Gene expression in response to acute unilateral ureteral obstruction

Acute unilateral ureteral obstruction results in differential growth characteristics of both the ipsilateral and contralateral kidney. The obstructed kidney undergoes cellular atrophy following an initial phase of interstitial proliferation while the contralateral kidney hypertrophies. To evaluate the molecular events occurring in both kidneys after obstruction, we examined the expression of growth related (c-fos, c-myc, cH-ras, HSP 70), cell maintenance (beta-actin), and cellular damage (TRPM-2) genes at the mRNA level. In the contralateral kidney an early and transitory induction of c-fos and c-myc expression occurred while a bimodal induction was noted in the obstructed kidney. The patterns of cH-ras, HSP 70 and actin expression also differed in both kidneys. Induction of TRPM-2 was noted only in the obstructed kidney. Rapid gene activation is evident in both the contralateral and obstructed kidney following unilateral ureteral obstruction. The patterns of expression are distinct and may reflect the cellular response to stress (cell death and stromal proliferation) in the obstructed kidney versus a response to a systemic stimulus resulting in cellular hypertrophy in the contralateral kidney.     

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.     

Renal hemodynamic response to ureteral obstruction during converting enzyme inhibition

Acute unilateral obstruction (UUO) of the pig kidney is associated with an increased secretion of intrarenally generated angiotensin II (ANG II). In order to clarify the importance of this intrarenal ANG II generation during acute UUO, ipsilateral and contralateral renal blood flow and renal secretion rate of ANG II were determined in pigs during continuous infusion of an angiotensin I converting enzyme (ACE) inhibitor. Pigs were operatively equipped with electromagnetic flow probes and catheters in the renal veins and aorta. Intravenous administration of the ACE inhibitor SQ 14 225 (captopril), 1 mg/kg per hour, resulted in a significant increase in renal blood flow in the contralateral kidney from 340±28 ml/min to 435±36 ml/min (P<0.01), whereas renal blood flow in the ipsilateral kidney was significantly reduced from 388±23 ml/min to 248±24 ml/min, similar to the reduction in controls. Captopril reduced mean aortic blood pressure, renal vascular resistance consistently on both sides, and plasma concentrations of ANG II and aldosterone from all sample sites. Renal secretion rate of ANG II showed a clear tendency to be reduced from the ipsilateral kidney. The results suggest that in UUO a compensatory increase in renal blood flow may be inhibited in part due to an enhanced secretion of ANG II in the ipsilateral kidney. However, a captopril-mediated inhibition of bradykinin breadown may also explain some of the observed changes.     

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。     

Renal structural and functional changes after unilateral ureteral obstruction in rabbits

Renal structural and functional changes following unilateral ureteral ligation for periods of 3 days to 6 weeks were studied in rabbits. The renal pelvic pressure increased to 20 cm H2O within 3 days of obstruction and in contrast to some previous investigations it was still raised after 6 weeks. Interstitial oedema, collapse of proximal tubules and dilatation of distal tubules were the earliest observed histological changes. Later findings were interstitial fibrosis, widespread atrophy of proximal tubules and, in the latest stages, dilatation of the collecting duct system. Thus, the distal tubules appeared considerably less resistant than the collecting ducts, to the increased pressure. Renal functional changes were studied one hour after release of obstruction of 3 days, 1-2-4 or 6 weeks' duration. In comparison to the contralateral kidney a rapid decrease of blood flow and glomerular filtration occurred in spite of a normal glomerular structure and collapsed proximal tubules and were probably related to haemodynamic disturbances such as arteriolar constriction. Although absolute electrolyte excretion was much reduced, the fractional excretion of several electrolytes, especially magnesium was increased already after 3 days of obstruction. These findings can presumably be correlated to the dilatation and early epithelial alterations in the distal tubules in which magnesium is predominantly reabsorbed.     

Regional changes in renal cortical glucose, lactate and urea during acute unilateral ureteral obstruction

