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115Increased expression of hepatocyte growth factor in fetal sheep kidney with obstructive nephropathy
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THE HISTOLOGICAL CHANGES AND EXPRESSION OF HIF-ltx A N D VEGF ACCORDING TO DIFFERENTIAL RENAL FUNCTION DURING ACUTE STAGE OF URETEROPELVIC JUNCTION OBSTRUCTION IN RABBIT MODEL
L O W E R URINARY TRACT DYSFUNCTION IN PATIENTS W I T H POSTERIOR URETHRAL VALVE AND URODYNAMICALLY DETECTED CHANGES ON LONG TERM FOLLOW-UP Ziylan O., Oktar T., Rodoptu H., Incesu O., Korgah E., Kodak T., Ander H.
Shim K. 1, Heo J?, Seo y.1, Lee S.z ~Busan Veterans Hospital, Urologic Department, Busan, South Korea, 2Busan National University Hospital, Urologic Department, Busan, South Korea
Istanbul University, Istanbul Medical Faculty, Department of Urology, Istanbul, Turkey ~_
INTRODUCTION & OBJECTIVES: This study aimed to evaluate the renal histological changes, renal hemodynamic changes and expression of HIF-la and VEGF according to differential renal function during acute stage of ureteropelvic jtmction obstruction in rabbit model.
INTRODUCTION & OBJECTIVES: Bladder dysfunction is important in the long term outcome of patients with posterior urethral valve (PUV). In our study, we aimed to determine the types of bladder dysfunction in boys with PUV and their course on long term follow-up.
MATERIAL & METHODS: 49 New Zealand white rabbits of control group (5 rabbits) and experimental group (16 rabbits in UPJO 3day group, 13 rabbits in UPJO 7day group, 15 rabbits in UPJO 14day group) were included. Renal blood flow of ipsilateral kidney was measured at left main renal artery by a laser flowmeter. 99mTC-DTPAdiuretic renogramwas measured in each group before and after ureteropelvic junction obstruction and then the kidney was reseeted. We set subgroups on the basis of differential renal function 40%. The histological changes were evaluated by H-E stain and the expression of HIF-la and VEGF was evaluated by immunohistochemicalstain. RESULTS: In control group, differential renal function (DRF) was more than 40% in all cases. DRF was less than 40% at 4 cases (25%) in UPJO 3day group, 7 cases (53%) in UPJO 7day group and 6 cases (40%) in UPJO 14day group. Post obstructive renal blood flow was decreased compared with preohstmctive blood flow in each group. And renal blood flow of lower DRF subgroup (less than 40%) was more decreased than higher DRF subgroup (more than 40%) in 3, 7 and 14day UPJO group. Dilatation of collecting duct, dilatation of proximal tubule, interstitial fibrosis and interstitial inflammation was more increased in experimental group than control group, and increased with the passage of obstructed time. But there was no difference according to DRF. Dilatation of Bowman's space was more increased in experimental group than control group, but there was no difference with the passage of obstructed time and according to DRF. The expression of HIF-la was more increased in experimental group than control group, and was more increased in lower DRY subgroup (less than 40%) of UPJO 3day group. But there was no difference according to DRF in UPJO 7 and 14day group. The expressionof VEGF was more increased in experimental group than control group, and was more increased in lower DRY subgroup (less than 40%) of UPJO 3, 7 and 14day group. CONCLUSIONS: During acute stage of ureteropelvic junction obstruction in rabbit model, the maintenance of ipsilateral renal blood flow may play an importantrole for preservation of differential renal function.
