Effects of a therapy with losartan and quinaprilat on the progression of chronic renal failure in rats after a single dose of uranyl nitrate or 5/6 nephrectomy

The renoprotective effect of losartan and quinaprilat was tested in two different animal models of renal failure [female Wistar rats, single administration of 0.5 mg uranyl nitrate (UN)/100 g body wt. or 5/6 nephrectomy (5/6NX)]. Losartan (1 mg/100 g body weight [wt.]) and quinaprilat (1mg/100 g body wt.) were administered intraperitoneally, once daily, starting 10 days after UN and one week after 5/6NX till the end of 10 weeks experimental period. Parameters characterizing the therapeutic effect were blood pressure, urinary protein excretion 4 and 10 weeks after the injury, and p-aminohippurate accumulation in renal cortical slices in vitro, hydroxy-proline concentration in renal tissue and morphology at the end of the experiment.

Summarizing our results we state: (1) the angiotensin 1 receptor blocker losartan is more effective in UN-treated than in 5/6 NX rats, and (2) the angiotensin converting enzyme inhibitor quinaprilat is more effective than losartan because of the amelioration of blood pressure and OH-proline concentration in renal tissue of UN-treated rats.     

Suitability of 5/6 nephrectomy (5/6NX) for the induction of interstitial renal fibrosis in rats – Influence of sex, strain, and surgical procedure

Chronic renal failure (CRF) is a serious clinical problem and currently there are no adequate therapeutic strategies for treatment. Many possible treatment strategies have been tested in rats with CRF induced by subtotal nephrectomy. However, reports in the literature concerning the consequences of this procedure on rat kidney function are contradictory. For instance, such an intervention in male Sprague-Dawley rats apparently initiates the development of interstitial renal fibrosis, while in our similar studies on female Wistar rats (HW) there was minimal renal fibrosis. Therefore, we carried out experiments in adult rats to investigate the long-term consequences of 5/6 nephrectomy (5/6NX) in relation to (1) sex, (2) strain, and (3) two methods of surgical ablation. Ten weeks after 5/6NX, body weight gain, systolic blood pressure, creatinine clearance, and urinary protein were measured, along with renal hydroxyproline concentration determinations to assess the deposition of extracellular matrix. Also, light microscopic investigations were done to characterize renal damage. The functional parameters clearly indicated the development of CRF, while morphologic investigations showed only moderate fibrotic areas containing atrophic tubules and lymphocytic infiltrates. However, 45-60% of glomeruli were sclerotic. In summary, 5/6NX, using either method of partial nephrectomy, induces signs of moderate glomerulonephritis preferentially in female HW rats. Thus 5/6NX in female HW rats can be recommended as a suitable model in the induction of renal fibrosis.     

Temporary warm ischaemia, 5/6 nephrectomy and single uranyl nitrate administration--comparison of three models intended to cause renal fibrosis in rats.

In patients the progression of pathologic renal processes after the treatment of primary disease is a problem of increasing importance and therapeutic strategies are insufficient till now. The aim of this paper was to search for rat models of interstitial fibrosis as a basis for testing therapeutic strategies to prevent end-stage renal failure. Experiments were done on adult female Wistar rats (Han:Wist) to investigate long-term consequences of temporary warm ischaemia, 5/6 nephrectomy (5/6 NX) and single uranyl nitrate (UN) administration (0.3 or 0.5 mg/ 100 g body wt. intraperitoneally). Observation time was 20 weeks after injury in each group. Creatinine clearance, urinary protein excretion and hydroxy-proline (OH-proline) concentration in renal tissue were measured and light microscopic investigations were done to characterise both quality and time course of long-term renal damage in relation to matched control animals. Temporary warm ischaemia and 5/6 NX did not cause any fibrotic changes during the 20 weeks observation period. The higher UN dose led to decreased creatinine clearance, increased urinary protein excretion and enhanced OH-proline concentration in renal tissue. Morphologic investigations showed fibrotic areas containing strongly dilated and atrophic tubules with thickened basal membranes. These effects can be seen from week four after UN administration up to the end of the observation period. In conclusion, administration of one single dose of UN is a simple procedure to induce interstitial renal fibrosis as an experimental model to investigate therapeutic strategies for their prevention.     

