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Altered renin synthesis and secretion in the kidneys of heterozygous mice with a null mutation in the TGF-beta(2) gene. tgf - β(2)基因零突变的杂合小鼠肾脏肾素合成和分泌的改变
Pub Date : 2002-01-01 DOI: 10.1159/000065302
Laurence Pietri, May Bloch-Faure, Marie-France Belair, L Philip Sanford, Tom Doetschman, Joël Ménard, Patrick Bruneval, Pierre Meneton

Transforming growth factors beta (TGF-betas) are peptides involved in autocrine and paracrine control of cell growth and differentiation. In the kidneys, TGF-beta(2) has been shown to localize specifically in renin-producing cells in various conditions stimulating the renin response. To test in vivo the functional role of TGF-beta(2), the renin response was investigated in mice heterozygous for a null mutation of the TGF-beta(2) gene, which had a twofold reduction in the amount of TGF-beta(2) mRNA. Although the increase in plasma renin concentration triggered by dehydration was not different from wild-type mice, renal renin mRNA and protein levels were higher in mutant mice under hydrated or dehydrated conditions. These data suggest that TGF-beta(2) exerts an inhibitory effect on renin synthesis and release from the juxtaglomerular apparatuses.

转化生长因子(tgf - β)是参与细胞生长和分化的自分泌和旁分泌控制的肽。在肾脏中,tgf - β(2)已被证明在各种条件下特异性定位于肾素产生细胞,刺激肾素反应。为了在体内测试tgf - β(2)的功能作用,研究了tgf - β(2)基因突变的杂合小鼠肾素反应,该突变使tgf - β (2) mRNA的数量减少了两倍。尽管脱水引起的血浆肾素浓度升高与野生型小鼠没有区别,但在脱水或脱水条件下,突变小鼠的肾素mRNA和蛋白水平更高。这些数据表明,tgf - β(2)对肾小球旁装置肾素的合成和释放有抑制作用。
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引用次数: 9
Mixed bone marrow or mixed stem cell transplantation for prevention or treatment of lupus-like diseases in mice. 混合骨髓或混合干细胞移植预防或治疗小鼠狼疮样疾病。
Pub Date : 2002-01-01 DOI: 10.1159/000065308
Robert A Good, Bing-Yan Wang, Nagwa S El-Badri, Ann Steele, Tazim Verjee

Scientific analyses fortified by interpretations of immunodeficiency diseases as 'experiments of nature' have revealed the specific immune systems to be comprised of T cells subserving cell-mediated immunities plus B cells and plasma cells which produce and secrete antibodies. These two separate cellular systems regularly interact with each other to produce a coordinated defense which permits mammals to live within a sea of microorganisms that threaten the integrity and the survival of individuals. We have shown that bone marrow transplantation (BMT) can be used as a form of cellular engineering to construct or reconstruct the immune systems and cure otherwise fatal severe combined immunodeficiency. When severe aplastic anemia complicated the first BMT which was performed to cure a fatal severe combined immunodeficiency, a second BMT cured for the first time a complicating severe aplastic anemia. Subsequently, BMT has been used effectively to treat some 75 otherwise fatal diseases such as resistant leukemias, lymphomas, inborn errors of metabolism, and genetic anomalies of the hematopoietic development such as sickle cell anemia, thalassemia, congenital neutropenias, and many other diseases. More recently, we have employed BMT in mice both to cure and cause autoimmunities, and, together, these experiments showed that autoimmunities actually reside in the hematopoietic stem cells. We have also found that mixed BMT or mixed hematopoietic stem cell transplantation (HSCT) can be used to prevent and cure the most complex autoimmunities such as those occurring in BXSB mice and in (NZW x BXSB)F1 W/BF1 mice. Untreated, the former develop fulminating lethal glomerulonephritis plus numerous humoral autoimmunities. Mice of the (W/B)F1 strain develop autoimmune thrombocytopenic purpura, coronary vascular disease with myocardial infarction, glomerulonephritis, and numerous autoantibodies. All of these abnormalities are prevented or cured by mixed syngeneic (autoimmune) plus allogeneic (normal healthy) BMT or mixed peripheral blood HSCT. Thus, the most complex autoimmune diseases can be prevented or cured in experimental animals by mixed syngeneic plus allogeneic BMT or HSCT which produce stable mixed chimerism as a form of cellular engineering.

