS: Rats with two-kidney, one-clip (2K1C) hypertension with and without treatment with the angiotensin II type 1 receptor antagonist valsartan (3 mg/kg/day) were studied. In these animals as well as in spontaneously hypertensive rats (SHR), stroke-prone SHR (SHR-SP), hypertensive mRen-2 transgenic rats (TGR), and respective control strains, MCP-1 expression in the kidney was investigated by Northern and Western blots and by immunohistochemistry. Glomerular and interstitial MPhis were counted. RESULTS: In the nonclipped kidney of 2K1C rats, MCP-1 expression was elevated at 14 and 28 days when significant MPhi infiltration was present. MCP-1 was localized to glomerular endothelial and epithelial cells, interstitial and tubular cells, MPhis, and vascular smooth muscle cells. A similar pattern of MCP-1 staining was present in TGR kidneys, whereas MCP-1 expression was not increased in SHR and SHR-SP. Valsartan reduced but did not normalize blood pressure, blocked the induction of MCP-1 protein in 2K1C kidneys, and decreased interstitial MPhi infiltration significantly. CONCLUSION: MCP-1 expression is increased in angiotensin II-dependent models of hypertensive nephrosclerosis and is temporally and spatially related to MPhi infiltration. The angiotensin II type 1 receptor mediates the induction of MCP-1.     

Dimethyl fumarate ameliorates endotoxin-induced acute kidney injury against macrophage oxidative stress

BackgroundCharacterized by macrophage infiltration, renal inflammation during septic acute kidney injury (AKI) reveals a ubiquitous human health problem. Unfortunately, effective therapies with limited side effects are still lacking. This study is aiming to elucidate the role of Dimethyl fumarate (DMF) in macrophages against oxidative stress of septic AKI.MethodsBalb/c mice were gavaged by 50 mg/kg DMF then injected with 10 mg/kg LPS by i.p. We examined LPS-induced renal dysfunction and histological features in murine kidneys. Raw264.7 macrophage cells were also treated with DMF and then induced by LPS. The mitotracker staining was used to follow mitochondria integrity by confocal microscopy. Flow cytometry measured the production of ROS by DCF-HDA and the expression of iNOS. Western blot detected the expression of Nrf-2 and Sirt1. Co-IP measured the interaction between Sirt1 and Nrf-2. Confocal microscopy observed the colocalization of Sirt1 and Nrf-2 in LPS-treated Raw264.7 macrophage cells.ResultsDMF ameliorated murine LPS nephritis with reduced blood urea nitrogen and serum creatinine, as well as decreased the histological alterations compared to the normal control. DMF significantly inhibited the expression of iNOS and reduced the production of nitrite in Raw264.7 cells following LPS treatment. Our study also revealed the role of DMF in protecting against intracellular ROS accumulation and mitochondria dysfunction in LPS-induced nephritis. DMF facilitated colocalization and interaction between Sirt1 and Nrf-2 in LPS-treated cells.ConclusionsThis study showed that DMF alleviated LPS-induced nephritis, indicating protective effects of DMF on macrophage against oxidative stress induced by LPS potentially involving Nrf-2-mediated pathway.     

Local macrophage and myofibroblast proliferation in progressive renal injury in the rat remnant kidney

Background. We have recently shown that blockade of angiotensin II activity inhibits local macrophage and myofibroblast proliferation in progressive non-immune renal injury in the rat remnant kidney. However, it is not known whether this local proliferation contributes to macrophages and myofibroblast accumulation and the development of renal injury. Therefore, we examined this issue in a detailed time-course study of the rat remnant kidney. Methods. Groups of five rats were killed 4, 8, 12 or 16 weeks after 5/6 subtotal nephrectomy (STNx) or a sham operation. Macrophage and myofibroblast proliferation was assessed by two-colour immunostaining for ED1⁺ macrophages or &agr;-smooth muscle actin (&agr;-SMA)-positive myofibroblasts with the proliferating cell nuclear antigen (PCNA) or bromodeoxyuridine. Results. All parameters of renal function and histology remained normal in the sham operated controls, and no macrophage or myofibroblast accumulation was evident. In contrast, prominent macrophage accumulation developed in both the glomerulus and tubulointerstitium in STNx animals, peaking at week 12. Many ED1⁺ macrophages showed PCNA expression, accounting for 19-34% of the total macrophage population. There was a highly significant correlation between proliferating macrophages and total macrophage accumulation in the glomerulus (r = 0.82, P <0.0001) and tubulointerstitium (r = 0.70, P <0.001). Macrophage proliferation was largely restricted to focal areas of renal damage, such as glomerular segmental lesions and severe tubulointerstitial damage. Also, the subpopulation of proliferating macrophages gave a highly significant correlation with loss of renal function, proteinuria, and glomerular and tubulointerstitial lesions. In addition, many &agr;-SMA myofibroblasts were evident within expanded mesangial areas and the tubulointerstitium following STNx. Interestingly, active lesions contained many large &agr;-SMA⁺ cells double-stained for PCNA, accounting for 24-29% of total myofibroblasts. There was a highly significant correlation between the number of proliferating myofibroblasts and total myofibroblast accumulation during the evolution of this disease, and both populations correlated with progressive renal injury. Conclusions. This study has shown that local proliferation is an important mechanism in both macrophage and myofibroblast accumulation during the development of renal injury in the rat remnant kidney. In addition, local macrophage proliferation is postulated as a mechanism for amplifying kidney damage in non-immune renal injury.     