OBJECTIVE: Acute unilateral ureteral obstruction (UUO) leads to changes in kidney function and metabolism. Microdialysis offers the possibility of topical analysis of changes in kidney metabolism. We applied microdialysis to the porcine kidney and evaluated its impact on gross kidney function. Furthermore, we investigated regional variations in renal interstitial fluid (RIF) glucose, lactate and urea during acute UUO. MATERIAL AND METHODS: Eight anesthetized pigs were used. Microdialysis probes were inserted in the upper, middle and lower thirds of the left renal cortex and perfused with Ringer's chloride at a rate of 0.3 microl/min. Dialysates were fractionated for 30-min periods. Bilateral intrapelvic pressure, urinary output, urinary osmolality, the excretion fractions of sodium and potassium, renal blood flow and the glomerular filtration rate were measured. Subsequently, left-sided graded ureteral obstruction was initiated, using the kidney's own urine production as a counter-pressure. RESULTS: The application of three microdialysis probes did not have any impact on kidney function. Ureteral obstruction decreased RIF glucose in the upper and lower thirds of the kidney, but not in the middle third. RIF lactate did not change. Interstitial urea increased in all regions of the kidney, but most markedly in the upper and lower poles. CONCLUSIONS: Microdialysis is of potential value for assessing the renal interstitial milieu under different pathophysiological conditions. Ureteral obstruction resulted in regional differences in cortical metabolites, predominantly affecting the upper and lower poles.     

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.     

Urinary PGE2 in rats with chronic partial unilateral ureteral obstruction

Urinary prostaglandin E2 (PGE2) was measured in Munich-Wistar rats with surgically created chronic partial unilateral ureteral obstruction (UUO). Mean values of bladder urine PGE2 were higher in sham than in UUO (24.5 +/- 14.4 vs 12.9 +/- 8.2 ng/mg creatinine, respectively, P less than 0.05). Following diuresis, both ureters were cannulated and urine was collected. PGE2 excretion was increased in sham (66.5 +/- 34.4 and 70.1 +/- 44.5 ng/mg creatinine, left and right, respectively). But in UUO, the obstructed kidney excreted less PGE2 than the contralateral kidney (32.1 +/- 6.0 vs 62.3 +/- 40.4 ng/mg creatinine, obstructed vs contralateral, respectively, P = 0.08). PGE2 synthesis was then determined in separated renal medullary and cortical slices. Renal medullary slices from kidneys with severe obstruction synthesized less PGE2 than the contralateral unobstructed side (3.30 +/- 1.22 vs 10.52 +/- 3.23 ng/mg wet wt-30 min, respectively, P less than 0.05) and failed to respond to arachidonic acid stimulation with any significant increase in PGE2 synthesis (3.30 +/- 1.22 vs 4.47 +/- 1.04 ng/mg wet wt-30 min, baseline vs stimulated). In contrast, contralateral unobstructed kidney slices responded with a significant increase in PGE2 synthesis (10.52 +/- 3.23 vs 21.10 +/- 2.50 ng/mg wet wt-30 min, baseline vs stimulated, P less than 0.05). We conclude that chronic partial UUO in the Munich-Wistar rats resulted in significantly less PGE2 elaboration.     

替普瑞酮对大鼠梗阻性肾病间质纤维化的影响

目的探讨替普瑞酮（GGA）对大鼠梗阻性肾病模型（UUO）肾间质纤维化的影响和可能机制。方法15只SD大鼠随机分成3组：假手术组、UUO模型组和GGA治疗组，每组5只。从建立UUO模型前1d开始，GGA治疗组和模型组分别给予400mg／kgGGA和溶媒（0．05％阿拉伯树胶＋0．008％维生素E）灌胃，每天1次，术后第7天处死大鼠。常规染色观察肾脏组织病理改变。间接免疫荧光和Western印迹检测肾脏E-钙黏蛋白（E—cadherin）和α-平滑肌肌动蛋白（α-SMA）的水平。TUNEL染色和PCNA免疫组织化学染色分别观察肾小管上皮细胞的凋亡和增生情况。结果GGA能诱导肾脏特异性高表达热休克蛋白72（HSP72）。与UUO模型组相比，GGA治疗组肾小管损伤和肾问质纤维化的程度明显减轻『肾小管损害百分比（48．7％±1．3％比65．8％±7．3％）；肾间质损害分值（0．40±0．08比1．36±0．50），P均〈0．05】；E—cadherin蛋白水平增加，α-SMA蛋白水平降低（P均〈0．05）；每高倍视野中TUNEL阳性和PCNA染色阳性的细胞数显著减少（分别为6．78±1．25比2．81±0．63，57．61±5．42比17．66±1．38，P均〈0．05）。结论GGA可能通过抑制肾小管上皮细胞的凋亡，延缓大鼠梗阻性肾病肾间质纤维化的进程。     

Eicosanoid production by isolated glomeruli of rats with unilateral ureteral obstruction