将免疫缺陷疾病解释为“自然实验”的科学分析表明,特异性免疫系统由提供细胞介导免疫的T细胞以及产生和分泌抗体的B细胞和浆细胞组成。这两个独立的细胞系统定期相互作用,形成协调的防御,使哺乳动物能够在威胁个体完整性和生存的微生物海洋中生存。我们已经证明骨髓移植(BMT)可以作为细胞工程的一种形式来构建或重建免疫系统,并治愈其他致命的严重联合免疫缺陷。第一次BMT是为了治疗致命的严重联合免疫缺陷而进行的,第二次BMT首次治愈了严重再生障碍性贫血。随后,BMT已被有效地用于治疗大约75种其他致命疾病,如耐药白血病、淋巴瘤、先天性代谢错误和造血发育的遗传异常,如镰状细胞性贫血、地中海贫血、先天性中性粒细胞减少症和许多其他疾病。最近,我们在小鼠身上使用BMT来治疗和引起自身免疫,这些实验表明,自身免疫实际上存在于造血干细胞中。我们还发现混合BMT或混合造血干细胞移植(HSCT)可用于预防和治疗最复杂的自身免疫,如BXSB小鼠和(NZW x BXSB)F1 W/BF1小鼠。未经治疗,前者发展为暴发性致死性肾小球肾炎并伴有大量体液自身免疫。(W/B)F1菌株小鼠可发生自身免疫性血小板减少性紫癜、冠状动脉血管疾病伴心肌梗死、肾小球肾炎和大量自身抗体。所有这些异常都可以通过混合的同基因(自身免疫)和异体(正常健康)BMT或混合外周血HSCT来预防或治愈。因此,在实验动物中,最复杂的自身免疫性疾病可以通过产生稳定的混合嵌合作为一种细胞工程形式的同种异体骨髓移植或造血干细胞移植来预防或治愈。
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引用次数: 9
Bactericidal activity of renal tubular cells: the putative role of human beta-defensins. 肾小管细胞的杀菌活性:人β -防御素的假定作用。
Pub Date : 2002-01-01 DOI: 10.1159/000065296
Martin Nitschke, Sandra Wiehl, Patrick C Baer, Burkhard Kreft

Renal tubular epithelial cells (RTC) form a barrier between the host and ascending microbes in upper urinary tract infection. Previous studies have shown the ability of the kidney to produce defensins--antimicrobial peptides that play a pivotal role in unspecific host defense. To further clarify the role of renal epithelium for direct antibacterial activity we investigated the expression, regulation and production of antimicrobial peptides by cultured human RTC. Cell culture supernatants of RTC exert strong bactericidal activity against Escherichia coli and Klebsiella pneumoniae, two of the most important pathogens in urinary tract infections. The antimicrobial effect depends on salt concentration, a typical feature of human defensins. RT-PCR of RNA from cultured proximal and distal RTC showed constitutive expression of human beta-defensin 1 (hbd-1) and human beta-defensin 2 (hbd-2) whereas only hbd-1 expression could be detected in RNA preparation from renal biopsy material. Hbd-2 expression of RTC was induced by inflammatory processes as shown by semiquantitative competitive RT-PCR. Coincubation of the cultured cells with IL-1alpha or E. coli promote the strongest hbd-2 induction whereas TNF-alpha and LPS lead to a weaker or no (IL-6) hbd-2 induction. This is the first evidence that human RTC are able to produce antibacterial substances in a biologically relevant amount and that beta-defensins are candidate proteins responsible for this effect.

