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Reduction in mean glomerular pore size coincides with the development of large shunt pores in patients with diabetic nephropathy. 糖尿病肾病患者肾小球平均孔径的减小与大分流孔的形成一致。
Pub Date : 2001-01-01 DOI: 10.1159/000020698
R Oberbauer, V Nenov, C Weidekamm, M Haas, T Szekeres, G Mayer

The glomerular size selectivity was determined by neutral dextran clearance sieving technique and plasma cystatin C levels in two groups of patients with long-standing type I diabetes mellitus and different stages of albuminuria but normal glomerular filtration rate and in a group of healthy controls. The sieving characteristics of the glomerular filter were determined using a mathematical model of log normal pore size distribution. Patients with albuminuria above 200 microg/min exhibited a significant increase of cystatin c plasma concentrations and a significant reduction in mean glomerular filtration slit size. Only these patients exhibited large, unrestrictive pores in the glomerular filter (shunt). The plasma cystatin c levels correlated significantly with 26-angstrom neutral dextran plasma levels in microalbuminuric patients and in patients with albuminuria above 200 microg/min. We conclude that a reduction in average pore size of the glomerular filter does not occur earlier than the development of large shunt pores. The renal clearance of cystatin c in patients with proteinuric diabetic nephropathy but a normal glomerular filtration rate is reduced due to its molecular size.

采用中性右旋糖酐清除率筛分技术和血浆胱抑素C水平测定两组长期合并不同阶段蛋白尿但肾小球滤过率正常的1型糖尿病患者和健康对照者的肾小球大小选择性。利用对数正态孔径分布的数学模型确定了肾小球滤过器的筛分特性。蛋白尿高于200微克/分钟的患者血浆胱抑素c浓度显著升高,平均肾小球滤过缝大小显著减小。只有这些患者在肾小球滤过器(分流)中表现出大的、不受限制的毛孔。血浆胱抑素c水平与26埃中性葡聚糖血浆水平在微量白蛋白尿患者和高于200微克/分钟的白蛋白尿患者中显著相关。我们得出的结论是,肾小球滤过器平均孔径的减小并不早于大分流孔的形成。蛋白尿糖尿病肾病患者的肾清除胱抑素c,但正常肾小球滤过率因其分子大小而降低。
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引用次数: 29
Intrarenal renin-angiotensin system contributes to tubular acidification adaptation following uninephrectomy. 肾内肾素-血管紧张素系统有助于肾切除术后肾小管酸化适应。
Pub Date : 2001-01-01 DOI: 10.1159/000020700
C Amorena, C Damasco, P Igarreta, M MacLaughlin

Background/aims: Reduction in renal mass by uninephrectomy induces a functional compensation in the remnant kidney. The activity of the angiotensin-converting enzyme (ACE) as well as renin mRNA in the proximal convoluted tubule (PCT) of uninephrectomized (UNx) rats increases. The aim of this work was to determine whether the increased activity of the local renin-angiotensin system (RAS) participates in the adaptation of renal function after uninephrectomy.

Method: We utilized normal two-kidney (2K) and 3-week UNx rats to study the activity of the ACE in vesicles obtained from luminal membranes of proximal tubular cells and the acidification kinectics in PCTs using micropuncture techniques.

Results: The converting enzyme activity was significantly larger in UNx (5.87+/-0.69 nmol x min(-1) x mg protein(-1)) than in 2K rats (2.43+/-0.13 nmol x min(-1) x mg protein(-1); p<0.05). The acidification rate constant (kappa) in PCT of 2K rats was 0.18+/-0.02 s(-1) and in UNx rats 0.30+/-0.04 s(-1) (p<0.001). In UNx rats, microperfusion with 10(-5) M ramipril or 10(-5) M losartan decreased kappa to 0.19+/-0.02 and 0.18+/-0.02 s(-1), respectively, but had no effect on 2K rats. Luminal steady-state pH (pH(infinity)) was the same in 2K and UNx rats, and was not modified by addition of 10(-5) M ramipril or 10(-5) M losartan in both groups. The proximal H(+) flux (J(H(+))), calculated from pH(infinity) and kappa, was 1.12 nmol x cm(-2) x s(-1) in 2K rats and, 1.77 nmol. cm(-2). s(-1) in UNx rats (p<0.001). In 2K rats, this value was not changed by 10(-5) M ramipril or 10(-5) M losartan, but in UNx rats J(H(+)) decreased 25 and 30% with ramipril or losartan, respectively (p<0.001).

