High urinary flow accelerates renal injury in young rats with partial unilateral ureteral obstruction

PURPOSE: We studied the effect of dietary manipulation and high urine flow on neonatal partial ureteral obstruction in a weanling rat preparation. MATERIALS AND METHODS: A total of 40, 3-week old Sprague-Dawley rats underwent unilateral ureteral obstruction by burial of the right ureter in the psoas muscle and 13 underwent sham operation. Low, high and normal salt, and high sucrose diets were administered for 2 months. The glomerular filtration rate of each kidney was measured by iothalamate clearance. Intrapelvic pressure and renal blood flow were measured before and after acute volume loading. RESULTS: Fluid intake and urine output were 8 to 10-fold greater in animals on high salt and high sucrose diets compared to those in rats on normal and low salt diets. Hydronephrosis was observed only in rats with partial obstruction and high urine flow. No difference in renal weight was noted. Relative glomerular filtration rate of the partially obstructed kidney was maintained when urine flow was normal but decreased significantly with high urine flow. Total glomerular filtration rate also decreased with high urine flow. Intrapelvic pressure was elevated significantly at baseline in partially obstructed kidneys with high urine flow. All kidneys with partial obstruction had significantly increased intrapelvic pressure with volume loading. Renal blood flow was not significantly decreased in rats with high urine flow. CONCLUSIONS: Chronic high urine flow causes loss of renal function in partially obstructed weanling rat kidneys. Research should be done to determine whether human infants with hydronephrosis and partial ureteral obstruction would benefit from the prevention of increased fluid and salt intake.     

姜黄素对单侧输尿管梗阻大鼠肾间质纤维化的影响

目的 探讨姜黄素对单侧输尿管梗阻(UUO)大鼠模型的影响及其可能机制.方法 将30只大鼠随机分为3组,每组10只:假手术组、模型组、姜黄素组.模型组和姜黄素组行右侧输尿管接扎术,假手术组只游离不接扎.术后第14天处死各组中的大鼠,股动脉取血,检测血清肌酐、尿素氮;留取梗阻侧肾脏,Maason染色观察肾间质纤维化程度,免疫组织化学方法测定TGF-β1、CTGF的表达情况,RT-PCR技术榆测肾组织TGF-β1 mRNA、CTGF mRNA表达.结果 姜黄素降低了BUN、Scr的含量,同时姜黄素显著减少了大鼠肾间质TGF-β1、CTGF的表达,并有效改善了肾脏的病理学损伤.结论 姜黄素对单侧输尿管梗阻大鼠有较明显的保护作用,这可能与其能减少大鼠肾间质TGF-β1、CTGF的表达有关.     

Dietary arginine supplementation attenuates renal damage after relief of unilateral ureteral obstruction in rats

BACKGROUND: Progression of renal injury after relief of unilateral ureteral obstruction (UUO) has been demonstrated. Nitric oxide (NO) may be an effective intervention due to its vasodilatory, antifibrotic, and anti-apoptotic effects. Herein, we used dietary L-arginine (ARG) supplementation in a UUO relief model. METHODS: This study comprised group 1, control (no treatment). All other rats were subject to 3-day UUO, which was then relieved, and the rats maintained for 7 additional days. Group 2, no additional treatment; group 3, L-ARG; group 4, L-NAME, NO synthase inhibitor; group 5, ARG and L-NAME. Urinary NO(2/3) was quantified. GFR and ERPF were measured at day 10. Interstitial fibrosis and fibroblast expression, macrophage infiltration, tubular apoptosis, and proliferation, NOS expression, and the levels of tissue TGF-beta were evaluated. RESULTS: Urinary NO(2/3) was significantly increased by ARG treatment and decreased by L-NAME. GFR and ERPF measured 7 days following relief were not significantly different in the previously obstructed kidneys (POK) of groups 2 and 3. L-NAME significantly reduced GFR and ERPF in the POK. ARG significantly reduced apoptosis, macrophage infiltration, and fibroblast expression in the POK. L-NAME exacerbated the effects on apoptosis and fibroblasts. Fibrosis was minimal in groups 1 through 3, but was significantly increased by L-NAME. ARG did not affect renal NOS expression and tissue TGF-beta1 levels. CONCLUSION: Dietary ARG supplementation during UUO relief did not improve ERPF or GFR. However, renal damage, including fibrosis, apoptosis, and macrophage infiltration was significantly improved by ARG treatment. This suggests that increasing NO availability could be beneficial in the setting of UUO relief.     

