Chronic Partial Ureteral Obstruction Research Articles

Evaluation of Diuretic Renal Doppler Ultrasonography Findings in Chronic Unilateral Partial Ureteral Obstruction in Rabbits

Evaluation of Diuretic Renal Doppler Ultrasonography Findings in Chronic Unilateral Partial Ureteral Obstruction in Rabbits

Vascular Endothelial Growth Factor is Augmented in the Kidney with Chronic Partial Ureteral Obstruction and Further Stimulated by Lipopolysaccharide

Vascular endothelial growth factor (VEGF), a critical mitogen for angiogensis, has been shown to be activated in the inflammatory process of fibrotic lung disease and inflammatory arthritis. In the present study we examined the expression of VEGF in Sprague‐Dawley rats subject to chronic partial ureteral obstruction (PUO) for 30 days to produce renal interstitial fibrosis. To create PUO, the right kidney was removed and the left ureter diverted into the psoas muscles. A sham operation was performed in the control group. In an additional group of PUO, the inflammatory response was augmented by intraperitoneal injection of lipopolysaccharide (LPS) (1 mg/kg BW) 24 hr before removal of the left kidney to examine renal histology and VEGF expression by immunoblot and RT‐PCR analyses. In PUO rats intense inflammation and tubulointerstitial fibrosis were seen on histology examination. Immunoblot analysis showed that VEGF/b‐actin in the renal cortex was 10.1±1.1 (mean±SD) (densitometry units) in 8 PUO rats, greater than 5.3±0.7 in the 8 sham‐operated rats (p<0.05), and increased further to 12.5±2.7 in 8 PUO rats receiving LPS (p<0.05). VEGF/b‐actin in the medulla of the PUO kidney was 9.6±1.8, greater than 5.5±1.2 in the sham‐operated rats (p<0.05) and increased to 13.1±1.6 in PUO rats receiving LPS (p<0.05). VEGF mRNA expression in the cortex increased by over two‐fold (2.17±0.28, p<0.03) in PUO rats compared with sham‐operated rats and increased further in PUO rats receiving LPS (fold change of 3.14±0.29, p<0.01 vs PUO). VEGF mRNA expression in the medulla increased by 3.15±0.43 in PUO rats compared with sham‐operated rats (p<0.03) and increased further by 5.09±0.47 in PUO rats receiving LPS (p<0.03 vs PUO). These results show that VEGF expression is augmented in chronic obstructed kidney and further stimulated by LPS, suggesting that it participates in chronic renal tubulointerstitial fibrosis.

MP53-20 RENOPROTECTIVE EFFECT OF DIRECT RENIN INHIBITOR (ALISKIREN) DURING ACUTE AND CHRONIC PARTIAL URETERAL OBSTRUCTION IN RAT SOLITARY KIDNEY