Conclusions: These data suggest that the increase in the local RAS activity could be an adaptive change that contributes to maintain the homeostasis of body fluids after uninephrectomy.

背景/目的:非肾切除术减少肾肿块可引起残肾的功能代偿。未肾切除术(UNx)大鼠近端曲小管(PCT)血管紧张素转换酶(ACE)和肾素mRNA活性升高。这项工作的目的是确定局部肾素-血管紧张素系统(RAS)活性的增加是否参与肾切除术后肾功能的适应。方法:采用微穿刺技术,采用正常双肾(2K)大鼠和3周龄UNx大鼠,研究近端小管细胞管腔膜囊泡中ACE的活性及PCTs的酸化动力学。结果:UNx组转化酶活性(5.87+/-0.69 nmol x min(-1) x mg蛋白(-1))明显高于2K组(2.43+/-0.13 nmol x min(-1) x mg蛋白(-1));结论:这些数据表明,局部RAS活性的增加可能是一种适应性变化,有助于维持非肾切除术后体液的稳态。
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引用次数: 5
ACE inhibition preserves heparan sulfate proteoglycans in the glomerular basement membrane of rats with established adriamycin nephropathy. ACE抑制可保留阿霉素肾病大鼠肾小球基底膜中的硫酸肝素蛋白多糖。
Pub Date : 2001-01-01 DOI: 10.1159/000020704
F H Wapstra, G J Navis, H van Goor, J van den Born, J H Berden, P E de Jong, D de Zeeuw

The gradual onset of the antiproteinuric effects of ACE inhibition suggests that structural effects on the glomerular basement membrane (GBM) may be involved in their renoprotective action. To test this hypothesis, we studied the effects of lisinopril (5 mg/kg/24 h) on proteinuria, focal glomerulosclerosis (FGS) and glomerular heparan sulfate (HS) proteoglycan (HSPG) GBM staining in rats with established Adriamycin nephrosis. Treatment was started 6 weeks after disease induction. As expected, lisinopril reduced blood pressure, proteinuria and the FGS score. In control rats, Adriamycin nephrosis was associated with significantly impaired GBM staining for both HSPG core protein (assessed from BL-31 staining) and HS staining (assessed from JM-403 staining) 12 weeks after disease induction. In rats treated with lisinopril (5 mg/kg/24 h) GBM staining was significantly better preserved for HS as well as for HSPG core protein. These data suggest that structural effects on the GBM, improving glomerular permselectivity, may be involved in the renoprotective effects of ACE inhibition in proteinuria-induced renal damage.

ACE抑制的抗蛋白尿作用的逐渐发生表明,对肾小球基底膜(GBM)的结构性影响可能参与其肾保护作用。为了验证这一假设,我们研究了赖诺普利(5 mg/kg/24 h)对阿霉素肾病大鼠蛋白尿、局灶性肾小球硬化(FGS)和肾小球硫酸肝素(HS)蛋白多糖(HSPG) GBM染色的影响。诱导发病后6周开始治疗。不出所料,赖诺普利降低了血压、蛋白尿和FGS评分。在对照大鼠中,阿霉素肾病在疾病诱导后12周与HSPG核心蛋白(BL-31染色)和HS染色(JM-403染色)的GBM染色显著受损相关。赖诺普利(5 mg/kg/24 h)处理的大鼠,HS和HSPG核心蛋白的GBM染色保存明显较好。这些数据表明,在蛋白尿引起的肾损害中,ACE抑制对GBM的结构性影响,改善肾小球过电选择性,可能涉及到肾保护作用。
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引用次数: 34
Low leptin mRNA level in adipose tissue and normoleptinemia in experimental chronic renal failure. 实验性慢性肾功能衰竭脂肪组织瘦素mRNA水平低与正常瘦素血症的关系。
Pub Date : 2001-01-01 DOI: 10.1159/000020699
J Swierczynski, J Korczynska, M Szolkiewicz, J Karbowska, Z Kochan, T Nieweglowski, E Kusiak, B Rutkowski