MATERIAL & M E T H O D S : Between 1986 and 2004, a total of 50 patients with PUV were evaluated by urodynamic studies and their records were retrospectively reviewed. Serial urodynamics were performed to 20 patients. Urodynamic evaluations were performed 1-16 years after ablations, RESULTS: Bladder dysfunction on urodynamic studies were detected in 36 (72%) cases. Large bladder capacity for age was detected in 13 (26%) cases whereas small capacity was noted in 15 patients (30%). Seventeen (34%) patients had increased residual urine volumes. Patients were also examined in 3 groups as 0- 5 years, 5-10 and above age 10. Loss of compliance was detected in 50% of patients under age 5 compared to 25% after age 10. Detrusor overactivity was noted in 50% of patients before 5 years of age; however it decreased to 20% after age 10. Bladder capacity was large for age in 18.2% before age 5 and 30% after 10 years of age. No significant change was detected in terms of residual volumes according to age groups. On serial urodynamic studies (n:20), after a mean follow-up of 4.8~:3.1 years, compliance was improved to normal in 50% of patients who had loss of compliance on initial evaluations. Also, mean bladder capacity increased by 82% on follow-up. However, no statistically significant difference was detected in terms of residual volumes and detrusor overactivity on serial urodynamic studies. CONCLUSIONS: In our series, bladder dysfimction was detected in 72% of our patients with PUV. Loss of compliance and detrusor overactivity were most commonly detected abnormalities at early childhood. On long term follow-up, increase in bladder capacity (82%) and compliance (50%) was noted.
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116
INCREASED EXPRESSION OF HEPATOCYTE G R O W T H FACTOR IN FETAL SHEEP KIDNEY W I T H OBSTRUCTIVE NEPHROPATHY
A NOVEL M E C H A N I S M F O R PRESSURE INDUCED CELL PROLIERATION IN HUMAN BLADDER SMOOTH MUSCLE CELLS
One O., Adam R., Khoury J., Peters C.A.
Lee S.D., Miseeri R., Akbal C., Jung C., Rink R., Kaefer M.
Children's Hospital, Harvard Medical School, Department of Urology, Boston, United States
Indiana University School of Medicine, Paediatric Urology, Indianapolis, United States
INTRODUCTION & OBJECTIVES: Hepatocyte growth factor (HGF) is an important regulatory cytokine involved in renal injury response associated with chronic renal failure. There is little information as to its possible role in obstructive uropathy. We sought to investigate the potential involvement of HGF in a fetal model of partial ureteral obstruction and its relationships with TGF-bl and the renal renin-angiotensin system (RAS). MATERIAL & M E T H O D S : At 95 days gestation, bilateral PUO (BPUO) was created in 4 fetal sheep and unilateral PUO (UPUO) in 4 for 6 weeks; 3 agematched (135 days gestation) served as controls. Total renal mRNA was probed for HGF, renin, angiotensinogen, type 1 and 2 angiotensin II receptors (AT-1 and AT-2) and transforming growth factor- bl (TGF-bl) and assessed by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: All animals in BPUO group had moderate to severe hydronephrosis with enlarged kidneys while only 1 had so in UPUO group (mean weight 22.7 g. in BPUO group versus 9.4 g. in controls). HGF mRNA expression was significantly increased in BPUO kidneys when compared to normal controls (p=0.01). A positive correlation was identified between renal weight and expression levels of HGF mRNA (r = 0.713; p = 0.0028). Transforming growth factor- bl mRNA expression was similar in normal and obstructed animals and no correlation of HGF and TGF-b 1 was noted. Renal weight and expression levels of TGF-bl mRNA did not correlate. No significant difference was present in gene expression of any component of the renal RAS and TGF-bl among the groups. No correlation was present between renal weight and any of the components of renal RAS. CONCLUSIONS: This study clearly demonstrates HGF mRNA induction in the fetal sheep kidney in response to partial ureteral obstruction with hydronephrosis and associated with obstructive hypertrophy. Fetal obsmlction did not lead to a significant change in gene expression of renal RAS components assessed at term. HGF induction, independent from renal RAS, may be related to the complex regulation of the fetal renal response to obstruction.