全反式维甲酸对大鼠残余肾功能的保护作用及其机制

目的：研究全反式维甲酸(atRA)能否延缓大鼠残余肾功能的丧失，并探讨其可能机制。 方法： Wistar大鼠40只，采用5/6肾大部切除大鼠模型，分别给予5 mg·kg-1·d-1（A1组，n=8）、10 mg·kg-1·d-1（A2组，n=8）、20 mg·kg-1·d-1（A3组，n=8）的atRA灌胃，单纯肾大部切除非干预组（NX组，n=8）和假手术组（sham组，n=8）为对照。采用反相高效液相色谱检测大鼠血浆atRA浓度；肾脏病理切片采用PAS染色，计算肾小球硬化指数；应用免疫组化和Western blotting等方法观察转化生长因子β1（TGFβ1）在残余肾组织上的分布水平。 结果： 3个不同剂量的atRA组血药浓度高出NX和sham组10倍以上，并呈现出同给药剂量相吻合的浓度梯度。肾小球硬化评分结果表明，atRA 干预的大鼠肾小球硬化明显轻于NX组，其中A3组硬化程度明显轻于A1组和A2组，P<0.05；A1组和A2组无显著差异，sham组无硬化表现； NX组肾小球TGFβ1表达量最多，atRA干预的3个组明显少于sham组，但A1、A2、A3组间无差异。 结论： atRA能减轻5/6肾大部切除大鼠残余肾硬化，可能是通过抑制TGFβ1起作用。     

Use of gene chip technology for the characterisation of the regulation of renal transport processes and of nephrotoxicity in rats

Gene expression profiling using microarrays (rat-specific array RG-U34A, Affymetrix, U.S.A.) was employed for the investigation of: (1) hormonal regulation of renal function and (2) nephrotoxicity. For this purpose about 8,800 genes were analysed in kidney and, additionally, in liver tissue.

Ad 1.) Kidney functions develop during postnatal life. Thus, in vivo transport and accumulation of p-aminohippurate (PAH) was investigated on renal cortical slices (RCS) from 10- and 55-day-old rats. The animals were treated with dexamethasone (DEXA; 60 μg/100 g b.wt./day) for 3 days, which caused a significant reduction in the accumulation of PAH in 10-day-old rats (42 ± 5% whereas it was only slightly reduced in 55-day-old rats (70 ± 8%). To further clarify the regulation of renal function by DEXA, results were compared with those obtained previously after in vitro stimulation with DEXA. RCS were incubated for 24 hours in DEXA-containing medium (10⁻⁹ M). Under these conditions DEXA significantly increased the PAH uptake capacity in RCS obtained from 10- and 55-day-old rats up to 126 and 136%, respectively. Thus a stimulation of tubular transport capacity is possible in vitro. The effect of DEXA treatment on the gene expression of the kidney (in vivo) was moderate. Focussing especially on transporters, ion channels, ATPases, glucuronyltransferases, glutathione-S-transferase and cytochrome P450, the expression of only few genes were significantly changed (3 to 50-fold up- or down-regulation). Moreover, distinct age differences were found after in vivo administration of DEXA. The investigation of in vitro effects of DEXA is currently been performed.

Ad 2.) The kidney is threatened by nephrotoxins because of its ability to accumulate them. We used a single administration of uranyl nitrate (UN; 0.5 mg/100 g b.wt.) as a model for chronic renal failure (CRF). Clearance experiments were performed 10 weeks after UN administration (maximal symptoms of CRF) in adult female rats. As expected, UN induced interstitial cicatrices with reduced GFR and diminished PAH transport capacity. Despite the impressive morphological and functional changes in the kidney after exposure to UN, the gene expression profiles in the kidneys were only minimally affected: we found significantly changed expression levels for only 20 genes (5 genes were up-regulated [e.g. transgelin], 15 down-regulated [among these the Na-K-Cl-symporter, insulin-like growth factor, kallikrein, and ornithine decarboxylase). The lack of agreement between gene expression data and the nephrotoxic effects of UN can probably be explained by the long time interval between dosing and the assessment of the effect. The results confirm that primary genomic responses are likely to be strongest transiently after exposure and then decrease in intensity.     

