Long-term renal effects of unilateral ureteral obstruction and the role of endothelin

BACKGROUND: Angiotensin II (Ang II) and endothelin (ET) are involved in the alteration of renal function in unilateral ureteral obstruction (UUO). The renal response to Ang II following the reversal of a 24-hour UUO and the effect of ET blockade by bosentan during the time of obstruction were investigated. METHODS: Following blockade of the endogenous production of Ang II by captopril, the renal response to Ang II was studied in rats 15 to 18 days after a 24-hour UUO (N = 10) or a sham operation (N = 9) both with (N = 10) and without (N = 8) bosentan treatment in the periobstruction period. Similar studies were performed in another group (N = 9) two months following the reversal of obstruction. RESULTS: In the sham-operated group, Ang II reduced renal blood flow (RBF) by 42 +/- 9% (P < 0.01), glomerular filtration rate (GFR) by 30 +/- 8% (P < 0.01), urine volume (UV) by 44 +/- 9% (P < 0.001), and absolute (UNaV) and fractional sodium excretion (FENa) by 52 +/- 9% (P < 0.001) and 33 +/- 9% (P = 0.054), respectively. In the previously obstructed kidney, Ang II did not change RBF but increased GFR by 106 +/- 40% (P < 0.01), UV by 75 +/- 21% (P < 0.001), UNaV by 190 +/- 60% (P < 0.001), and FENa by 40 +/- 13% (P < 0.05). Bosentan treatment in the obstructed group prevented these Ang II-induced effects and did not have any effect on the sham-operated kidney. Two months following reversal of the obstruction, the response of the kidney was similar to that of the control kidney. CONCLUSION: Twenty-four-hour UUO results in a temporary abnormality in the renal response to Ang II, which is due, in part, to the actions of ET at the time of obstruction.     

The effects of pentoxifylline on renal function and free radical production in unilateral ureteral obstruction

There is an ongoing discussion about ureteral obstruction-related renal dysfunction. In this study, we aimed to test the effect of pentoxifylline (PTX) on both kidneys in unilateral ureteral obstruction (UUO), and to determine its interaction of with prostaglandin E₂ (PGE₂), and diclofenac sodium (DIS). A sham operation was performed in group 1. Placebo, PTX, DIS, and PTX+DIS were administrated to groups 2, 3, 4 and 5, respectively. The left ureter was ligated in all groups except group 1. At 24 h, technetium 99m diethylenetriamine penta-acetic acid scintigraphy was performed to determine renal function. Additionally, the tissue levels of thiobarbituric acid reactive substances (TBARS) and PGE₂ in both kidneys were measured to determine cytotoxic and cytoprotective mechanisms. When the ipsilateral kidneys were evaluated: (1) UUO significantly reduced DTPA uptake and none of the medications used prevented the reduction, (2) UUO significantly increased TBARS production, and only PTX prevented the increase, (3) UUO caused a significant increase in PGE₂ production, and only DIS significantly decreased this. When the contralateral kidneys were evaluated: (1) UUO significantly increased DTPA uptake but DIS and PTX+DIS prevented this, (2) UUO significantly elevated TBARS levels and DIS and PTX+DIS caused an additional elevation, (3) UUO significantly increased PGE₂ production, and only DIS prevented this. In conclusion, UUO caused ipsilateral renal hypofunction and contralateral hyperfunction, which are related to increased TBARS and PGE₂ levels. PTX markedly decreased free radical activity in the ipsilateral kidney. While PTX showed a placebo effect, DIS prevented the compensatory contralateral renal response through increased TBARS and decreased PGE₂ levels. The beneficial effect of PTX on the ipsilateral kidney, and the hazardous effect of DIS on the contralateral kidney may be explained by more complex interactions among TBARS, PGE₂, PTX, DIS and UUO-related renal dysfunction.     

Atorvastatin preserves renal function in chronic complete unilateral ureteral obstruction

PURPOSE: The pleiotropic effects of hMG-CoA (3-hydroxy-3-metylglutaryl coenzyme A) reductase inhibitors may provide renal protection in chronic kidney disease. We examined whether atorvastatin administration preserved renal function in rats with chronic unilateral ureteral obstruction. MATERIALS AND METHODS: Renal clearance experiments were performed in sham operated rats and rats subjected to 3 or 12-day unilateral ureteral obstruction. Hemodynamics parameters and urinary microalbumin levels from the obstructed kidney were also measured. The rats were maintained on a regular diet or the same diet but supplemented with atorvastatin (50 mg/kg daily). RESULTS: Atorvastatin administration did not alter plasma total cholesterol but it significantly decreased triglyceride levels. In sham operated and 3-day unilateral ureteral obstruction rats atorvastatin treatment did not have effects on the glomerular filtration rate or effective renal plasma flow and it also did not affect urinary microalbumin levels. In rats with 12-day unilateral ureteral obstruction the glomerular filtration rate but not effective renal plasma flow was significantly higher and urinary microalbumin was significantly lower in atorvastatin treated rats than in those without atorvastatin treatment. CONCLUSIONS: Atorvastatin treatment decreased microalbuminuria and helped preserve filtration function in chronic unilateral ureteral obstruction without altering plasma cholesterol levels, suggesting that pleiotropic renal protection is offered by this statin.     