You have accessJournal of UrologyTrauma/Reconstruction/Diversion: Ureter (including Pyeloplasty) and Bladder Reconstruction (including fistula), Augmentation, Substitution, Diversion II (MP53)1 Sep 2021MP53-20 RENOPROTECTIVE EFFECT OF DIRECT RENIN INHIBITOR (ALISKIREN) DURING ACUTE AND CHRONIC PARTIAL URETERAL OBSTRUCTION IN RAT SOLITARY KIDNEY Mohamed Essam, Nashwa Barakat, Ahmed Elkashef, Amira Awadalla, A. E. Behery, and Mahmoud Abdel-Maboud Mohamed EssamMohamed Essam More articles by this author , Nashwa BarakatNashwa Barakat More articles by this author , Ahmed ElkashefAhmed Elkashef More articles by this author , Amira AwadallaAmira Awadalla More articles by this author , A. E. BeheryA. E. Behery More articles by this author , and Mahmoud Abdel-MaboudMahmoud Abdel-Maboud More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002083.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Obstructive uropathy is a major clinical problem that can result in permanent renal damage. The renoprotective effect of direct renin inhibitor (aliskiren) has been demonstrated in many experimental animal models mainly renal ischemia/reperfusion injury. Therefore, we studied the effect of aliskiren on the renal function during acute and chronic partial ureteral obstruction (PUO) in rat solitary kidney. METHODS: 60 male Sprague–Dawley rats were randomly allocated into 3 groups (20 rats each); sham, PUO and aliskiren groups. Right nephrectomy was performed in all groups. Rats in PUO and aliskiren groups were subjected to left PUO and received no treatment and aliskiren (10 mg/kg, orally, once per day till sacrification), respectively. Blood samples were then collected for biochemical measurements. 10 rats from each group were sacrificed after 2 weeks, while the remaining rats were sacrificed after 4 weeks. Left kidneys were harvested for histopathological examination, BCL-2, IL-6, TGF-β1, collagen I and fibronectin relative gene expression and assessment of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) activity. RESULTS: After 2 and 4 weeks of PUO, aliskiren significantly recompensed the rise of serum creatinine (Scr) and blood urea nitrogen (BUN). Aliskiren also revealed significantly better histopathological results regarding cortical and medullary necrosis, regeneration and inflammatory cell infiltration (table 1). Aliskiren group showed significant up-regulation of BCL-2 and down-regulation of IL-6, TGF-β1, collagen I and fibronectin gene expression (table 2). Aliskiren also significantly increased GSH and SOD activity and reduced MDA and NO activity (table 2). Moreover, aliskiren administration for 4 weeks after PUO significantly yielded more renoprotective effect compared to its administration for 2 weeks. CONCLUSIONS: Aliskiren ameliorates the deterioration of the renal function during acute and chronic PUO in a solitary kidney. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e947-e947 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mohamed Essam More articles by this author Nashwa Barakat More articles by this author Ahmed Elkashef More articles by this author Amira Awadalla More articles by this author A. E. Behery More articles by this author Mahmoud Abdel-Maboud More articles by this author Expand All Advertisement Loading ...

Functional and molecular evaluation of using aliskiren during acute and chronic partial ureteral obstruction in rat solitary kidney

AimsTo study the effect of direct renin inhibitor (aliskiren) on the renal function during acute and chronic partial ureteral obstruction (PUO) in rat solitary kidney. Main methodsSixty male Sprague–Dawley rats were randomly allocated into three groups (20 rats each); sham, PUO and aliskiren groups. Right nephrectomy was performed in all groups. Rats in PUO and aliskiren groups were subjected to left PUO and received no treatment and aliskiren (10 mg/kg, orally, once per day till sacrification), respectively. Blood samples were then collected for biochemical measurements. Ten rats from each group were sacrificed after two weeks, while the remaining rats were sacrificed after four weeks. Left kidneys were harvested for histopathological examination, BCL-2, interleukin (IL)-6, transforming growth factor (TGF)-β1, collagen I and fibronectin relative gene expression and assessment of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) activity. Key findingsAfter two and four weeks of PUO, aliskiren significantly recompensed the rise of serum creatinine (Scr) and blood urea nitrogen (BUN). Aliskiren also revealed significantly better histopathological results regarding cortical and medullary necrosis, regeneration and inflammatory cell infiltration. Aliskiren group showed statistically significant up-regulation of BCL-2 and down-regulation of IL-6, TGF-β1, collagen I and fibronectin relative gene expression. Aliskiren significantly increased GSH and SOD activity and reduced MDA and NO activity. Moreover, aliskiren administration for four weeks after PUO significantly yielded more renoprotective effect compared to its administration for two weeks. SignificanceAliskiren ameliorates the deterioration of the renal function during acute and chronic PUO in a solitary kidney.

Pentoxifylline protects against loss of function and renal interstitial fibrosis in chronic experimental partial ureteral obstruction

Tubulointerstitial fibrosis (TIF) is a hallmark of chronic kidney disease resulting from diverse etiologies and predicts severity and progression of the kidney disease. To investigate the pathogenesis of TIF, complete unilateral ureteral obstruction (UUO) is the most widely used animal model. However, UUO precludes evaluation of renal function. In the present study, we created a rat model of chronic partial ureteral obstruction (PUO), which allowed assessment of renal function at different intervals after obstruction. We examined the effects of pentoxifylline (PTF), a phosphodiesterase inhibitor used clinically to treat peripheral artery disease, on renal function and TIF. Studies were performed in sham-PUO rats and rats with 14-day PUO or 30-day PUO receiving vehicle in drinking water or PTF (400 mg/liter in drinking water). At day-14 PUO, glomerular filtration rate (GFR) was markedly and similarly depressed in rats receiving vehicle or PTF as compared with sham-operated rats. However, at day-30 PUO, GFR in rats receiving PTF was significantly higher than that in rats receiving vehicle, approaching the level seen in the sham-operated rats. At day-30 PUO, histologic studies also revealed a marked reduction of TIF in rats treated with PTF as compared with the rats receiving vehicle in drinking water. Western blot analysis demonstrated that at day-30 the expression of α-smooth muscle actin (an indicator of renal fibrosis) in the medulla was significantly reduced in PUO rats treated with PTF. In conclusion, PTF treatment ameliorated renal fibrosis and helped preserve renal function in a rodent model of PUO.