肾小管上皮细胞(RTC)在上尿路感染中形成宿主和上行微生物之间的屏障。先前的研究表明肾脏有能力产生防御素——抗菌肽,在非特异性宿主防御中起关键作用。为了进一步阐明肾上皮在直接抗菌活性中的作用,我们研究了培养的人RTC抗菌肽的表达、调控和产生。RTC细胞培养上清液对大肠埃希菌和肺炎克雷伯菌这两种尿路感染最重要的病原体具有较强的杀菌活性。抗菌效果取决于盐浓度,这是人体防御素的典型特征。RT-PCR结果显示,培养的近端和远端RTC的RNA组成部分表达人β -防御素1 (hbd-1)和人β -防御素2 (hbd-2),而肾活检材料的RNA制备中只能检测到hbd-1的表达。半定量竞争性RT-PCR结果显示,炎症过程诱导RTC的Hbd-2表达。培养的细胞与il -1 α或大肠杆菌共孵育促进了最强的hbd-2诱导,而tnf - α和LPS导致较弱或没有(IL-6) hbd-2诱导。这是人类RTC能够产生与生物学相关的抗菌物质的第一个证据,并且β -防御素是负责这种作用的候选蛋白质。
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引用次数: 47
Unexpected renal actions of erythropoietin. 促红细胞生成素对肾脏的意外作用。
Pub Date : 2002-01-01 DOI: 10.1159/000065304
Christof Westenfelder

Erythropoietin (EPO) in the renal cortex is synthesized by fibroblast-like cells that are in direct contact with capillaries and adjacent tubular cells. Prompted by this anatomical relationship, we asked whether renal cells express EPO receptors (EPORs) through which EPO could act as a renotropic cytokine. We found that all regions of human, rat and mouse kidney, mesangial and proximal and distal tubular cells express authentic EPORs. Similar EPOR expression was detected in kidney cancer cells, and in cyst epithelia from polycystic kidneys. In vitro, EPO stimulated mitogenesis in all normal and malignant cells, and cell survival and motogenesis in injured tubular cells. Since the normal kidney is essentially unresponsive to EPO, we hypothesized that EPO's cytokine effects in the kidney are revealed when tubular cells are induced to proliferate by a prior insult, as occurs in acute renal failure. Accordingly, we found that EPO treatment of rats with 'ischemic' acute renal failure afforded renoprotection and accelerated functional recovery.

肾皮质的促红细胞生成素(EPO)是由与毛细血管和相邻小管细胞直接接触的成纤维细胞样细胞合成的。在这种解剖关系的提示下,我们询问肾细胞是否表达促生成素受体(EPORs),通过这种受体EPO可以作为嗜肾性细胞因子。我们发现人、大鼠和小鼠肾脏、系膜和近端和远端小管细胞的所有区域都表达真实的epor。在肾癌细胞和多囊肾的囊肿上皮中也检测到类似的EPOR表达。在体外,EPO刺激所有正常和恶性细胞的有丝分裂发生,并刺激损伤小管细胞的细胞存活和运动发生。由于正常肾脏基本上对EPO没有反应,我们假设EPO在肾脏中的细胞因子作用是在肾小管细胞被先前的损伤诱导增殖时显示出来的,就像急性肾衰竭中发生的那样。因此,我们发现EPO治疗缺血性急性肾功能衰竭大鼠具有肾保护作用并加速功能恢复。
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引用次数: 56
Coagulation, fibrinolysis and angiogenesis: new insights from knockout mice. 凝血、纤溶和血管生成:来自基因敲除小鼠的新见解。
Pub Date : 2002-01-01 DOI: 10.1159/000065305
Sergey V Brodsky

Angiogenesis plays a key role in a broad array of physiologic and pathologic processes. Two major systems--coagulation and fibrinolysis--maintaining hemostasis, have recently been implicated in angiogenesis. Generation of mice deficient in components of coagulation and plasminogen systems has provided an extraordinary opportunity to define the role of each of these systems in vivo and to elucidate molecular mechanisms involved in angiogenesis. It appears that several factors of the coagulation system, such as the tissue factor, the factor V and the thrombin receptor, play an important role in embryonic vessel formation, most probably in the formation of the primitive vascular wall. In addition, the plasminogen system appears to play a significant role in angiogenesis in adulthood, regulating the migration of endothelial and smooth muscle cells, the degradation of the extracellular matrix and activity of the metalloproteinase system. These new revelations open a possibility for future therapeutic strategies to specifically control angiogenesis in different pathological processes where abnormalities of tissue vascularization are pathogenetically prominent.