Impaired renal sensory responses after unilateral ureteral obstruction in the rat

Renal responses to the activation of renal sensory receptors were examined in rats after release of 24-h unilateral ureteral obstruction of the left kidney. The integrity of the renorenal reflex was examined in both 24-h unilateral ureteral obstruction-treated (UUO) and sham-operated (Sham) rats. Increased ipsilateral afferent renal nerve activity (ARNA) and reflexly decreased efferent renal nerve activity (ERNA) and increased contralateral diuresis and natriuresis produced by increasing the left intrapelvic pressure were observed in Sham rats but not in UUO rats. The lack of responsiveness of the renorenal reflex in UUO rats was associated with lower release of substance P (SP) and increased neutral endopeptidase (NEP) activity in the renal pelvis in the postobstructive kidney. Compared with Sham rats, urine and sodium excretion after acute saline loading was significantly reduced in the postobstructive kidney. The blunted excretory responses were accompanied by lower activation of ARNA and less reflex inhibition of ERNA. Renal sensory dysfunction in the postobstructive kidney was further examined by stimulation of renal mechanoreceptors and chemoreceptors. Graded increases in intrapelvic pressure or renal pelvic perfusion with hypertonic saline solution elicited, respectively, a pressure- or concentration-dependent increase in ARNA in the control kidney of Sham rats, this response being greatly attenuated in the postobstructive kidney. Western blots showed no quantitative difference in the expression of renal pelvic neurokinin 1 (NK-1) receptors between the two groups. It was concluded that renal sensory function is impaired in the postobstructive kidney of UUO rats and that this defective activation of renal sensory receptors results in an impaired renorenal reflex, which is associated with enhanced NEP activity and catabolism of SP released in the renal pelvis and is not related to the expression of NK-1 receptor protein.     

Partial unilateral ureteral obstruction in rats

This review comprises an overview of the current knowledge on experimental partial unilateral ureteral obstruction (PUUO) and a summary of our latest original experimental PUUO studies in rats. Neonatal PUUO is the type of obstruction that is most often encountered in pediatric clinical practice. However, the pathogenesis of PUUO is still incompletely understood. Most of our knowledge on PUUO has been derived from experimental studies in a variety of animal models. Although progress has been made, the natural history of congenital hydronephrosis is still incompletely described. The effects on kidney functions of long-term urinary tract obstruction, especially PUUO, have been less intensively studied. Recently, we created models with mild and severe PUUO in young rats by embedding the upper one fourth or the upper two thirds of the left ureter into the psoas muscle, respectively. Thereafter, the technique was used to create mild and severe PUUO in newborn rats and magnetic resonance imaging studies showed that both mild and severe obstruction caused a time-dependent decrease in renal blood flow. Compensatory increase in total kidney volume and renal vein blood flow in contralateral non-obstructed kidneys was not detectable when functional deterioration in the partially obstructed kidneys was present. Finally, we investigated the dynamic changes in renal relative signal intensity (RSI) of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) using magnetic resonance imaging in rats with partial, complete unilateral ureteral obstruction and sham-operated controls. The results showed that changes in Gd-DTPA RSI are compatible with the known physiological and anatomical changes in kidneys in response to ureteral obstruction and useful for distinguishing an obstructed from a non-obstructed collecting system and also for differentiating a partially obstructed from a completely obstructed collecting system.     