38 - Attenuation of partial unilateral ureteral obstruction-induced renal damage with hyperbaric oxygen therapy in a rat model

ABSTRACT Objective: The objective of the present study was to evaluate the effectiveness of HBO therapy on biochemical parameters, renal morphology and renal scintigraphy in rats undergoing chronic unilateral partial ureteral obstruction (UPUO). Material and methods: Thirty-five rats were divided into five equal groups: Control group; Sham group; HBO group; UPUO group and UPUO/HBO group. The effects of HBO therapy were examined using biochemical parameters and histopathological changes. After calculating the score for each histopathological change, the total histopathological score was obtained by adding all the scores. In addition, dynamic renal scintigraphy findings were evaluated. Results: Serum parameters indicating inflammation, serum tumor necrosis factor- alpha, ischemia modified-albumin, IMA/albumin ratio and Pentraxin-3 levels, were observed to be high in the UPUO group and low in the UPUO/HBO treatment group. Similarly, in the treatment group, the reduction in malondialdehyde, total oxidant status and oxidative stress index levels and increase in total antioxidant capacity values were observed to be statistically significant compared to the UPUO group (p<0.001, p=0.007, p<0.001, p=0.001, respectively). The total score and apoptosis index significantly decreased after administration of HBO treatment. Dynamic 99mTc-MAG3 renal scintigraphy also showed convincing evidence regarding the protective nature of HBO against kidney injury. In the UPUO/HBO therapy group, the percentage contribution of each operated kidney increased significantly compared to the UPUO group (41.73% versus 32.72%). Conclusion: The findings of this study indicate that HBO therapy had a reno-protective effect by reducing inflammation and oxidative stress, and preserving renal function after renal tissue damage due to induction of UPUO.

Attenuation of partial unilateral ureteral obstruction - induced renal damage with hyperbaric oxygen therapy in a rat model.

ABSTRACTObjective:The objective of the present study was to evaluate the effectiveness of HBO therapy on biochemical parameters, renal morphology and renal scintigraphy in rats undergoing chronic unilateral partial ureteral obstruction (UPUO).Material and methods:Thirty-five rats were divided into five equal groups: Control group; Sham group; HBO group; UPUO group and UPUO/HBO group. The effects of HBO therapy were examined using biochemical parameters and histopathological changes. After calculating the score for each histopathological change, the total histopathological score was obtained by adding all the scores. In addition, dynamic renal scintigraphy findings were evaluated.Results:Serum parameters indicating inflammation, serum tumor necrosis factor- alpha, ischemia modified-albumin, IMA/albumin ratio and Pentraxin-3 levels, were observed to be high in the UPUO group and low in the UPUO/HBO treatment group. Similarly, in the treatment group, the reduction in malondialdehyde, total oxidant status and oxidative stress index levels and increase in total antioxidant capacity values were observed to be statistically significant compared to the UPUO group (p<0.001, p=0.007, p<0.001, p=0.001, respectively). The total score and apoptosis index significantly decreased after administration of HBO treatment. Dynamic 99mTc-MAG3 renal scintigraphy also showed convincing evidence regarding the protective nature of HBO against kidney injury. In the UPUO/HBO therapy group, the percentage contribution of each operated kidney increased significantly compared to the UPUO group (41.73% versus 32.72%).Conclusion:The findings of this study indicate that HBO therapy had a reno-protective effect by reducing inflammation and oxidative stress, and preserving renal function after renal tissue damage due to induction of UPUO.