血管生成在一系列广泛的生理和病理过程中起着关键作用。两个主要的系统——凝血和纤溶——维持止血,最近被认为与血管生成有关。产生凝血和纤溶酶原系统成分缺乏的小鼠提供了一个非凡的机会来定义这些系统在体内的作用,并阐明参与血管生成的分子机制。似乎凝血系统的几个因子,如组织因子、因子V和凝血酶受体,在胚胎血管形成中起重要作用,最有可能在原始血管壁的形成中起重要作用。此外,纤溶酶原系统似乎在成人血管生成中发挥重要作用,调节内皮细胞和平滑肌细胞的迁移,细胞外基质的降解和金属蛋白酶系统的活性。这些新发现为未来的治疗策略提供了一种可能性,可以在组织血管化异常的病理突出的不同病理过程中特异性地控制血管生成。
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引用次数: 15
Nephrotoxicity of angiotensin inhibition during the perinatal period. 围产期血管紧张素抑制的肾毒性。
Pub Date : 2001-01-01 DOI: 10.1159/000020702
Y Miyazaki, I Ichikawa

As the only ex utero mechanism for the removal of nitrogenous waste, the mammalian kidney achieves some 50-fold increase in urine production during the perinatal period when the placental circulation becomes no longer available as a functional dialyzer. This urine is efficiently removed from the kidney by the renal pelvis, a smooth muscle structure unique to mammals, which develops during the perinatal period. We found that mutant mice completely devoid of angiotensinogen or its type 1 receptor, as well as wild-type neonates given an ACE inhibitor, fail to develop a renal pelvis or a ureteral peristaltic movement. These structural and functional defects in the urinary tract are followed by severe obstructive injury of the renal parenchyma. The ability of angiotensin to directly induce the pelvis is demonstrated in an organ culture system, in which treatment with angiotensin induces the characteristic smooth muscle layer in the wild type, but not in homozygous null mutants. Upregulation of both renal angiotensin content and type 1 receptor at the renal hilum are also demonstrated in the wild type during the transition from intra- to extra-uterine life. By inducing the timely development of the renal pelvis, angiotensin thus facilitates the removal from the renal parenchyma of the urine that promptly increases at birth, thereby effectively preventing a buildup of intrarenal pressure and a consequent development of dysmorphic kidney.

作为唯一的体外清除含氮废物的机制,在围产期,当胎盘循环不再作为功能透析器时,哺乳动物肾脏的尿产量增加了约50倍。这些尿液通过肾盂有效地从肾脏中排出,肾盂是哺乳动物特有的平滑肌结构,在围产期发育。我们发现,完全缺乏血管紧张素原或其1型受体的突变小鼠,以及给予ACE抑制剂的野生型新生儿,不能形成肾盂或输尿管蠕动。这些尿路的结构和功能缺陷会导致严重的肾实质梗阻性损伤。血管紧张素直接诱导骨盆的能力在器官培养系统中得到证实,血管紧张素在野生型中诱导了特征性的平滑肌层,而在纯合的零突变体中则没有。肾血管紧张素含量和肾门1型受体的上调也在野生型从子宫内到子宫外生活的过渡过程中得到证实。通过诱导肾盂的及时发育,血管紧张素促进了出生时迅速增加的尿液从肾实质中排出,从而有效地防止了肾内压力的积累和随后的畸形肾的发展。
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引用次数: 2
Renal and urinary glycosaminoglycans in an experimental model of chronic renal failure in rats. 肾和尿糖胺聚糖在大鼠慢性肾功能衰竭实验模型中的作用。
Pub Date : 2001-01-01 DOI: 10.1159/000020706
Y M Michelacci, R A Cadaval, R M Rovigatti, O Kohlman