四氢生物喋呤对肾切除5／6大鼠高血压和尿蛋白的治疗作用

目的：探讨四氢生物喋呤（BH4）对肾切除5／6（NX）后大鼠血压和尿蛋白的影响。方法38只大鼠按照处理方法的不同分为五组：NX组、NX＋BH4组（腹腔注射）、NX＋L-精氨酸（LA）组、NX＋口服地尔硫卓（DILT）组和假手术组。手术24小时后开始给药，并分别在给药前和给药后的第4周和第8周测量收缩压、测定尿蛋白和肌酐清除率。在实验的第8周末观察肾脏的组织学改变。结果：与假手术组比较，NX大鼠收缩压和尿蛋白均明显升高（P〈O．01）；BH4、LA及DILT对NX所产生的高血压均有降低作用（P〈O．01）；BH4、LA和DILT均使N-X的尿蛋白明显减少（P〈0．01），但DILT的减少幅度相对较小；NX各组，血尿素和血清肌酐都升高，血浆肌酐清除率都降低，各组之间无明显差别（P〉0．05）。NX后的大鼠出现肾小球系膜扩张，而各治疗组肾小球系膜扩张的程度较轻。结论：NX大鼠，手术24小时后补充BH4，在8周的观察期内可以使血压保持正常，并有减少尿蛋白、阻止肾小球系膜扩张的作用。     

Renal interstitial fibrosis (RIF): II. Ultrasound follow up study of single uranyl nitrate administration causing renal dysfunction in rats – comparison with histologic and functional renal parameters

A single administration of uranyl nitrate (UN; 0.5 mg/100 g b. wt. i.p.) to adult female Wistar rats reliably induces renal interstitial fibrosis (RIF) providing an experimental model to investigate therapeutic strategies. It was the aim of this study to further characterise a rat model of UN induced RIF which we have studied previously (APPENROTH et al. 2001) by the comparison of functional parameters with ultrasonographic examination over a period of 30 weeks after injury. In the acute phase after UN administration (between days 2 and 17) signs of inflammation (increase in renal blood flow, swelling of renal cortex, enlargement of renal pelvis) could be detected by ultrasound. After four weeks UN led to functional changes (decreased creatinine clearance, increased urinary protein excretion and increased OH-proline concentration in renal tissue). In vitro, the accumulation of p-aminohippurate and the gluconeogenesis were reduced. In accordance with the functional changes, distinct ultrasonographic abnormalities could be seen between weeks 10 and 30 after UN with regard to changes in kidney size and shape, reduced renal perfusion and enlargement of renal pelvis. The sensitivity of ultrasonography in small laboratory animals is limited and most useful for follow-up studies of acute renal changes after administration of nephrotoxins. Ultrasonography can not be recommended for non-invasive screening of the progression of chronic renal failure.     

Renal interstitial fibrosis (RIF): II. Ultrasound follow up study of single uranyl nitrate administration causing renal dysfunction in rats--comparison with histologic and functional renal parameters.

A single administration of uranyl nitrate (UN; 0.5 mg/100 g b. wt. i.p.) to adult female Wistar rats reliably induces renal interstitial fibrosis (RIF) providing an experimental model to investigate therapeutic strategies. It was the aim of this study to further characterise a rat model of UN induced RIF which we have studied previously (Appenroth et al. 2001) by the comparison of functional parameters with ultrasonographic examination over a period of 30 weeks after injury. In the acute phase after UN administration (between days 2 and 17) signs of inflammation (increase in renal blood flow, swelling of renal cortex, enlargement of renal pelvis) could be detected by ultrasound. After four weeks UN led to functional changes (decreased creatinine clearance, increased urinary protein excretion and increased OH-proline concentration in renal tissue). In vitro, the accumulation of p-aminohippurate and the gluconeogenesis were reduced. In accordance with the functional changes, distinct ultrasonographic abnormalities could be seen between weeks 10 and 30 after UN with regard to changes in kidney size and shape, reduced renal perfusion and enlargement of renal pelvis. The sensitivity of ultrasonography in small laboratory animals is limited and most useful for follow-up studies of acute renal changes after administration of nephrotoxins. Ultrasonography can not be recommended for non-invasive screening of the progression of chronic renal failure.     