Enhanced prostaglandin biosynthesis in chronic partial ureteral obstruction is suppressed by atorvastatin

Progressive loss of renal function in obstructive uropathy is invariably associated with tubulointerstitial inflammation and fibrosis. We have created a rat model of chronic partial ureteral obstruction (PUO) to study means of attenuating renal fibrosis. Atorvastatin is a statin widely used in clinical practice as an HMG‐CoA reductase inhibitor. Besides lipid‐lowering effects, statins may exert pleiotropic actions such as constraining inflammatory processes. In rats with chronic PUO, we have previously reported that administration of atorvastatin decreases tubulointerstitial fibrosis and improves renal function (J Urol. 182:1860‐8, 2009). In view of augmented prostaglandin synthesis in obstructive uropathy, we examined in the present study the effects of atorvastatin on renal biosynthesis of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2, a stable metabolite of TXA2) in rats with PUO. Four groups of rats, consisting of 8 rats in each group, were studied. All rats underwent removal of the right kidney. To create PUO, the left ureter was incorporated into the psoas muscle, which was split and reapproximated. The rats received a regular diet or the same diet but supplemented with atorvastatin (50 mg/kg body weight atorvastatin per day) and were studied 30 days after the surgery. Four groups of rats were studied. Group 1 rats served as the control, underwent a sham surgery, and were fed on a regular diet. In Group 2, rats were subjected to PUO and placed on a regular diet. In Group 3, sham‐operated rats were fed on a regular diet containing atorvastatin. In Group 4, PUO rats were on a diet supplemented with atorvastatin. After the kidneys were harvested, the cortical and medullary tissues were separately homogenized, centrifuged and the extracts measured for PGE2 and TXB2 by ELISA. In Group 2, the tissue level of PGE2 was 4.2±0.5 in the cortex and 802.4±95.3 ng/g protein in the medulla, significantly higher than those in Group 1 (1.1±0.3 in the cortex and 348.8±70.1 in the medulla, respectively). In Group 2, TXB2 was 2.4±0.2 in the cortex, and 75.2±9.2 in the medulla, significantly greater than those in Group 1 (1.4±0.2 and 5.7±0.6 ng/g protein, respectively). Treatment with atorvastatin in PUO rats (Group 4) resulted in a significant reduction in the tissue levels of both PGE2 and TXB2, while no significant changes occurred in the sham‐operated rats (Group 3). In Group 4, the tissue level of PGE2 was 2.1±0.3 in the cortex and 522.2±62.1 ng/g protein in the medulla, significantly lower than those in Group 2. In Group 4, the TXB2 level was 1.9±0.3 in the cortex, and 51.3±6.2 in the medulla, significantly lower than those in Group 2. These results demonstrate that PUO enhances renal biosynthesis of PGE2 and TXB2, suggesting involvement of prostaglandins in the inflammatory process in chronic obstructive uropathy. This process is ameliorated by the use of a statin such as atorvastatin, thereby renal fibrosis is reduced.Support or Funding InformationInstitute Support.

Expression of Toll‐like Receptor 4 Is Augmented in the Kidney with Chronic Partial Ureteral Obstruction and Further Stimulated by Lipopolysaccharide

Urinary traction infection frequently occurs in the obstructed kidney. Toll‐like receptor 4 (TLR‐4) plays a critical role in recognizing pathogen‐associated molecular patterns and actives innate immunity by mediating production of inflammatory cytokines. In the present study we examined the expression of TLR‐4 in Sprague‐Dawley rats with partial ureteral obstruction (PUO) for 30 days. After removal of the right kidney, the left ureter was diverted into the psoas muscles to create PUO. In an additional group of PUO rats, lipopolysaccharide (LPS)(1 mg/kg BW) was administered intraperitoneally 24 hr before removal of the kidney for immunoblot and RT‐PCR analyses. Immunoblot analysis showed that TLR‐4/b‐actin in the renal cortex of 8 PUO rats was 10.1±0.7 (mean±SE)(densitometry units), significantly greater than 5.3±0.7 in the 8 sham‐operated rats, and increased significantly to 12.5±2.7 in 8 PUO rats receiving LPS. TLR‐4/b‐actin in the medulla of the PUO kidney was 9.6±1.8, significantly greater than 5.5±1.2 in the sham‐operated rats, and increased significantly to 13.1±0.9 in PUO rats receiving LPS. In the RT‐PCR analysis, TLR‐4 mRNA expression in the cortex increased significantly by 1.2±0.1(2‐exp‐DD Ct) in PUO rats when compared with sham‐operated rats and increased further by 1.4±0.3 in PUO rats receiving LPS. These results show that TLR‐4 expression is augmented in the obstructed kidney and further stimulated by LPS, suggesting an important role of TLR‐4 in the defense against urinary tract infection in obstructive uropathy.