The present paper reports the glomerular and renal individual glycosaminoglycan levels in an experimental model of chronic renal failure (CRF) that was induced in Wistar rats by five-sixths mass ablation. Glycemia, body weight, blood systolic pressure and urinary excretions of creatinine, albumin and glycosaminoglycans were measured for 12 weeks. At the end of the experiment, the weight and the glycosaminoglycan composition of the kidneys were determined. In control rats, heparan sulfate was the main glycosaminoglycan found both in whole kidney and isolated glomeruli, with trace amounts of dermatan sulfate. Isolated glomeruli presented higher heparan sulfate concentrations than whole kidney (expressed as mg/g dry weight). In CRF rats, albuminuria appeared from the 2 week on, and dermatan sulfate and chondroitin sulfate contents of the kidney increased, whereas heparan sulfate levels remained unaltered. Changes in urine glycosaminoglycans (heparan sulfate, chondroitin sulfate and dermatan sulfate) were not statistically significant. The increase in glomerular dermatan sulfate and chondroitin sulfate observed in this experimental model could be related to the mechanisms involved in the glomerulosclerosis and proteinuria that occur in CRF.

本文报道了Wistar大鼠慢性肾功能衰竭(CRF)实验模型中肾小球和肾脏个体糖胺聚糖水平的变化。测定血糖、体重、收缩压和尿肌酐、白蛋白、糖胺聚糖排泄量,持续12周。实验结束时,测定肾脏重量和糖胺聚糖组成。对照大鼠全肾和离体肾小球中均以硫酸肝素为主要糖胺聚糖,并有微量硫酸皮聚糖。离体肾小球的硫酸肝素浓度高于全肾(以mg/g干重表示)。在CRF大鼠中,从2周开始出现蛋白尿,肾脏中硫酸皮肤素和硫酸软骨素含量增加,而硫酸肝素水平保持不变。尿中糖胺聚糖(硫酸肝素、硫酸软骨素和硫酸皮聚糖)的变化无统计学意义。在该实验模型中观察到的肾小球硫酸皮肤素和硫酸软骨素的增加可能与肾小球硬化和蛋白尿发生的机制有关。
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引用次数: 16
Oxidant stress activates AP-1 and heparin-binding epidermal growth factor-like growth factor transcription in renal epithelial cells. 氧化应激激活AP-1和肝素结合表皮生长因子样生长因子在肾上皮细胞中的转录。
Pub Date : 2001-01-01 DOI: 10.1159/000020705
M Sakai, T Tsukada, R C Harris

Ischemia/reperfusion injury increases the expression of bioactive heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the rat kidney, suggesting that oxidant stress or cell injury related to oxidant stress might affect HB-EGF expression in the injured renal parenchyma. We utilized a nontransformed rat renal epithelial cell line (NRK-52E cells) to investigate whether reactive oxygen species induced transcriptional activation of HB-EGF mRNA. Hypoxia/reoxygenation increased HB-EGF expression in NRK-52E cells, and at concentrations that induced sublethal cell injury, hydrogen peroxide (H(2)O(2)) increased HB-EGF mRNA expression 4.7-fold. The free radical scavengers, dimethylthiourea and N-acetylcysteine inhibited HB-EGF mRNA induction. In contrast, another free radical scavenger, pyrrolidine thiocarbamate (PDTC), augmented H(2)O(2)-mediated HB-EGF expression. Since PDTC has been reported to augment AP-1-mediated transcriptional activation, we utilized an electrophoretic mobility shift assay to confirm that H(2)O(2) administration to NRK-52E cells did increase nuclear extract DNA-binding activity to a consensus AP-1 sequence. Using a CAT reporter assay coupled to the proximal 2,000 bp of the human HB-EGF 5'-untranslated region, we determined that H(2)O(2) administration increased CAT activity 5.5-fold. Truncation or deletion mutations of a putative AP-1-binding site reduced the H(2)O(2)-stimulated activity by >60%, and there was increased DNA binding of nuclear extracts from H(2)O(2)-treated cells to a 24-bp oligonucleotide containing this putative AP-1 site. Anti-fos and jun antibodies inhibited this binding, and there was no binding to an oligonucleotide in which the putative AP-1 site was mutated. The site of the residual activation was found to exist in the most proximal 5'-untranslated region (-121 to +60), which contains two putative SP1 sites. Timing and localization of AP-1-binding activity from nuclear extracts from the post-ischemic tissue correlated with HB-EGF mRNA expression. Therefore, in renal epithelial cells, oxidant stress increases HB-EGF expression, which appears to be mediated in part by an increase in AP-1 binding. This activation may play an important role in the induction of HB-EGF mRNA in response to tissue injury and may regulate early stages of recovery following ischemic damage.