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.     

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.     

EDRF modulates renal hemodynamics during unilateral ureteral obstruction in the rat.

Unilateral ureteral obstruction (UUO) results in vasoconstriction of the ipsilateral kidney, and vasodilatation of the intact opposite kidney. To investigate the role of endogenous nitric oxide, an endothelial-derived relaxing factor (EDRF), in the regulation of renal hemodynamics during UUO, Sprague-Dawley rats were anesthetized for study 24 hours after left UUO or sham-operation. Total vascular resistance (TVR) and renal vascular resistance (RVR) were measured using radioactive microspheres during control periods and following infusion of the nitric oxide synthase inhibitor, L-NAME (2.5 mg/kg). Blood pressure and RVR were increased by L-NAME, with a greater increment in the RVR/TVR ratio of the kidney with ipsilateral UUO than in the intact opposite kidney or sham-operated kidneys. Infusion of L-arginine (L-Arg), a substrate for nitric oxide synthase, did not alter the RVR/TVR ratio of either kidney of rats with UUO, but reduced the ratio in sham-operated animals. L-NAME tended to reduce urine flow and urinary sodium and cyclic GMP excretion, whereas L-Arg resulted in a marked diuresis, natriuresis, and increased excretion of cyclic GMP in both operative groups. We conclude that EDRF activity is increased in the kidney with ipsilateral UUO, which serves to counteract renal vasoconstriction. This response is not limited by availability of substrate (L-Arg). Vasodilatation of the intact opposite kidney appears to be mediated by factors other than EDRF.     

大黄酸对单侧输尿管梗阻大鼠肾脏的抗氧化保护作用

目的观察大黄酸（RH）对单侧输尿管梗阻（UUO）大鼠肾间质损伤的抗氧化保护作用。方法将30只雄性SD大鼠分成假手术组（Sham组）6只;UUO模型组（UUO组）和RH干预组（UUO＋RH组）各12只。除Sham组外,UUO组和UUO＋RH组分别在第3、7天测定大鼠左肾皮质匀浆中脂质过氧化物标志物丙二醛（MDA）及抗氧化酶过氧化氢酶（CAT）和超氧化物歧化酶（SOD）含量。结果UUO组较Sham组肾脏病理改变加重、肾组织MDA含量升高（P〈0.05）、SOD和CAT含量下降（P〈0.05）;UUO＋RH组较UUO组肾间质纤维化程度减轻、。肾组织MDA含量降低（P〈0.01）、SOD和CAT含量升高（P〈0.01）。结论RH能减少单侧输尿管梗阻侧肾皮质脂质过氧化物的产生,同时增加抗氧化酶的含量,通过改善UUO大鼠肾脏氧化应激来发挥肾脏保护作用。     

Effects of 24-hour unilateral ureteral obstruction on glomerular hemodynamics in rat kidney.

Glomerular hemodynamics were studied, by micropuncture, in Munich-Wistar rats submitted to 24-hour unilateral ureteral ligation (UUL). Glomerular capillary pressure (PG), intratubular pressure (PT) and pressure in the first-order peritubular capillaries (EAP) were measured with a servonulling device. Single nephron filtration fraction (SNIFF) was calculated fmom arterial and peritubular blood protein concentration. SNGFR was both measured by conventional micropuncture techniques and calculated from efferent arteriole blood flow (EABF) and SNFF. Afferent arteriole blood flow (AABF) and resistance of afferent (Ra) and efferent (Re) arterioles were calculated. Measurements were repeated 1 to 2 hours after the release of the ureter. Sham-operated rats were used as control. UUL caused a marked increase in Ra (from 4.9 +/- [SD] 2.4 to 12.7 +/- 5.1 dynes/sec/cm-5). The fall in SNGFR (from 111.9 +/- [SD] 23.9 to 34.4 +/- 23.1 nl/min/kg body wt) was secondary to a decrease in both PG and AABF. A further increase in Ra (16.0 +/- 6.7 dynes.sec.cm-5) occurred after releasing the ureter. SNGFR, however, was unaltered (33.7 +/- 16.6 nl/min/kg body wt) since PG decreased parallel to PT, but AABF did not significantly change. Conclusion. Ureteral obstruction determines, in 24 hours, a marked cortical ischemia that is not promptly reversed by ureteral release.     