Factors Predicting Improvement of Renal Function After Pyeloplasty in Pediatric Patients: A Prospective Study

We assessed the specific preoperative sonographic and urinary factors that may be important in predicting renal function outcomes after pyeloplasty. We prospectively studied 52 consecutive patients with ureteropelvic junction obstruction who underwent pyeloplasty at our tertiary care center between September 2009 and January 2011. Mean ± 2 SD patient age was 4.26 years (range 3 months to 18 years), and minimum followup was 6 months. Preoperative ultrasound findings recorded were pelvic anteroposterior diameter, pelvic cortical thickness, pelvic volume and pelvic cortical ratio. Spot urine protein-to-creatinine ratio from the renal pelvis and bladder was measured intraoperatively. Based on changes in differential renal function on diuretic renogram, patients were divided into 3 groups. Group 1 had stable differential renal function with less than 5% change, group 2 had improved differential renal function greater than 5% and group 3 had deterioration of differential renal function greater than 5%. Data were analyzed using SPSS®, version 17 with cross-tabulation, nonparametric tests and logistic regression. On ultrasound only anteroposterior diameter (p = 0.018) and pelvic cortical ratio (p = 0.038) were significantly different among the 3 groups. Difference in bladder sample protein-to-creatinine ratio was not significant (p = 0.69), while pelvic urine protein-to-creatinine ratio was significant (p = 0.001). Anteroposterior diameter, pelvic protein-to-creatinine ratio and pelvic cortical ratio were less than 50 mm, 0.5 and 15, respectively, in all patients with improved renal function. Sonographic and urinary biochemical parameters may predict improvement in renal function after pyeloplasty. Pelvic anteroposterior diameter, pelvic cortical ratio and pelvic urine protein-to-creatinine ratio are the most useful parameters.

Causal link between neonatal hydronephrosis and later development of hypertension

1. Although congenital ureteral obstruction is a common disorder in infants, its pathophysiology remains poorly understood and its clinical management continues to be debated. During the past decade, the surgical management of non-symptomatic hydronephrosis in children has become more conservative, but the long-term physiological consequences of this new policy are unclear. 2. In experimental models with complete ureteral obstruction, tubular atrophy and interstitial inflammation occur rapidly. Although this type of obstruction is very rare in clinical practice, it is often referred to in clinical discussions. New studies, using a model with chronic partial ureteral obstruction, have demonstrated that hydronephrosis is associated with renal injuries and is causally related to hypertension. 3. The mechanisms underlying the development of hypertension in experimental hydronephrosis are complex and involve changes in both the renin-angiotensin system and renal sympathetic nerve activity. Furthermore, oxidative stress and nitric oxide deficiency in the diseased kidney, with consequent resetting of the tubuloglomerular feedback mechanism, appear to play a pivotal role in the development and maintenance of hyper-tension. 4. In view of the new knowledge regarding the long-term effects of partial ureteral obstruction, today's non-operative management of hydronephrosis should be reconsidered to prevent obstructive nephropathy and hypertension in later life.

Atorvastatin Ameliorates Tubulointerstitial Fibrosis and Protects Renal Function in Chronic Partial Ureteral Obstruction Cases

Tubulointerstitial fibrosis, the histological feature of chronic obstructive nephropathy, is delineated in complete unilateral ureteral obstruction models. Histological changes during chronic partial ureteral obstruction are not well studied. We describe changes in a rat model of partial ureteral obstruction. We examined the effects of atorvastatin on histological alterations, fibrosis and function in this model. All rats underwent right nephrectomy. To create partial ureteral obstruction the left ureter was incorporated into the psoas muscle, which was split and reapproximated. Excretory urogram, histology, Western blot of alpha-smooth muscle actin and renal clearance were examined in rats with sham, 14-day or 30-day partial ureteral obstruction. Obstructed rats received a regular or a diet supplemented with 50 mg/kg body weight atorvastatin per day. At 14 days of partial ureteral obstruction pyelogram showed hydronephrosis, which was more pronounced on obstruction day 30. Histological studies on obstruction days 14 and 30 revealed tubulointerstitial fibrosis in the medulla and cortex. Atorvastatin significantly decreased tubulointerstitial fibrosis seen in alpha-smooth muscle actin expression. On obstruction day 14 or 30 the glomerular filtration rate in rats on a regular diet was significantly lower than in sham PUO rats or rats on atorvastatin. This model of partial ureteral obstruction enables chronic studies of morphological and histological changes of the obstructed kidney. It showed progressive fibrosis and decreased filtration function. Atorvastatin ameliorated fibrosis and helped preserve kidney filtration function.