缺血/再灌注损伤可增加大鼠肾脏中生物活性肝素结合表皮生长因子样生长因子(HB-EGF)的表达,提示氧化应激或氧化应激相关的细胞损伤可能影响损伤肾实质中HB-EGF的表达。我们利用未转化的大鼠肾上皮细胞系(NRK-52E细胞)来研究活性氧是否诱导HB-EGF mRNA的转录激活。缺氧/再氧化增加了NRK-52E细胞中HB-EGF的表达,在诱导亚致死细胞损伤的浓度下,过氧化氢(H(2)O(2))使HB-EGF mRNA表达增加4.7倍。自由基清除剂、二甲基硫脲和n -乙酰半胱氨酸抑制HB-EGF mRNA的诱导。相反,另一种自由基清除剂吡咯烷硫代氨基甲酸酯(PDTC)增强了H(2)O(2)介导的HB-EGF表达。由于PDTC已被报道增强AP-1介导的转录激活,我们利用电泳迁移率转移试验证实,H(2)O(2)给药NRK-52E细胞确实增加了核提取物dna结合活性,达到一致的AP-1序列。通过与人HB-EGF 5'-未翻译区近2000 bp相结合的CAT报告基因试验,我们确定H(2)O(2)使CAT活性增加了5.5倍。假设AP-1结合位点的截断或缺失突变使H(2)O(2)刺激的活性降低了60%以上,并且H(2)O(2)处理细胞的核提取物与含有该假设AP-1位点的24bp寡核苷酸的DNA结合增加。抗fos和jun抗体抑制了这种结合,并且没有与推定的AP-1位点突变的寡核苷酸结合。残馀激活位点存在于最近的5′-未翻译区(-121 ~ +60),其中包含两个假定的SP1位点。缺血后组织核提取物ap -1结合活性的时间和定位与HB-EGF mRNA表达相关。因此,在肾上皮细胞中,氧化应激增加HB-EGF的表达,这似乎部分是由AP-1结合的增加介导的。这种激活可能在组织损伤诱导HB-EGF mRNA中发挥重要作用,并可能调节缺血损伤后恢复的早期阶段。
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引用次数: 36
Genetic models of hypertension in experimental animals. 实验动物高血压遗传模型。
Pub Date : 2001-01-01 DOI: 10.1159/000020701
Y Yagil, C Yagil

Genetic animal models are central to ongoing efforts to elucidate the pathophysiology and genetic basis of hypertension. The rat is the leading species in experimental hypertension. Several rat models of hypertension are available for research, including inbred strains, congenic lines, transgenic animals and recombinant inbred strains. Each of these models has been designed to express different phenotypes, including spontaneous hypertension, salt sensitivity, stress sensitivity and susceptibility to end-organ damage. All these models have been extremely useful in the search for the physiological mechanisms that underlie hypertension, but some of them have been specifically designed for detecting the hypertension genes. This latter task is extremely complex in spontaneous hypertension, but genetic animal models may simplify the task by enabling to focus on specific phenotypes. Despite intensive efforts over nearly 3 decades, the genetic basis of hypertension has not been unveiled so far in the rat or in other species. Recent dense mapping of the rat genome, the development of new strategies and technologies in molecular genetics including differential gene expression, expressed sequence tags and DNA biochips render hope that the formidable task of identification of new candidate genes in hypertension will move another major step forward. Once these genes are identified, their function and role in hypertension will have to be determined, utilizing functional genomic strategies and bioinformatics. Finally, the findings in genetic animal models of hypertension will have to be extrapolated to humans by homology and syntenic mapping strategies.