The role of mesenchymal stem cells in the functional improvement of chronic renal failure

The most commonly used therapeutic targets in nephrology are the reduction of injury, the delay of progression, or renal replacement therapy. Many animal and human studies demonstrated the role of stem cells in repair and regenerations of kidney. Mesenchymal stem cells (MSCs) have shown to improve outcome of acute renal injury models. It is controversial whether MSCs can reduce injury following a toxic/ischemic event and delay renal failure in chronic kidney disease. We evaluated the hypothesis that the treatment with MSCs could improve renal function and attenuate injury in chronic renal failure (CRF). Sprague-Dawley female rats (8 weeks old, 182.2 +/- 7.2 g) underwent modified 5/6 nephrectomy. Rats in the MSC group received an injection of MSCs (1 x 10(6) cells) via tail vein 1 day after nephrectomy. Blood and urine samples were collected after 7 days and every month thereafter. The kidneys of rats were removed for histologic evaluation after 24-h urine collection and blood sampling. The Y-chromosome stain using fluorescent in situ hybridization was performed to verify the presence of male MSCs in the kidney of female recipients. No significant differences in blood urea nitrogen and creatinine concentration were observed between the MSC group and the untreated CRF group. However, the weight gain in the MSC group was greater than those in the CRF group after 4 months. Proteinuria in the MSC group was less than that in the CRF group over time. Y chromosome was detected in the kidney of MSC group. Although no significances were observed between these two groups, the histologic analysis suggests that MSCs have positive effect against glomerulosclerosis. These results suggest that MSCs help preserve renal function and attenuate renal injury in CRF.     

Decreased nitric oxide synthesis in rats with chronic renal failure

The present study was aimed at investigating whether an altered role of nitric oxide (NO) is involved in chronic renal failure (CRF). Rats were subjected to 5/6 nephrectomy and kept for 6 weeks to induce CRF. On the experimental day, after measurement of arterial pressure under anesthesia, the arterial blood was collected, and thoracic aorta and kidney were rapidly taken. NO metabolites (NOx) were determined in the plasma, urine, aorta and kidney. The expression of NO synthase (NOS) isozymes was determined in the kidney and aorta by Western blot analysis. The expression of NOS mRNA in the glomeruli was also determined by RT-PCR. There were significant increases in arterial pressure and serum creatinine levels in CRF. Urine NOx levels were decreased in CRF, whereas plasma NOx levels were not altered. Aorta and kidney tissue NOx levels were also decreased in CRF. The expression of endothelial constitutive (ec) and inducible (i) isoforms of NOS proteins was decreased in the kidney and aorta in CRF. Accordingly, the expression of ecNOS and iNOS mRNA was decreased in the glomeruli in CRF. In conclusion, NO synthesis is decreased in the kidney and vasculature of CRF rats.     

Ultrastructural and ultraimmunohistochemical changes upon partial nephrectomy and uranyl intoxication in the rat kidney

We studied kidneys of rats intoxicated with uranylnitrate (UN) or subjected to 5/6 nephrectomy (NX) or after a combination of both procedures (NX–UN). Our observations indicate that UN causes impressive changes of ultrastructure (partial loss of brush border, appearance of intercellular clefts in the epithelial barrier) and altered protein expression (α-SMA, collagen I and III) in proximal tubule cells. Renal parameters (creatinine clearance, proteinuria) seemed to be unaffected. Blood pressure recovered to normal values within 12 months. However ultrastructural and functional restoration of modified proximal tubules was not complete. We conclude that changed proximal tubules may induce progression of interstitial fibrosis causing renal failure. NX animals and more pronounced NX–UN animals showed dramatic changes in renal function. We observed increased levels of proteinuria, blood pressure and decreased creatinine clearance. Progressive glomerular reorganization includes loss of filtration gaps and enhanced thickness of glomerular basement membranes (GBM) with increased immunoreactivity for collagen IV. Cells in vicinity of Bowman's capsule contained high amounts of immunoreactive α-smooth muscle actin. The NX–UN group showed more dramatic changes in ultrastructure of proximal tubules including apoptosis. Enhanced expression and secretion of extracellular matrix proteins (ECM e.g. collagens I, III, fibronectin) indicate progressive epithelial–mesenchymal transition (EMT) leading to permanent impairment of renal function.     