INTRODUCTION & OBJECTIVES: Bladder outlet obstruction with intravesical pressures exceeding 40 cm-H20 can result in urinary tract deterioration. Anticholinergic medications represent one important means to oppose imminent injury by improving bladder dynamics and possibly inhibiting long term decreases in bladder wall compliance. Previous.reports have demonstrated a mitogenic effect of acetylcholine (Ach) in other organ systems. We evaluated whether hydrostatic pressure and/or acetylcholine increase human bladder smooth muscle cell (HBSMC) proliferation and subsequently determine whether highly selective anticholinergic medications have the ability to inhibit HBSMC growth. MATERIAL & METHODS: Cultured HBSMC were exposed to varying concentrations (10nM-100pM) of Ach in the presence and absence of 40 cm-H20 hydrostatic pressure. DNA synthesis was measured using a radio-labeled thymidine incorporation assay. Thereafter, cells exposed to hydrostatic pressure were treated with either l~tM AF-DX 16 (M2 antagonist), 1 gM 4-DAMP (M3 antagonist) or 1 ~M atropine (Both M2 and M s antagonist) and the effect on proliferation evaluated. RESULTS: Although there was a trend towards increased incorporation of thymidine at the higher concentrations ofAch (10gM and 100 ~M), at no point did the differences reach statistical significance. Cells maintained at 40 cm- H20 also demonstrated an increase in growth rate but this likewise failed to reach statistical significance, to both stimuli a statistically significant increase in thymidine incorporation was appreciated at Ach concentrations of > 1 gM. Antimuscarinic agents had no apparent effect on proliferative rate in cells grown at atmospheric pressure. However, there was a dramatic decrease in thymidine incorporation for cells that were simultaneously exposed to increased hydrostatic pressure. This effect was most pronounced when the combined M2/M3 receptor antagonist was applied. , CONCLUSIONS: Ach acts as a mitogen for HBSMC. This effect is most pronounced at hydrostatic pressures known to increase muscarinic receptor expression. In addition muscarinic receptor inhibition results in a profound decrease in HBSMC growth. This data suggests that anti-muscarinic drugs may prove beneficial in inhibiting long term bladder injury observed in bladder outlet obstruction and neurogenic bladder.
European Urology Supplements 4 (2005) No. 3, pp. 31
114
THE HISTOLOGICAL CHANGES AND EXPRESSION OF HIF-ltx A N D VEGF ACCORDING TO DIFFERENTIAL RENAL FUNCTION DURING ACUTE STAGE OF URETEROPELVIC JUNCTION OBSTRUCTION IN RABBIT MODEL
L O W E R URINARY TRACT DYSFUNCTION IN PATIENTS W I T H POSTERIOR URETHRAL VALVE AND URODYNAMICALLY DETECTED CHANGES ON LONG TERM FOLLOW-UP Ziylan O., Oktar T., Rodoptu H., Incesu O., Korgah E., Kodak T., Ander H.
Shim K. 1, Heo J?, Seo y.1, Lee S.z ~Busan Veterans Hospital, Urologic Department, Busan, South Korea, 2Busan National University Hospital, Urologic Department, Busan, South Korea
Istanbul University, Istanbul Medical Faculty, Department of Urology, Istanbul, Turkey ~_
INTRODUCTION & OBJECTIVES: This study aimed to evaluate the renal histological changes, renal hemodynamic changes and expression of HIF-la and VEGF according to differential renal function during acute stage of ureteropelvic jtmction obstruction in rabbit model.
INTRODUCTION & OBJECTIVES: Bladder dysfunction is important in the long term outcome of patients with posterior urethral valve (PUV). In our study, we aimed to determine the types of bladder dysfunction in boys with PUV and their course on long term follow-up.