Triptolide attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction

Aim: Extracts of Tripterygium wilfordii Hook F. have been used to treat glomerulonephritis for more than 30 years in China. Most of the anti‐inflammatory and immunosuppressive activities of these extracts can be attributed to triptolide (Trip). The present study was to investigate the effect of Trip on renal interstitial fibrosis in a model of unilateral ureteral obstruction (UUO). Methods: UUO or sham‐operated rats were randomly assigned to receive mycophenolate mofetil (MMF), Trip or vehicle and were killed on days 7 and 14 after UUO or sham operation. Kidney specimens were fixed for immunohistochemistry for myofibroblasts (α‐smooth muscle actin, α‐SMA), macrophages (ED‐1), monocyte chemoattractant protein‐1 (MCP‐1) and osteopontin. Interstitial collagen deposition and amounts of transforming growth factor‐β1 (TGF‐β1) were determined by Sirius red staining and enzyme‐linked immunosorbent assay, respectively. The mRNA expression of TGF‐β1, connective tissue growth factor (CTGF), MCP‐1 and osteopontin were measured by real‐time polymerase chain reaction analysis. Results: The scores for the density of α‐SMA‐ and ED‐1‐positive cells, the staining of MCP‐1 and osteopontin, interstitial collagen deposition and amounts of TGF‐β1 were significantly reduced by MMF or Trip. MMF or Trip significantly reduced the mRNA expression of TGF‐β1, CTGF, MCP‐1 and osteopontin. Conclusion: Trip significantly attenuated tubulointerstitial fibrosis in a rat UUO model and the effect of Trip on renal fibrosis was similar to that of MMF. Trip may be useful as a potential candidate in the treatment of renal fibrosis.     

Recovery of renal function after prolonged unilateral ureteral obstruction.

Concepts of renal counterbalance and animal experiments have long supported nephrectomy for prolonged complete unilateral ureteral obstruction. The situation in humans has been clarified by only a few reported cases. Herein we report 3 cases with relief of obstruction after at least 28, 28 and 150 days. Evidence is presented to support renal preservation in similar cases.     

雌激素对单侧输尿管梗阻大鼠肾间质纤维化的保护作用

目的探讨雌激素对单侧输尿管梗阻（UUO）大鼠肾间质纤维化的作用。方法雌性SD大鼠30只，随机分为4组：Ⅰ组对照组；Ⅱ组生理雌激素组；Ⅲ组低雌激素组；Ⅳ组高雌激素组。UUO术后21d处死各组大鼠，光镜观察梗阻肾组织病理变化，并分别用免疫组化和RT-PCR方法检测各组肾组织α-平滑肌肌动蛋白（α-SMA）和金属蛋白酶1组织抑制剂（TIMP-1）的表达。结果低雌激素组间质纤维化病变最明显，高雌激素组病变显著减轻（P〈0．01）。与生理雌激素组相比，低雌激素组α—SMA和TIMP-1蛋白和基因的表达增加（P〈0．05）；高雌激素组上述物质表达则减少（P〈0．05）。结论雌激素可能通过抑制α-SMA和TIMP-1的表达进而减少细胞外基质的沉积而发挥肾保护作用。     

双环醇对单侧输尿管梗阻大鼠肾间质纤维化的影响及作用机制

肾间质纤维化是反映肾功能下降严重程度和判断预 后最重要的指标[1],寻求抗肾间质纤维化的新药物已成为当前肾脏病研究的热点之一.双环醇是在联苯双酯的基础上,经结构改造和筛选得到的国家Ⅰ类抗肝炎新药.近来研究发现,双环醇对肝纤维化具有明显的抑制作用[2].本研究应用双环醇动态观察单侧输尿管梗阻(UUO)术后肾组织NF-κB的表达水平,探讨双环醇对UUO大鼠肾间质纤维化的影响及其可能机制.     