Leucine and protein metabolism in rats with chronic renal insufficiency

The aim of this study was to evaluate the effect of chronic uremia induced by 5/6 nephrectomy (5/6NX) on changes in protein and branched-chain amino acid (BCAA; valine, leucine and isoleucine) metabolism. The control group consisted of sham operated rats. Twenty eight weeks after surgery the parameters of protein and amino acid metabolism were evaluated using a primed constant intravenous infusion of L-[1-(14)C]leucine. A drop in BCAA levels and a significant increase in urea, creatinine and cholesterol were observed in plasma of all 5/6NX rats. However, severe uremia with acidosis developed only in one third of rats with 5/6NX. In 5/6NX rats with acidosis significant increases in proteolysis, leucine oxidation, leucine oxidized fraction, and leucine clearance were observed in comparison with the control group and rats with 5/6NX without acidosis. In addition, in 5/6NX rats with acidosis a significant decrease in valine concentration in gastrocnemius muscle was found. We conclude that marked activation of proteolysis occurs in severe chronic renal failure and is probably caused by metabolic changes related to acidosis development.     

肾平滑肌瘤六例的影像学表现

目的 探讨肾平滑肌瘤的影像学表现特征,以提高对该病的诊断水平,从而选择更合理的治疗方案。方法 回顾性分析2005年1月—2016年12月4所医院经手术病理确诊的6例肾平滑肌瘤患者的影像学资料,其中男5例、女1例,年龄26～77岁。6例患者均行CT平扫及增强扫描;MRI平扫2例, 其中1例同时行增强检查。结果 6例共发现7个平滑肌瘤病灶,肿瘤最大径2.5～7 cm,平均5.3 cm;其中5个位于右肾,2个位于左肾;5个位于肾脏边缘,1个位于肾实质内,1个位于肾盂。肿瘤呈圆形和椭圆形各3个,呈分叶状1个。CT平扫5个病灶呈高密度,2个呈等密度;1个病灶密度不均,肿块内见坏死、囊变,其它6个密度均匀。CT增强扫描7个病灶均表现出渐进性延迟强化的特点,其中6个呈均匀强化,1个强化不均。MRI平扫2例共检出3个病灶:2个信号均匀,其中1个呈T₁WI低信号、T₂WI略高信号,1个呈 T₁WI等信号、T₂WI明显低信号;1个信号不均,T₁WI、T₂WI均呈高低混杂信号,T₂WI上病灶周围可见低信号肿瘤包膜;2个瘤体内见斑点状钙化。MRI增强检查1个病灶呈均匀延迟强化。结论 肾平滑肌瘤的主要影像学特征为发生于肾脏边缘密度或信号均匀的软组织肿块,CT 或 MRI增强扫描呈均匀延迟强化特点;虽然确诊需要依靠组织病理学检查,但熟悉其影像表现特点,可以帮助临床医生尽早选择更合适的治疗措施,减少不必要的肾切除。     

Angiotensin II AT1 receptor blockade changes expression of renal sodium transporters in rats with chronic renal failure