Background: Anorexia and weight loss frequently accompany chronic renal failure (CRF). Although multiple metabolic changes occur during CRF, a bulk of evidence indicates that the decrease in caloric intake plays a major role in CRF-induced weight loss. Recently, it has been suggested that elevated plasma leptin concentrations could contribute to anorexia and to downregulation of leptin gene expression in CRF patients. However, in some CRF patients, plasma leptin concentrations have been found to be lower than one could expect. Thus we assumed that inhibition of leptin synthesis plays an important role in the regulation of plasma leptin concentrations in CRF patients.

Methods: To test this assumption, the leptin mRNA level in rat white adipose tissue from ad-libitum-fed control (sham operated), pair-fed control (sham operated) and rats with experimentally induced CRF has been measured by Northern blotting analysis. In addition, serum leptin concentration (by radioimmunoassay) was determined in all three groups of animals.

Results: The results of the present study indicate that in experimental CRF the leptin mRNA level is decreased by about 50% as compared to the sham-operated animals (ad-libitum-fed and pair-fed controls). The mean serum leptin concentration in CRF rats was essentially similar to the leptin concentration in sham-operated ones.

Conclusion: The data obtained suggest that in CRF animals the serum leptin concentration might be affected not only by the decrease in leptin removal in the kidney, but also by the decrease in leptin secretion from adipose tissue. Furthermore, the results of the study suggest that leptin may be only one of many factors involved in the pathogenesis of malnutrition associated with CRF.

背景:厌食症和体重减轻经常伴随慢性肾功能衰竭(CRF)。尽管在CRF期间会发生多种代谢变化,但大量证据表明,热量摄入的减少在CRF诱导的体重减轻中起主要作用。最近,有研究表明血浆瘦素浓度升高可能导致厌食症和CRF患者瘦素基因表达下调。然而,在一些慢性肾功能衰竭患者中,发现血浆瘦素浓度低于预期。因此,我们认为抑制瘦素合成在CRF患者血浆瘦素浓度的调节中起重要作用。方法:为了验证这一假设,采用Northern blotting分析方法,测定了自由喂养对照组(假手术)、成对喂养对照组(假手术)和实验性诱导CRF大鼠白色脂肪组织中瘦素mRNA的水平。此外,用放射免疫法测定了三组动物的血清瘦素浓度。结果:本研究结果表明,与假手术动物(自由喂养和配对喂养对照)相比,实验CRF中瘦素mRNA水平下降了约50%。CRF大鼠的平均血清瘦素浓度与假手术大鼠基本相似。结论:CRF动物血清瘦素浓度不仅受到肾脏中瘦素去除量减少的影响,还受到脂肪组织中瘦素分泌量减少的影响。此外,研究结果表明,瘦素可能只是参与CRF相关营养不良发病机制的众多因素之一。
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引用次数: 26
Mechanisms of renal calcium transport. 肾钙转运机制。
Pub Date : 2000-11-01 DOI: 10.1159/000020688
P A Friedman

The kidneys play a key role in the integrated regulation of calcium homeostasis. Calcium absorption takes place throughout the nephron. Proximal tubules, thick ascending limbs of Henle's loop, and distal tubules are the major sites of calcium absorption. The mechanisms of absorption vary significantly from one segment to another, as does the extent of hormonal regulation. At one extreme is the considerable reabsorption by proximal tubules that proceeds primarily, if not entirely, by a paracellular pathway that is not regulated by hormones or drugs. In thick ascending limbs, calcium absorption occurs through a combination of transcellular and paracellular routes. The active, transcellular component is regulated by parathyroid hormone (PTH) and calcitonin, whereas the passive, paracellular route is governed by the extent of concomitant sodium absorption. At the other extreme is the distal tubule, where calcium absorption is entirely transcellular and is regulated by PTH,1,25[OH(2)] vitamin D(3), calcitonin, and by calcium-sparing drugs such as thiazide-type diuretics. The present review focuses on recent insights into the mechanisms of transcellular calcium movement and highlights the discovery of an epithelial calcium channel, ECaC, that may mediate calcium entry in distal tubules.