Partial Unilateral Ureteral Obstruction in Newborn Mice: Magnetic Resonance Imaging and Pathology Studies

The mechanism underlying the evolution of congenital obstructive hydronephrosis in humans is still unclear. Although partial unilateral ureteral obstruction has been extensively explored in rats, studies in neonatal mice may lead to new insights into underlying cellular mechanisms, especially with the availability of mutant mice. We developed a model of partial unilateral ureteral obstruction in newborn mice. Mice were operated on by the fifth day of life. We created 3 groups, namely partial unilateral ureteral obstruction (embedding the ureter in the psoas muscle), complete unilateral ureteral obstruction (ligating the ureter) and sham (exposing the ureter). We studied pelvis diameter and kidney length on magnetic resonance imaging, and kidney weight, inflammation, apoptosis and fibrosis on histological assessment during the second (early) and fourth weeks (late) postoperatively. Magnetic resonance imaging showed enlarged pelvis diameter in late partial unilateral ureteral obstruction, and in early and late complete unilateral ureteral obstruction. Pathological studies revealed parenchyma atrophy in early and late partial unilateral ureteral obstruction. Apoptosis occurred early in partial unilateral ureteral obstruction and decreased later. Macrophage infiltration was enhanced in early and late partial unilateral ureteral obstruction. Fibrosis increased in late partial unilateral ureteral obstruction. All of these results were significantly intermediate between mice with complete unilateral ureteral obstruction and sham operated mice. It is possible to create renal lesions in newborn mice specific to partial ureteral obstruction. Magnetic resonance imaging of morphological changes demonstrated specific features of partial unilateral ureteral obstruction. Being noninvasive, this approach opens the way for further studies to investigate prognostic parameters after partial ureteral obstruction. In the future this model could be used in knockout mice to study the pathogenesis of renal lesions secondary to obstruction.

Reduction of renal interstitial fibrosis and protection of renal function by pentoxifylline in chronic partial ureteral obstruction

Tubulointerstitial fibrosis (TIF) is a hallmark of progressive renal disease from diverse etiologies and is a reliable marker of disease severity. In the present study, we examined whether pentoxifylline (PTF), a phosphodiesterase inhibitor, reduced TIF in a rat model of chronic partial ureteral obstruction (PUO). Male Sprague‐Dawley rats underwent removal of the right kidney and diversion of the left ureter into the psoas muscle which was split and reapproximated to produce retroperitoneal fibrosis and PUO. Studies were performed in sham‐PUO rats and 30‐day PUO rats receiving PTF (400 mg/liter in drinking water) or no PTF (control) (4 rats in each group). Intravenous pyelogram showed hydronephrosis in PUO rats. Western blot showed that the α‐smooth muscle actin expression (an indicator of renal fibrosis) in the medulla was 1.16±0.40 (densitometry unit) in control rats, significantly greater than 0.37±0.03 in PTF‐treated rats. Histological examination revealed less TIF in kidneys in PTF‐treated rats than in control rats. GFR in PTF‐treated rats was 0.89±0.04 ml/min/g, greater than 0.24±0.16 ml/min/g in control rats (p&lt;0.001). In conclusion, PTF treatment ameliorated renal fibrosis and helped preserve renal function in a rodent model of PUO.