The production of PGE2 6-keto PGF1 alpha and TxB2 under basal conditions and after exposure to angiotensin II was examined in vitro in isolated glomeruli from sham-operated control rats and rats with unilateral ureteral obstruction of 24 hour duration, that were or were not pretreated with an inhibitor of the angiotensin I converting enzyme (ACE). Basal prostanoid production was greater in glomeruli from the obstructed kidney (OK) than in glomeruli from the contralateral kidney (CLK) of rats with obstruction or glomeruli from the kidneys of sham-operated rats. Glomeruli obtained from the CLK of rats with unilateral obstruction also produced more PGE2 and 6-keto PGF1 alpha than glomeruli obtained from kidneys of sham-operated rats. Administration of an ACE inhibitor to rats with unilateral obstruction in vivo returned basal prostanoid production in vitro to levels seen in glomeruli of sham-operated rats. The increase in prostanoid production in response to angiotensin II added in vitro was less in glomeruli from rats with unilateral obstruction than in glomeruli from sham-operated rats. However, the response was restored to that seen in glomeruli of sham-operated rats after blockade of angiotensin II synthesis in vivo in rats with unilateral obstruction. Blockade of angiotensin II synthesis in sham-operated rats did not affect prostanoid synthesis by their glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Reflex anuria from unilateral ureteral obstruction

Renal function is usually normal or only marginally affected in patients with unilateral ureteral obstruction due to the vicarious function of the contralateral kidney. Few reports exist in which unilateral renal obstruction is associated with anuria (reflex anuria, RA) and acute renal failure. We report the clinical case of a female patient who was referred to the emergency department due to anuria of 72 h duration and acute renal failure (serum creatinine 9 mg/dl) associated with several episodes of violent right flank pain with hematuria following extracorporeal shock wave lithotripsy (ESWL). A few weeks before ESWL, urography showed a 2-cm stone located in the right pelvis whilst the left kidney was functionally normal. On admission, renal ultrasound documented a normal left kidney, whilst the right pelvis was hydronephrotic and there were two indwelling stones at the right pyeloureteral junction. After the patient passed a urinary stone, diuresis restarted and acute renal failure was resolved. Thereafter, urography confirmed that the left kidney, the left ureter and bladder were functionally and morphologically normal. RA with acute renal failure has been so scarcely documented that it is considered to be legend by many clinicians. Major textbooks do not discuss RA with acute renal failure. Vascular or ureteral spasm related in part to a peculiar hyperexcitability of the autonomic nervous system may explain RA. We suggest that nephrologists should always consider RA when evaluating acute renal failure. On the other hand, RA might be relatively common and we cannot rule out that only the most severe and/or better-documented cases have been reported in the medical literature.     

Effect of intermedin on microvascular injury of unilateral ureteral obstruction rats

Objective To observe the effect of intermedin(IMD) on microvascular injury of renal fibrosis in unilateral ureteral obstruction (UUO) rat model. Methods Seventy-two male Wistar rats were randomly divided into two groups: the sham - operation group (n=24) underwent the left ureteral dissection, the other 48 rats were made as unilateral ureteral obstruction models and sub - divided into model group(UUO, n=24) and IMD group (n=24). At the 7, 14, 21, 28 day after the operation, 6 randomly - selected rats from each of the three groups respectively were blooded by abdominal arotic and their obstructive kidneys were taken out. The renal histopathological changes were observed through HE and Masson staining, the contents of BUN, Scr and cystatin C (CysC) of the obstructive kidneys were determined, the expressions of transforming growth factor - β1 (TGF - β1), α-SMA, bone morphogenetic protein-7 (BMP-7), E-cadherin, thrombospondin 1 (TSP-1) and vascular endothelial growth factor (VEGF) were detected by RT - PCR and immunohistochemistry. Results Compared with the sham-operated group, the pathological changes of kidney in the model group showed that the degree of fibrosis was obvious, tubular interstitial damage aggravated, the levels of BUN, Scr, CysC in the model group increased (P＜0.05), the mRNA expression and protein content of TGF-β1, α-SMA, TSP-1 increased (P＜0.05), while the levels of BMP-7, E-cadherin and VEGF decreased (P＜0.05). Compared with the UUO group, renal tubular damage, interstitial fibrosis in the IMD group were lighter, the levels of BUN, Scr, CysC in the IMD group were lower (P＜0.05), the mRNA expression and protein content of TGF-β1, α-SMA,TSP-1 were down-regulated (P＜0.05), while the levels of BMP-7, E-cadherin and VEGF were up-regulated (P＜0.05). Conclusion IMD can ameliorate the renal interstitial fibrosis, and the mechanism may be related to the fact that VEGF mediated by IMD can reduce vascular injury.