螺内酯对梗阻性肾病大鼠肾间质纤维化的防治作用

肾小管间质纤维化是进行性肾损害的主要病理特征,阻抑肾间质纤维化的进展意义重大。醛固酮在肾脏病进展中起重要作用,然而拮抗醛固酮的作用对肾间质纤维化的影响及其机制仍未阐明。在本研究中我们观察了醛固酮受体拮抗剂螺内酯对肾间质纤维化的影响并初步探讨了其可能的作用机制。一、材料与方法     

Effect of lisinopril on renal tissue damage in unilateral ureteral obstruction in rats

In this study, it was aimed to investigate apoptosis in renal injury and the effect of lisinopril in rat model, which constitute unilateral ureteral obstruction. The retroperitoneal ureter was ligated with a 4.0 silk for the experimental model of ureteral obstruction in Wistar albino rats. Untreated group (n = 20) received no treatment. For the lisinopril-treated group (n = 20), 20 mg/kg/day of drug was given orally. Ultrastructural differences were analyzed using electron microscopic technique; apoptotic distribution was analyzed using the TUNEL method. After electron microscopic evaluation, on the 4th and 14th day in the untreated group, edema in the glomeruli, loss of microvillus and apoptotic cells in proximal tubule cells and sclerosis in the glomeruli were detected. On the 4th day in the lisinopril-treated group, the kidney was ultrastructurally normal and a less number of apoptotic cells were only observed on the 14th day. On light microscopic examination on the 4th and 14th day in the untreated group, while the glomeruli were normal in structure, the boundary of the proximal tubule was disrupted and some picnotic cells in both the proximal and collecting tubules were observed. In both 4th and 14th day of the lisinopril-treated group, kidney showed normal structure, although in some places picnotic cells in the collecting tubules were observed. In conclusion, lisinopril was effective and it may prevent early renal damage in the direct obstruction model.     

intermedin对单侧输尿管梗阻大鼠肾间质纤维化的影响

目的 观察intermedin( IMD)对单侧输尿管梗阻(UUO)大鼠肾间质纤维化的影响.方法 雄性Wistar大鼠40只,按随机数字表法分为假手术组(n=10,行左输尿管分离术)、模型组(UUO,n=10)、氯沙坦组(n=10)和IMD组(n=10),后3组行左输尿管结扎术.各组大鼠分别于术后第14、21天随机选取5只,腹主动脉采血并留取梗阻侧肾组织之后处死.HE、Masson染色观察肾组织病理变化;比色法测定血尿素氮(BUN)、血肌酐(Scr)及新鲜肾组织羟脯氨酸(Pro)含量;免疫组化方法检测肾组织中转化生长因子β1 (TGF-β1)、IMD的表达水平,并进行半定量分析.结果 与假手术组相比,不同时间点UUO组血BUN、Scr、肾组织Pro含量及TGF-β1、IMD的阳性表达均显著升高(P＜0.05);与UUO组相比,氯沙坦组血BUN、Scr、肾组织Pro含量及TGF-β1、IMD表达均降低(P＜0.05),IMD组除IMD表达增加外,其余均降低(P＜0.05).结论 IMD可减轻UUO肾间质纤维化,改善肾功能,其机制可能与拮抗纤维化炎性介质TGF-β1有关.     

Effects of renal sympathetic denervation on renal interstitial fibrosis in rats with unilateral ureteral obstruction

Objective To observe the influence of renal sympathetic denervation (RSD) on renal interstitial fibrosis and transforming growth factor beta 1(TGF-β1) and microRNA-21 (miR-21) in rats with unilateral ureteral obstruction(UUO). Methods 40 male Wistar rats were randomly divided into UUO group (A group, n=10), sham UUO group (B group, n=10), RSD+UUO group (C group, n=10) and RSD+sham UUO group (D group, n=10). Rats in A group and C group underwent unilateral ureteral ligation, while those in B group and D group underwent sham operation. Rats in C group and D group were followed by RSD. Rats were sacrificed at 21 days after the operation to evaluate the fibrosis by Masson staining. Immunohistochemical staining and Western blotting were used to detect the expressions of collagen I (COL-I), collagen Ⅲ(COL-Ⅲ) and TGF-β1 in four groups. The expression of miR-21 was detected by fluorescence in situ hybridization (FISH) and quantitative real-time PCR (RT-qPCR). Results A large amount of collagen deposition was observed in the renal interstitial area in A and C group compared to either B or D group (P＜0.05), but the change in C group was decreased significantly than that in A group (P＜0.05). Similarly, the expressions of COL-I, COL-Ⅲ, TGF-β1 and miR-21 were obviously higher in A and C group compared to either B or D group (P＜0.05), but those change in C group were decreased significantly than those in A group (P＜0.05). The above indexes were not significantly different between B group and D group (P＞0.05). Conclusion RSD may relieve the renal interstitial fibrosis in UUO rats, and down-regulate the expression of TGF-β1 and miR-21.     