Chronic partial ureteral obstruction and the developing kidney

Although congenital urinary tract obstruction is a common disorder, its pathophysiology remains poorly understood and clinical practice is controversial. Animal models have been used to elucidate the mechanisms responsible for obstructive nephropathy, and the models reveal that renal growth and function are impaired in proportion to the severity and duration of obstruction. Ureteral obstruction in the neonatal rat or mouse leads to activation of the renin-angiotensin system, renal infiltration by macrophages, and tubular apoptosis. Nephrons are lost by glomerular sclerosis and the formation of atubular glomeruli, and progressive injury leads to tubular atrophy and interstitial fibrosis. Recovery following release of obstruction depends on the timing, severity, and duration of obstruction. Growth factors and cytokines are produced by the hydronephrotic kidney, including MCP-1 and TGF-beta1, which are excreted in urine and can serve as biomarkers of renal injury. Because MRI can be used to monitor renal morphology, blood flow, and filtration rate, its use might supplant current imaging modalities (ultrasonography and diuretic renography), which have significant drawbacks. Combined use of MRI and new urinary biomarkers should improve our understanding of human congenital obstructive nephropathy and should lead to new approaches to evaluation and management of this challenging group of patients.

Glomerulotubular disconnection in neonatal mice after relief of partial ureteral obstruction

Ureteropelvic junction obstruction is a common cause of congenital obstructive nephropathy. To study the pathogenesis of nephropathy, a variable-partial, complete or a sham unilateral ureteral obstruction (UUO) was produced in mice within 2 days of birth. The obstruction was released in some animals at 7 days and kidneys harvested at 7-42 days of age for histologic and morphometric study. Renal parenchymal growth was stunted by partial UUO with the impairment proportional to the duration and severity of obstruction. Proximal tubule apoptosis and glomerulotubular disconnection led to nephron loss. Relief of partial UUO arrested glomerulotubular disconnection, resolved tubule atrophy, and interstitial fibrosis with remodeling of the renal architecture. Relief of severe UUO did not result in recovery. Compensatory growth of the contralateral kidney depended on the severity of obstruction. Our studies indicate that relief of moderate UUO will minimize nephron loss. Application of this technique to mutant mice will help develop future therapies to enhance nephron recovery.

Relief of chronic partial ureteral obstruction attenuates salt‐sensitive hypertension in rats

The incidence of hydronephrosis due to ureteropelvic junction obstruction is approx. 0.5%. During the last decade, the management of non-symptomatic hydronephrosis has become much more conservative, but the long-term physiological consequences of this policy are not clear. Previously, we have shown that animals with chronic partial unilateral ureteral obstruction develop salt-sensitive hypertension. In this study, the effects of ipsilateral and contralateral nephrectomy and ureterovesicostomy on blood pressure were studied in hydronephrotic animals. Partial unilateral ureteral obstruction was created in 3-week-old male Sprague-Dawley rats and blood pressure was measured telemetrically 4-6 weeks later during a normal and high salt diet before and after uninephrectomy or ureterovesicostomy. Plasma samples for renin assay were collected during both diets before and after ipsilateral nephrectomy. All hydronephrotic animals developed salt-sensitive hypertension, of different degrees. Before nephrectomy the plasma renin concentration was significantly higher in the hydronephrotic animals than in controls (160 +/- 15 microGU mL(-1) vs. 96 +/- 12 microGU mL(-1), respectively), but after the ipsilateral nephrectomy no differences were found between the groups. In the hydronephrotic animals both ipsilateral nephrectomy and ureterovesicostomy reduced the blood pressure and salt-sensitivity but the former still differed significantly from the controls. In contralaterally, nephrectomized hydronephrotic animals the salt-sensitive hypertension became more pronounced. Hydronephrosis in rats causes salt-sensitive hypertension that can be markedly reduced by removing the hydronephrotic kidney or relieving the obstruction by ureterovesicostomy. The mechanisms appear to be intrarenal and primarily located in the diseased kidney, but a secondary mechanism is also present.

Contribution of the renin-angiotensin system to the intrarenal resistive index in chronic unilateral partial ureteral obstruction in dogs.

We investigated the role of the renin-angiotensin system on intrarenal hemodynamics in chronic unilateral partial ureteral obstruction (UPUO) using Doppler ultrasound (US). In 11 dogs with chronic UPUO, we determined the renal resistive index (RI) before and 1 h after the intravenous infusion of an angiotensin-converting enzyme (ACE) inhibitor (captopril), an angiotensin II receptor type 1 (ART1) antagonist (L-158,809), and the combination of these two drugs. Change in resistive index (ΔRI) was calculated as RI after the administration of each tested material minus baseline RI. At the baseline measurement, significant differences in RI were seen between obstructed and nonobstructed kidneys. ACE inhibitor, ART1 antagonist, or the combination of these drugs did not result in any significant changes in RI in either obstructed or nonobstructed kidneys. However, in obstructed kidneys, ΔRI in the combination of ACE inhibitor and ART1 antagonist were significantly greater than those in ACE inhibitor or ART1 antagonist alone, whereas there were no significant differences in those values in nonobstructed kidneys. These observations suggest that the renin-angiotensin system in dogs with chronic UPUO may not contribute significantly to the differences in intrarenal RI between obstructed and nonobstructed kidneys. However, the angiotensin-producing pathways and angiotensin II receptor subtypes other than ACE and ART1 may have some different effects between obstructed and nonobstructed kidneys.