Preventive effects of propofol and ketamine on renal injury in unilateral ureteral obstruction

Purpose  

The aim of the present study was to investigate the preventive effects of propofol and ketamine as anesthetics on renal injury in unilateral ureteral obstruction (UO).     

Long-term partial ureteral obstruction and its effects on kidney function.

Previously it has been shown that partial ureteral obstruction present in young rats for 12 weeks results in small morphological changes in the kidney as well as slightly decreased kidney function. In the present study the aim was to examine whether rats obstructed for one year had more advanced changes in morphology and kidney function. The first group of animals examined after three weeks of obstruction showed only modest changes in kidney function with a reduced potassium concentration in the urine but no reduction in the glomerular filtration rate. After one year there was a reduction in urine flow as well as in the excretion of both potassium and sodium. Urine osmolality was also reduced. Glomerular filtration rate measured in this group of animals was reduced in the obstructed kidney by about 60% compared to the contralateral one. There were only small changes in the morphology with no loss in parenchymal weight or compensatory hypertrophy, but there was a significant deformation of the papilla and an increase in inflammatory cells in the parenchyma. In conclusion hydronephrosis during a shorter period is not harmful to kidney function but if sustained for an extended time period kidney function will deteriorate.     

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

肾间质纤维化几乎是所有慢性肾脏疾病发展至终末期肾衰竭(ESRD)的共同通路.梗阻性肾病的病理变化主要表现为肾小管萎缩和间质纤维化,而肾小管上皮细胞凋亡是肾小管萎缩和肾实质丧失的主要原因[1,2].红细胞生成素(EPO)能调节红细胞生成以增加组织供氧,除此之外,EPO也是一种抗凋亡因子,介导多种细胞抗凋亡作用.Koury等[3]报道EPO调节红细胞生成的一种主要机制就是防止红系祖细胞凋亡.而EPO对肾间质纤维化的影响及其机制尚未见阐明.本研究旨在观察EPO对肾间质纤维化的影响并初步探讨其可能的作用机制.     

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.     

Partial ureteric obstruction in the pubescent rat. I. Long-term effects on renal function

A partial obstruction of the left ureter was created in six-week-old rats. The effects on renal function were studied after three, nine and 15 weeks, first in normal hydration, and then after extracellular volume expansion. Moderate hydronephrosis without parenchymal weight reduction developed within three weeks. The hydronephrotic kidney i) excreted during normal hydration less urine and sodium than the intact one, because of increased reabsorption, ii) was capable of reacting fully on volume expansion and iii) had, after volume expansion, a higher renal blood flow and GFR but also a higher reabsorption of water, sodium, potassium and osmoles, resulting in excretions similar to those on the intact side. The differences noted were small (less than 20%) except for sodium excretion. The hydronephrotic kidney seemed to tolerate an increase in ureteral resistance better than the intact one would do. There were no significant differences between the three, nine and 15-week groups, with regard to the effects on the hydronephrotic kidney. Thus, except for a tendency to sodium retention, the effects of partial ureteric obstruction in young rats seem to be relatively harmless and do not increase with time.     