肾脏在钙稳态的综合调节中起着关键作用。钙的吸收贯穿于肾元。近端小管、Henle’s袢的粗升肢和远端小管是钙吸收的主要部位。不同部位的吸收机制差异很大,激素调节的程度也是如此。一个极端是近端小管的大量重吸收,如果不是全部,则主要通过不受激素或药物调节的细胞旁途径进行。在粗大的升肢中,钙的吸收通过细胞外和细胞旁途径的结合发生。活性的、跨细胞的成分是由甲状旁腺激素(PTH)和降钙素调节的,而被动的、细胞旁的途径是由伴随钠吸收的程度控制的。另一个极端是远端小管,钙的吸收完全是跨细胞的,由甲状旁腺素、1,25[OH(2)]、维生素D(3)、降钙素以及噻嗪类利尿剂等保钙药物调节。本综述着重于最近对跨细胞钙运动机制的见解,并强调了上皮钙通道ECaC的发现,该通道可能介导钙进入远端小管。
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引用次数: 71
Defects in processing and trafficking of cystic fibrosis transmembrane conductance regulator. 囊性纤维化跨膜传导调节剂的加工和转运缺陷。
Pub Date : 2000-11-01 DOI: 10.1159/000020687
K Kunzelmann, R Nitschke

In most epithelial tissues Cl(-) transport relies on the cystic fibrosis transmembrane conductance regulator (CFTR) which has dual function as a Cl(-) channel and as a regulator of other ion channels. More than 900 different mutations in the CFTR gene are the cause for defective transport of Cl(-) and Na(+) and impaired secretion or absorption of electrolytes in cystic fibrosis. However, the CFTR mutation delta F508 is the most common reason for the frequently inherited disease among the Caucasian population. Maturation and processing of delta F508-CFTR is defective which leads to expression of only very little but functional CFTR in the cell membrane. Understanding the processing and trafficking of CFTR may give a clue to the question as to how the expression and residual function of delta F508-CFTR can be enhanced, and may lead to the development of new pharmacological tools for the treatment of cystic fibrosis.

在大多数上皮组织中,Cl(-)转运依赖于囊性纤维化跨膜传导调节剂(CFTR), CFTR具有Cl(-)通道和其他离子通道调节剂的双重功能。超过900种不同的CFTR基因突变是囊性纤维化中Cl(-)和Na(+)运输缺陷和电解质分泌或吸收受损的原因。然而,CFTR突变δ F508是高加索人群中常见遗传性疾病的最常见原因。delta F508-CFTR的成熟和加工存在缺陷,导致在细胞膜中仅表达少量但具有功能的CFTR。了解CFTR的加工和贩运可能会为如何增强delta F508-CFTR的表达和剩余功能提供线索,并可能导致开发新的药物工具来治疗囊性纤维化。
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引用次数: 10
Disorders of the epithelial Na(+) channel in Liddle's syndrome and autosomal recessive pseudohypoaldosteronism type 1. Liddle综合征和常染色体隐性假醛固酮增多症1型中上皮Na(+)通道的紊乱
Pub Date : 2000-11-01 DOI: 10.1159/000020685
Y S Oh, D G Warnock