Contralateral renal hyperplasia and increased renal function after relief of chronic unilateral ureteral obstruction

Following relief of 1, 2 or 3 weeks of unilateral ureteral obstruction, contralateral compensatory renal growth and increased renal function were measured 3 and 6 months later. Compensatory growth occurred predominantly by hyperplasia, demonstrated by a significant increase in DNA content and a decrease in the RNA:DNA ratio (p less than 0.04). This is in contrast to compensatory growth following nephrectomy or unrelieved unilateral ureteral obstruction, which occurred primarily by hypertrophy with no significant change in DNA content but a significant increase in RNA content and the RNA:DNA ratio (p less than 0.04). Contralateral renal function in animals with relieved unilateral ureteral obstruction was greater than in controls with 2 normal kidneys (p less than 0.05). The contralateral increase in renal function was greater than that in animals subjected to ipsilateral nephrectomy or unrelieved ureteral obstruction, but this did not reach statistical significance. Thus, when growth occurred by hyperplasia, there was a trend to greater increases in renal function than when growth occurred by hypertrophy. Contralateral compensatory renal hyperplasia and increased renal function occurred in conjunction with a decrease in renal mass and function of the ipsilateral post-obstructed kidney. These experiments suggest that the post-obstructed, poorly functioning kidney stimulates contralateral hyperplastic growth and increased renal function. This hyperplastic response is different from the hypertrophic response following nephrectomy or unrelieved unilateral ureteral obstruction, implicating the post-obstructed kidney as the stimulus of the hyperplastic response.     

Beneficial effects montelukast,cysteinyl-leukotriene receptor antagonist,on renal damage after unilateral ureteral obstruction in rats

Introductıon

Ureteral obstruction is a common pathology and caused kidney fibrosis and dysfunction at late period. In this present, we investigated the antifibrotic and antiinflammatory effects of montelukast which is cysteinyl leukotriene receptor antagonist, on kidney damage after unilateral ureteral obstruction(UUO) in rats.

Mateirıals and Methods

32 rats divided four groups. Group 1 was control, group 2 was sham, group 3 was rats with UUO and group 4 was rats with UUO which were given montelukast sodium (oral 10 mg/kg/day). After 14 days, rats were killed and their kidneys were taken and blood analysis was performed. Tubular necrosis, mononuclear cell infiltration and interstitial fibrosis scoring were determined histopathologically in a part of kidneys; nitric oxide(NO), malondialdehyde(MDA) and reduced glutathione(GSH) levels were determined in the other part of kidneys. Urea-creatinine levels were investigated at blood analysis. Statistical analyses were made by the Chi-square test and one-way analysis of variance (ANOVA).

Results

There was no difference significantly for urea-creatinine levels between groups. Pathologically, there was serious tubular necrosis and fibrosis in group 3 and there was significantly decreasing for tubular necrosis and fibrosis in group 4(p<0.005). Also, there was significantly increasing for NO and MDA levels; decreasing for GSH levels in group 3 compared the other groups(p<0.005).

Conclusıon

We can say that montelukast prevent kidney damage with antioxidant effect, independently of NO.     

红细胞生成素对单侧输尿管梗阻大鼠肾间质纤维化的保护作用

肾间质纤维化是各种肾脏疾病进展到终末期肾病过程的共同途径.转化生长因子β1(TGF-β1)-Smads信号传导通路在肾间质纤维化的发生发展过程中起重要作用[1].