遗传动物模型是阐明高血压的病理生理和遗传基础的核心。大鼠是实验性高血压的主要物种。高血压大鼠模型有多种,包括自交系、同源系、转基因动物和重组自交系。这些模型中的每一个都被设计来表达不同的表型,包括自发性高血压、盐敏感性、应激敏感性和终末器官损伤的易感性。所有这些模型在寻找高血压的生理机制方面都非常有用,但其中一些模型是专门为检测高血压基因而设计的。后一项任务在自发性高血压中非常复杂,但遗传动物模型可以通过关注特定表型来简化这项任务。尽管经过近30年的努力,高血压的遗传基础至今尚未在大鼠或其他物种中揭晓。最近大鼠基因组的密集定位,分子遗传学新策略和新技术的发展,包括差异基因表达,表达序列标签和DNA生物芯片,使人们希望鉴定新的高血压候选基因的艰巨任务将向前迈进一大步。一旦确定了这些基因,就必须利用功能基因组策略和生物信息学来确定它们在高血压中的功能和作用。最后,在高血压遗传动物模型中的发现将不得不通过同源性和合成作图策略外推到人类。
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引用次数: 14
Interactions between mitochondrial proteins and lipid peroxidation products in the maintenance of the glomerular filtration barrier in the in vitro perfused kidney. 线粒体蛋白和脂质过氧化产物在体外灌注肾脏肾小球滤过屏障维持中的相互作用。
Pub Date : 2001-01-01 DOI: 10.1159/000020703
S Wang, M Solin, H Ahola, P Luimula, H Holthöfer

Background: The fourth complex of the mitochondrial respiratory chain, cytochrome-c oxidase (CytC) consists of thirteen both mitochondrially and nuclearly encoded subunits, which are differently regulated in proteinuric kidneys. The effect of mitochondrial involvement on proteinuria is not known.

Methods: We set up an in vitro kidney perfusion model to study the direct effect of inhibitors of the mitochondrial respiratory chain, rotenone and antimycin A, on the glomerular filtration barrier by using immunohistochemistry and Northern blotting and quantitating the resulting proteinuria.

Results: Rapid onset of proteinuria and characteristic changes in CytC subunits were seen in the perfused kidneys. Urinary protein excretion increased significantly in the rotenone- and antimycin-A-treated groups during perfusion. Downregulation of CytC subunits I and IV was similarly found in the groups treated with rotenone and antimycin A, while increases in the lipid peroxidation (LPO) products malondialdehyde and 4-hydroxynonenal which reflect mitochondrial damage, were observed.

Conclusions: These data show rapid changes in mitochondrial proteins and induction of proteinuria in response to exposure to mitochondrial inhibitors. Together with the concomitant increase in local LPO products, these results suggest that continuous maintenance of a proper energy balance is important to maintain the glomerular filtration barrier.

背景:细胞色素c氧化酶(CytC)是线粒体呼吸链的第四个复合体,由13个线粒体和核编码亚基组成,它们在蛋白尿肾中受到不同的调节。线粒体参与对蛋白尿的影响尚不清楚。方法:建立离体肾灌注模型,采用免疫组化和Northern blotting方法,研究线粒体呼吸链抑制剂鱼藤酮和抗霉素A对肾小球滤过屏障的直接影响,并定量测定其产生的蛋白尿。结果:灌注肾中出现蛋白尿的快速发作和CytC亚单位的特征性变化。鱼藤酮组和抗霉素a组在灌注期间尿蛋白排泄量显著增加。在鱼tenone和抗霉素A组中同样发现CytC亚基I和IV的下调,同时观察到反映线粒体损伤的脂质过氧化(LPO)产物丙二醛和4-羟基壬烯醛的增加。结论:这些数据表明,暴露于线粒体抑制剂后,线粒体蛋白的快速变化和蛋白尿的诱导。结合局部LPO产物的增加,这些结果表明持续维持适当的能量平衡对于维持肾小球滤过屏障是重要的。
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引用次数: 3
期刊
Experimental nephrology
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