The epithelial Na(+) channel (ENaC) is the key step in many Na(+)-absorptive epithelia, such as kidney and distal colon, that controls the overall rate of transepithelial Na(+) transport. ENaC is composed of three homologous subunits, alpha, beta, and gamma. The alpha subunit is the key subunit for the formation of a functional ion channel, while the beta and gamma subunits can greatly potentiate the level of expressed Na(+) currents. ENaCs belong to the recently identified DEG/ENaC supergene family, sharing the same basic structure with cytoplasmic amino and carboxy termini, two transmembrane regions, and a large extracellular loop. The human ENaC genes have been cloned, and using genetic linkage analysis the involvement of ENaC gene mutations in two distinct human diseases, Liddle's syndrome and autosomal recessive pseudohypoaldosteronism type 1 (PHA-1), has been demonstrated. In Liddle's syndrome, gain-of-function mutations in the beta or gamma ENaC subunits have been found; all identified mutations so far reside in the carboxy terminus of the protein, either deleting or modifying the functionally important PY motif. In PHA-1, loss-of-function mutations in the alpha, beta, or gamma subunits have been found; these mutations either truncate a significant portion of the structure or modify an amino acid that plays an important role in channel function. In this review, our current understanding about ENaC and the pathophysiology of Liddle's syndrome and PHA-1 caused by ENaC mutations will be discussed.

上皮Na(+)通道(ENaC)是许多Na(+)吸收上皮(如肾和远端结肠)的关键步骤,它控制着上皮Na(+)运输的总体速率。ENaC由三个同源亚基组成,α, β和γ。α亚基是形成功能性离子通道的关键亚基,而β和γ亚基可以极大地增强Na(+)电流的表达水平。ENaCs属于最近发现的DEG/ENaC超基因家族,具有相同的细胞质氨基端和羧基端、两个跨膜区和一个大的细胞外环的基本结构。人类ENaC基因已被克隆,并使用遗传连锁分析,ENaC基因突变参与两种不同的人类疾病,利德尔综合征和常染色体隐性假醛固酮减少症1型(PHA-1),已被证明。在利德尔综合征中,发现了β或γ ENaC亚基的功能获得突变;到目前为止,所有已发现的突变都位于蛋白质的羧基端,删除或修饰了功能重要的PY基序。在PHA-1中,发现了α、β或γ亚基的功能丧失突变;这些突变要么截断结构的重要部分,要么修饰在通道功能中起重要作用的氨基酸。在这篇综述中,我们将讨论目前对ENaC的认识以及ENaC突变引起的Liddle综合征和PHA-1的病理生理。
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引用次数: 30
Defective processing and trafficking of water channels in nephrogenic diabetes insipidus. 肾源性尿崩症的水渠加工和运输缺陷。
Pub Date : 2000-11-01 DOI: 10.1159/000020686
E J Kamsteeg, P M Deen, C H van Os

Nephrogenic diabetes insipidus (NDI) is a disease characterized by the inability of the kidney to concentrate urine upon stimulation with vasopressin. Mutations in the gene for aquaporin-2 (AQP2) are the cause of the autosomal recessive and autosomal dominant forms of NDI. Mutant AQP2 proteins, found in autosomal recessive NDI, were shown to be misfolded and retarded in the endoplasmic reticulum. One mutant protein leading to autosomal dominant NDI, E258K, has been analyzed in detail. It was shown that this mutant was not retarded in the endoplasmic reticulum but mainly retained in the Golgi network. Furthermore, this particular mutant was able to form heterotetramers with wild-type AQP2, in contrast to mutants found in autosomal recessive NDI. The subsequent misrouting of complexes containing wild-type and mutant AQP2 proteins explains dominant NDI.

肾源性尿崩症(NDI)是一种以肾脏在加压素刺激下不能浓缩尿液为特征的疾病。水通道蛋白-2 (AQP2)基因突变是常染色体隐性和常染色体显性NDI的病因。在常染色体隐性NDI中发现的AQP2突变蛋白在内质网中被证明是错误折叠和发育迟缓的。一种导致常染色体显性NDI的突变蛋白E258K已被详细分析。结果表明,该突变体在内质网中并不迟滞,而主要保留在高尔基网中。此外,与常染色体隐性NDI中发现的突变体相比,这种特殊的突变体能够与野生型AQP2形成异源四聚体。随后含有野生型和突变AQP2蛋白的复合物的错误路线解释了显性NDI。
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引用次数: 22
Severely impaired urine-concentrating ability in mice lacking the CLC-K1 chloride channel. 缺乏CLC-K1氯离子通道的小鼠尿浓缩能力严重受损。
Pub Date : 2000-11-01 DOI: 10.1159/000020690
S Uchida, F Marumo