We aimed to examine the effects of angiotensin II AT(1) receptor blocker on the expression of major renal sodium transporters and aquaporin-2 (AQP2) in rats with chronic renal failure (CRF). During 2 wks after 5/6 nephrectomy or sham operation, both CRF rats (n=10) and sham-operated control rats (n=7) received a fixed amount of low sodium diet and had free access to water. CRF rats (n=10) were divided into two groups which were either candesartan-treated (CRF-C, n=4) or vehicle-treated (CRF-V, n=6). Both CRF-C and CRF-V demonstrated azotemia, decreased GFR, polyuria, and decreased urine osmolality compared with sham-operated rats. When compared with CRF-V, CRF-C was associated with significantly higher BUN levels and lower remnant kidney weight. Semiquantitative immunoblotting demonstrated decreased AQP2 expression in both CRF-C (54% of control levels) and CRF-V (57%), whereas BSC-1 expression was increased in both CRF groups. Particularly, CRF-C was associated with higher BSC-1 expression (611%) compared with CRF-V (289%). In contrast, the expression of NHE3 (25%) and TSC (27%) was decreased in CRF-C, whereas no changes were observed in CRF-V. In conclusion, 1) candesartan treatment in an early phase of CRF is associated with decreased renal hypertrophy and increased BUN level; 2) decreased AQP2 level in CRF is likely to play a role in the decreased urine concentration, and the downregulation is not altered in response to candesartan treatment; 3) candesartan treatment decreases NHE3 and TSC expression; and 4) an increase of BSC-1 is prominent in candesartan-treated CRF rats, which could be associated with the increased delivery of sodium and water to the thick ascending limb.     

BOVINE SERUM ALBUMIN (BSA) NEPHRITIS IN RATS IV. A SEQUENTIAL EVALUATION OF MONONUCLEAR PHAGOCYTE SYSTEM (MPS) FUNCTION

A clearance kinetic study of intravenously administered ¹²⁵I-labeled aggregated human IgG (¹²⁵I-AHIgG) from the circulation and its distribution in various organs was performed weekly during the course in a model of experimental immune complex glomerulonephritis which was induced in rats immunized 8 weeks previously with 6 times a week administration of 2 mg of bovine serum albumin (BSA) for 4 weeks from week 8 to 12. The removal rates of the injected ¹²⁵I-AHIgG from the circulation were retarded in nonproteinuric rats of week 9 and 10, at almost every checked point (p-value was <0.01). The clearance in those rats with severe proteinuria returned to the level of the control and of rats in week 8. The distribution of ¹²⁵I-AHIgG in the liver 4 hours after the administration revealed a considerable decrease in non-overt proteinuric rats of weeks 9, 10, and 11. A similar tendency of decreasing depositions of the radioactivity was shown in the spleen at each 4 hours. In contrast, the uptakes in the kidney and lung at the final week of 12 were larger. Delayed clearance from the circulation and a decreasing handle of the injected macromolecule in the liver and possibly in the spleen may suggest the presence of some impairment of the MPS function in the course of this experimental glomerulonephritis.     

大鼠残肾细胞凋亡及凋亡相关基因的动态表达及意义

目的： 研究在5/6肾切除大鼠不同时段残肾组织中肾实质细胞凋亡及相关基因Bax、Bcl-2、caspase-3、caspase-8、caspase-9 mRNA、蛋白质的动态表达变化及其意义。 方法: SD大鼠5/6肾切除后,分别在1周、2周、4周、8周、12周、16周、26周、40周采集标本，普通光镜、电镜观察残肾病理改变、TUNEL法检测肾脏细胞凋亡、RT-PCR和Western blotting检测残肾组织凋亡相关基因mRNA和蛋白质的变化、免疫组织化学进行蛋白质定位，分析凋亡、增殖与肾小球硬化和间质纤维化的相关关系。 结果: 5/6肾切除后大鼠残肾出现进行性肾小球硬化及间质纤维化病变。肾增殖与凋亡水平高于对照组，肾实质凋亡细胞以肾小管上皮细胞和肾间质细胞为主。肾小球凋亡指数与肾间质炎细胞浸润和24 h尿蛋白呈显著正相关(r=0.788、r=0.822,P<0.01);肾小管凋亡指数与血肌酐、尿素氮、24 h尿蛋白、炎细胞浸润指数呈显著正相关（r=0.824、0.794、0.883、0.948，P<0.01）。促凋亡相关基因Bax、caspase-3、caspase-8、caspase-9mRNA及相应蛋白质明显增加且表达一致，在病变过程中呈波浪式上调，高峰分别在4周和40周，这些变化与肾间质炎细胞浸润指数的变化呈显著正相关（P<0.01）；抑制凋亡因子Bcl-2表达与对照组比较无明显差异。 结论: 细胞凋亡参与肾小球硬化、肾小管萎缩及间质纤维化的过程，肾间质炎细胞的浸润更促进残肾凋亡的发生。     