Tranilast ameliorates renal tubular damage in unilateral ureteral obstruction

PURPOSE: We determined whether tranilast, the anti-allergic agent N-(3, 4-dimethoxyciannamoyl)-anthranilic acid, would diminish renal transforming growth factor-beta (TGF-beta) levels in unilateral ureteral obstruction and concomitantly affect renal tubular apoptosis and proliferation in that condition. MATERIALS AND METHODS: Tranilast (150 mg./kg.) was administered to rats 1 day before unilateral ureteral obstruction and each day thereafter. Kidneys were harvested day 14 after unilateral ureteral obstruction. Tissue TGF-beta was measured by bioassay using mink lung epithelial cells. Renal tubular proliferation and apoptosis were detected by immunostaining proliferating cell nuclear antigen and the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling assay, respectively. Fibrosis was assessed by measuring collagen deposition with trichrome stained slides. RESULTS: TGF-beta bioassay showed that obstructed kidneys in controls contained significantly higher mean TGF-beta plus or minus standard deviation than unobstructed kidneys in controls (73.7 +/- 13.6 versus 14.1 +/- 5.5 pg./mg. tissue) and tranilast significantly decreased tissue TGF-beta in obstructed kidneys (15.9 +/- 4.8 pg./mg. tissue). The terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling assay demonstrated that obstructed kidneys in controls had significantly more mean tubular apoptosis than the unobstructed counterparts (36.6 +/- 6.7 versus 5.8 +/- 5.5 nuclei per high power field) and tranilast significantly decreased mean renal tubular apoptosis in obstructed kidneys (16.2 +/- 1.7 nuclei per high power field). In addition, immunostaining proliferating cell nuclear antigen showed that obstructed kidneys in controls had significantly more mean renal tubular proliferation than unobstructed kidneys (20.7 +/- 3.4 versus 6.2 +/- 2.1 per high power field) and tranilast significantly increased proliferating renal tubules in obstructed and unobstructed kidneys (26.5 +/- 8.3 and 14.5 +/- 3.4 per high power field, respectively). Control obstructed kidneys exhibited significantly more fibrosis, which was also blunted by tranilast. CONCLUSIONS: Tranilast significantly decreases tissue TGF-beta, resulting in a reduction in tubular apoptosis and an increase in tubular proliferation. This finding suggests that tranilast is a promising agent for preventing renal tubular damage in unilateral ureteral obstruction.     

Sulfasalazine reduces inflammatory renal injury in unilateral ureteral obstruction

The purpose of this study was to test whether sulfasalazine has a protective action against interstitial inflammation and the development of renal fibrosis in obstructive nephropathy. Female rats were subjected to a sham (n = 10) or unilateral ureteral obstruction (UUO, n = 30). UUO was induced in rats by ligating the left ureter. Three days after operation, rats subjected to UUO were randomized to receive tretment with either sulfasalazine (100 mg/kg) or vehicle every day for the last 7 days of the experiment. At 10 days following UUO, the obstructed kidney exhibited tubulointerstitial injury and leukocyte infiltration (mainly monocytes) that were associated with high levels of reactive oxygen species, cytokines, transforming growth factor (TGF)-β1, myeloperoxidase (MPO), and lipid peroxidation. Ten days after UUO, the obstructed kidney was also associated with increased nuclear factor kappa beta (NF-κβ) expression in saline-treated rats. Compared with sham-operated rats, UUO rat kidneys showed lower concentrations of antioxidant enzymes in the obstructed kidney tissue. All of these changes were significantly attenuated by treatment with sulfasalazine in the obstructed kidney. Sulfasalazine protected against the renal interstitial inflammation and tissue damage elicited by ureteral occlusion. Inhibition of the NF-κβ-dependent pathway and inflammatory response and oxidative stress inhibition is likely to be involved in the beneficial effects of sulfasalazine.     

Long-term effects of partial unilateral ureteral obstruction on renal hemodynamics and morphology in newborn rats: a magnetic resonance imaging study

We assessed the longitudinal changes in renal vein blood flow (RVBF) and kidney volume in response to neonatally induced partial unilateral ureteral obstruction (PUUO) in rats with a magnetic resonance imaging (MRI) technique. During anesthesia, either the upper third or two thirds of the left ureter was embedded into the psoas muscle in newborn rats, creating either a mild (n=20) or a severe (n=9) partial obstruction. Control groups consisted of sham-operated (n=12) and non-operated (n=15) rats. During the following 24 weeks, RVBF and kidney volume were measured sequentially every 2-6 weeks with MRI, beginning 9 days after the operation. Both mild and severe obstruction caused a time-dependent decrease in RVBF. At week 24, the mean RVBF had decreased to 79% of the controls in the mildly obstructed kidneys (mean+/-SE: 1.45+/-0.14 vs 1.84+/-0.08 ml/min/100 g body weight, P<0.05) and to 57% of controls in the severely obstructed kidneys (1.05+/-0.10 vs 1.84+/-0.08 ml/min/100 g body weight, P<0.05). The renal pelvis volume increased and the renal parenchymal volume decreased significantly in the severely obstructed kidneys compared to the mildly obstructed kidneys. A good correlation was found between kidney volume measured in vivo using MRI and that measured in vitro (r>0.8, P<0.05), and between RVBF and renal parenchymal volume (r=0.758, P<0.01). In conclusion, the degree of reduction in RVBF depends on the severity and the duration of the PUUO. MRI can safely and reliably be used to monitor the longitudinal changes in RVBF and kidney volume in rats from early life.     

Acute unilateral renal failure and contralateral ureteral obstruction.

After obstetrical surgery, a young woman developed an acute renal failure of one kidney, the other having been protected by a fortuitous ureteral ligation. The possible effects of a temporary kidney exclusion on itself and on the other kidney are discussed.     

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