Association between preoperative hydration status and acute kidney injury in patients managed surgically for kidney tumours

Purpose

The purpose of this study was to investigate whether preoperative dehydration and intraoperative hypotension were associated with postoperative acute kidney injury in patients managed surgically for kidney tumours.

Methods

A retrospective analysis of 184 patients who underwent nephrectomy at a single centre was performed, investigating associations between acute kidney injury after nephrectomy, and both intraoperative hypotension and preoperative hydration/volume status. Intraoperative hypotension was defined as mean arterial pressure?<?60 mmHg for ≥?5 min. Urine conductivity was evaluated as a surrogate measure of preoperative hydration (euhydrated?<?15 mS/cm; mildly dehydrated 15–20 mS/cm; dehydrated?>?20 mS/cm). Multivariable logistic regression was used to evaluate associations between exposures and the primary outcome, with adjustment made for potential confounders.

Results

Patients who were dehydrated and mildly dehydrated had an increased risk of acute kidney injury (adjusted odds ratio [aOR] 4.1, 95% CI 1.3–13.5; and aOR 2.4, 95% CI 1.1–5.3, respectively) compared with euhydrated patients (p?=?0.009). Surgical approach appeared to modify this effect, where dehydrated patients undergoing laparoscopic surgery were most likely to develop acute kidney injury, compared with patients managed using an open approach. Intraoperative hypotension was not associated with acute kidney injury.

Conclusion

Preoperative dehydration may be associated with postoperative acute kidney injury. Avoiding dehydration in the preoperative period may be advisable, and adherence to international evidence-based guidelines on preoperative fasting is recommended.

     

The induction of macrophage hemeoxygenase-1 is protective during acute kidney injury in aging mice

Aging is thought to be associated with a higher susceptibility to renal ischemia-reperfusion injury (IRI). To study whether defective induction of hemeoxygenase-1 (HO-1, a protective and anti-inflammatory enzyme) might contribute to this, we found that while 12-month-old mice had similar baseline renal function and HO-1 expression, the induction of HO-1 usually seen in ischemia-reperfusion was reduced. This was also associated with worsened renal function and acute tubular necrosis in the aged compared with young mice. In the older mice, heme arginate (HA) induced HO-1 in the cortex and medulla, significantly improved renal function, and reduced tissue injury. Cellular HO-1 induction in the medulla in response to injury or HA treatment was found to be interstitial rather than epithelial, as evidenced by its colocalization with macrophage markers. In vitro, HA treatment of primary macrophages resulted in marked HO-1 induction without impairment of classical activation pathways. Macrophage depletion, caused by diphtheria toxin treatment of 12-month-old CD11b-DTR transgenic animals, resulted in the loss of interstitial HO-1-positive cells and reversal of the protective phenotype of HA treatment. Thus, failure of HO-1 induction following renal IRI worsens structural and functional injury in older mice and represents a therapeutic target in the elderly. Hence, HO-1-positive renal macrophages mediate HA-induced protection in IRI.     

Chronic-on-acute kidney injury

Although older teaching suggested that patients who survived an episode of acute kidney injury (AKI) had a benign course, recent studies have demonstrated that AKI is strongly associated with increased risk for development of progressive chronic kidney disease (CKD) and longer-term mortality. Much as we understand that CKD predisposes to the development of AKI, we must recognize that the relationship is bidirectional and that our patients with AKI are at risk for chronic-on-acute kidney disease.