An experimental model of chronic renal failure in mice

Chronic renal failure (CRF) was induced in CBA/J mice by a combination of surgery and diathermy to the right kidney followed 2 weeks later by complete removal of the left kidney. This procedure resulted in a progressive rise in blood urea nitrogen (BUN) levels accompanied by a fall in packed cell volume (PCV). In a typical group of mice BUN rose to 156.9 +/- 9.1 mg/100 ml and PCV fell to 36.4 +/- 1.9%, 8 weeks after removal of the left kidney, compared to 23.3 +/- 2.8 mg/100 ml and 51.6 +/- 2.1%, respectively, in normal mice. These changes were accompanied by other serum abnormalities in potassium, sodium, calcium, phosphate, chloride, and silicon levels. The surviving renal tissue showed histological changes, and skeletal changes were also evident on radiological examination. Mice in CRF had an increased mean survival time of tail skin allografts and a significant reduction in thymus weight, supporting the use of this model to investigate the well-documented phenomenon of immunosuppression in human patients with uremia.     

Alkali Therapy Attenuates the Progression of Kidney Injury via Na/H Exchanger Inhibition in 5/6 Nephrectomized Rats

Metabolic acidosis is a cause of renal disease progression, and alkali therapy ameliorates its progression. However, there are few reports on the role of renal acid-base transporters during alkali therapy. We evaluated the effect of sodium bicarbonate therapy and the role of acid-base transporters on renal disease progression in rats with a remnant kidney. Sprague-Dawley rats consumed dietary sodium bicarbonate (NaHCO₃) or sodium chloride (NaCl) with 20% casein after a 5/6 nephrectomy. After being provided with a casein diet, the NaHCO₃-treated group had higher levels of serum bicarbonate than the control group. At week 4, the glomerular filtration rate in the NaHCO₃ group was higher than that in the NaCl group, and the difference became prominent at week 10. The glomerulosclerosis and tubulointerstitial damage indices in the NaHCO₃ group were less severe compared with controls at week 4 and 10. The expression of the Na/H exchanger (NHE) was decreased, and apical reactivity was decreased in the NaHCO₃ group, compared with the NaCl group. Endothelin-1 levels in the kidney were also decreased in the NaHCO₃ group. Dietary sodium bicarbonate has the effects of ameliorating renal disease progression, which may be related to the altered expression of NHE in the remaining kidney.

Graphical Abstract

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Effects of Sodium Citrate on Salt Sensitivity and Kidney Injury in Chronic Renal Failure

Metabolic acidosis, which is observed in salt-sensitive hypertension, is also associated with kidney injury. Alkali therapy in chronic renal failure (CRF) may ameliorate the progression of kidney disease; however, few studies have examined the effects of alkali therapy on salt sensitivity and kidney injury in CRF. We randomly administered standard diet (SD), sodium chloride with 20% casein diet (NACL), or sodium citrate with 20% casein diet (NACT) to Sprague-Dawley rats after a CRF or a sham operation. Four weeks after 5/6 nephrectomy, serum bicarbonate levels were higher in the NACT-treated group. On the pressure-natriuresis curve, NACT-treated CRF rats were more salt-resistant than NACL-treated CRF rats. Additionally, the NACT-treated CRF group showed less tubulointerstitial damage than the NACL-treated CRF group. The expression and immunoreactivity of NHE3 in the kidney in the NACT-treated CRF group were lower than those in the NACL-treated CRF group. We observed that dietary NACT as alkali therapy in CRF might improve the altered salt-sensitivity and ameliorate the progression of kidney injury compared to the NACL diet, which may be related to reduced renal NHE3 expression.

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