To analyze the physiological functions of CLC-K1 in vivo, we generated mice lacking CLC-K1 by targeted gene disruption. Homozygous mutant Clcnk1-/- mice produced approximately 5 times more urine than Clcnk1+/- and Clcnk1+/+ mice. After 24-hour water deprivation, Clcnk1-/- mice became severely dehydrated and lethargic. Intraperitoneal injection of the V2 agonist, deamino-Cys(1), D-Arg(8) vasopressin, induced an increase in urine osmolarity in Clcnk1+/- and Clcnk1+/+ mice from approximately 1,000 to approximately 3,000 mosm/kg H(2)O, whereas the increase in Clcnk1-/- mice was only from approximately 600 to approximately 840 mosm/kg H(2)O, indicating nephrogenic diabetes insipidus in Clcnk1-/- mice. These results clearly established that CLC-K1 plays a major role in the urinary-concentrating mechanisms.

为了分析CLC-K1在体内的生理功能,我们通过靶向基因破坏产生了缺乏CLC-K1的小鼠。纯合子突变的Clcnk1-/-小鼠产生的尿液大约是Clcnk1+/-和Clcnk1+/+小鼠的5倍。24小时缺水后,Clcnk1-/-小鼠出现严重脱水和嗜睡。腹腔注射V2激动剂,脱胺-胱氨酸(1),d -精氨酸(8)抗利尿素,诱导Clcnk1+/-和Clcnk1+/+小鼠的尿渗透压从约1,000 mosm/kg H(2)O增加到约3,000 mosm/kg H(2)O,而Clcnk1-/-小鼠的尿液渗透压仅从约600 mosm/kg H(2)O增加到约840 mosm/kg H(2)O,表明Clcnk1-/-小鼠肾源性尿中毒。这些结果清楚地表明CLC-K1在尿浓缩机制中起主要作用。
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引用次数: 8
Molecular pathology of renal chloride channels in Dent's disease and Bartter's syndrome. 登特病和巴特综合征肾氯离子通道的分子病理学研究。
Pub Date : 2000-11-01 DOI: 10.1159/000020689
R V Thakker

Recent advances in molecular biology have characterised a new class of chloride channels that are referred to as voltage-gated chloride channels (CLCs). To date 9 such CLCs (CLC-1 to CLC-7, CLC-Ka and CLC-Kb which are respectively encoded by the genes CLCN1 to CLCN7, CLCNKa and CLCNKb) have been identified in mammals. Mutations in 2 of these, referred to as CLC-5 and CLC-Kb, have been defined in the hypercalciuric nephrolithiasis disorders of Dent's disease and a form of Bartter's syndrome, respectively. In addition, other forms of Bartter's syndrome have been defined with mutations involving the bumetanide-sensitive sodium-potassium-chloride co-transporter (NKCC2) and the potassium channel ROMK. Finally, mutations of the thiazide-sensitive sodium chloride co-transporter (NCCT) are associated with Gitelman's syndrome, in which hypocalciuria and hypomagnesaemia are notable features. These molecular genetic studies have increased our understanding of the renal tubular mechanisms that regulate mineral homeostasis.

分子生物学的最新进展描述了一类新的氯离子通道,称为电压门控氯离子通道(CLCs)。迄今为止,在哺乳动物中已鉴定出9个这样的clc(分别由CLCN1至CLCN7、CLCNKa和CLCNKb基因编码的CLC-1至CLC-7、CLC-Ka和CLC-Kb)。其中2种基因的突变,被称为CLC-5和CLC-Kb,分别在登特病的高钙尿酸性肾结石疾病和巴特综合征的一种形式中被定义。此外,其他形式的巴特氏综合征已被定义为涉及布美他尼敏感的钠-钾-氯化钾共转运体(NKCC2)和钾通道ROMK的突变。最后,噻嗪类敏感氯化钠共转运体(NCCT)突变与Gitelman综合征有关,其中低钙尿和低镁血症是显著特征。这些分子遗传学研究增加了我们对调节矿物质稳态的肾小管机制的理解。
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引用次数: 31
期刊
Experimental nephrology
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