Variable chronic partial ureteral obstruction in the neonatal rat: A new model of ureteropelvic junction obstruction1

Congenital ureteropelvic junction (UPJ) obstruction is a common developmental anomaly. To elucidate the mechanisms underlying the renal consequences of congenital UPJ obstruction, we have developed a new model of variable partial unilateral ureteral obstruction (UUO) in the neonatal rat. Rat pups were subjected to sham-operation, complete UUO, or variable partial UUO within the first day of life. After 14 or 28 days, the relative number of glomeruli, cell proliferation, tubular apoptosis, tubular atrophy, and interstitial fibrosis were quantitated in histologic sections. Glomerular filtration rate (GFR) was determined after 28 days of partial or complete UUO. Following 70% to 75% reduction in ureteral diameter, renal growth from 14 to 28 days was reduced by 60%, and the number of glomeruli decreased by 50%. Renal pelvic diameter increased in proportion to the severity of obstruction following 14 days of partial UUO, and by 28 days, was maximally dilated regardless of the luminal diameter. Renal proliferation was increased, while tubular apoptosis, tubular atrophy, and interstitial fibrosis were less severe 14 days following partial UUO than in complete UUO. GFR was reduced by 80%, and proteinuria developed following 28 days of partial UUO. Renal function is impaired by chronic ipsilateral partial UUO, which reduces the number of nephrons, and leads to progressive renal pelvic dilatation. Tubular atrophy and interstitial fibrosis develop prior to significant renal pelvic dilatation. Correlation of clinically measurable parameters with renal morphometry or imaging studies in this model may lead to new approaches to the management of congenital UPJ obstruction.

ATORVASTATIN AMELIORATES RENAL TISSUE DAMAGE IN UNILATERAL URETERAL OBSTRUCTION

The current study was done to determine whether atorvastatin, the HMGCoA (3-hydroxy-3-methylglutaryl CoA) reductase inhibitor, could decrease renal transforming growth factor-beta (TGF-beta) levels in unilateral ureteral obstruction (UUO) and concomitantly affect renal tissue damage in UUO. Atorvastatin (20 mg/kg) was administered to rats 1 day prior to UUO and every day thereafter. Kidneys were harvested at day 14 after UUO. 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 polyclonal antisingle strand DNA antibody, respectively. Fibrosis was assessed by measuring collagen deposition with trichrome stained slides. Interstitial leukocyte was detected by immunostaining CD45. TGF-beta bioassay showed that the obstructed kidney in the control group contained significantly higher TGF-beta than the unobstructed kidney in the control group (mean +/- SD 79.1 +/- 48.5 vs 28.7 +/- 13.7 pg/mg tissue) and atorvastatin significantly decrease tissue TGF-beta in the obstructed kidney (53.4 +/- 37.0 pg/mg tissue). Immunostaining polyclonal antisingle strand DNA antibody demonstrated that the obstructed kidney in the control group has significantly more tubular apoptosis than the unobstructed counterpart (4.8 +/- 2.8 vs 2.1 +/- 1.2 nuclei per high power field) and atorvastatin significantly decreased renal tubular apoptosis in the obstructed kidney (1.1 +/- 0.7 nuclei per high power field). In addition, immunostaining proliferating cell nuclear antigen showed that the obstructed kidney in the atorvastatin group had significantly more renal tubular proliferation than the obstructed kidney in the control group (48.7 +/- 20.8 vs 17.3 +/- 10.6 per high power field). Control obstructed kidney showed significantly more fibrosis, which was also blunted by atorvastatin. Atorvastatin significantly decreases tissue TGF-beta, resulting in a decrease in tubular damage and interstitial fibrosis. This suggests that atorvastatin is a promising agent for preventing renal tubular damage in UUO.