MATERIAL & METHODS: 49 New Zealand white rabbits of control group (5 rabbits) and experimental group (16 rabbits in UPJO 3day group, 13 rabbits in UPJO 7day group, 15 rabbits in UPJO 14day group) were included. Renal blood flow of ipsilateral kidney was measured at left main renal artery by a laser flowmeter. 99mTC-DTPAdiuretic renogramwas measured in each group before and after ureteropelvic junction obstruction and then the kidney was reseeted. We set subgroups on the basis of differential renal function 40%. The histological changes were evaluated by H-E stain and the expression of HIF-la and VEGF was evaluated by immunohistochemicalstain. RESULTS: In control group, differential renal function (DRF) was more than 40% in all cases. DRF was less than 40% at 4 cases (25%) in UPJO 3day group, 7 cases (53%) in UPJO 7day group and 6 cases (40%) in UPJO 14day group. Post obstructive renal blood flow was decreased compared with preohstmctive blood flow in each group. And renal blood flow of lower DRF subgroup (less than 40%) was more decreased than higher DRF subgroup (more than 40%) in 3, 7 and 14day UPJO group. Dilatation of collecting duct, dilatation of proximal tubule, interstitial fibrosis and interstitial inflammation was more increased in experimental group than control group, and increased with the passage of obstructed time. But there was no difference according to DRF. Dilatation of Bowman's space was more increased in experimental group than control group, but there was no difference with the passage of obstructed time and according to DRF. The expression of HIF-la was more increased in experimental group than control group, and was more increased in lower DRY subgroup (less than 40%) of UPJO 3day group. But there was no difference according to DRF in UPJO 7 and 14day group. The expressionof VEGF was more increased in experimental group than control group, and was more increased in lower DRY subgroup (less than 40%) of UPJO 3, 7 and 14day group. CONCLUSIONS: During acute stage of ureteropelvic junction obstruction in rabbit model, the maintenance of ipsilateral renal blood flow may play an importantrole for preservation of differential renal function.
MATERIAL & M E T H O D S : Between 1986 and 2004, a total of 50 patients with PUV were evaluated by urodynamic studies and their records were retrospectively reviewed. Serial urodynamics were performed to 20 patients. Urodynamic evaluations were performed 1-16 years after ablations, RESULTS: Bladder dysfunction on urodynamic studies were detected in 36 (72%) cases. Large bladder capacity for age was detected in 13 (26%) cases whereas small capacity was noted in 15 patients (30%). Seventeen (34%) patients had increased residual urine volumes. Patients were also examined in 3 groups as 0- 5 years, 5-10 and above age 10. Loss of compliance was detected in 50% of patients under age 5 compared to 25% after age 10. Detrusor overactivity was noted in 50% of patients before 5 years of age; however it decreased to 20% after age 10. Bladder capacity was large for age in 18.2% before age 5 and 30% after 10 years of age. No significant change was detected in terms of residual volumes according to age groups. On serial urodynamic studies (n:20), after a mean follow-up of 4.8~:3.1 years, compliance was improved to normal in 50% of patients who had loss of compliance on initial evaluations. Also, mean bladder capacity increased by 82% on follow-up. However, no statistically significant difference was detected in terms of residual volumes and detrusor overactivity on serial urodynamic studies. CONCLUSIONS: In our series, bladder dysfimction was detected in 72% of our patients with PUV. Loss of compliance and detrusor overactivity were most commonly detected abnormalities at early childhood. On long term follow-up, increase in bladder capacity (82%) and compliance (50%) was noted.
115
116
INCREASED EXPRESSION OF HEPATOCYTE G R O W T H FACTOR IN FETAL SHEEP KIDNEY W I T H OBSTRUCTIVE NEPHROPATHY
A NOVEL M E C H A N I S M F O R PRESSURE INDUCED CELL PROLIERATION IN HUMAN BLADDER SMOOTH MUSCLE CELLS
One O., Adam R., Khoury J., Peters C.A.
Lee S.D., Miseeri R., Akbal C., Jung C., Rink R., Kaefer M.
Children's Hospital, Harvard Medical School, Department of Urology, Boston, United States
Indiana University School of Medicine, Paediatric Urology, Indianapolis, United States
INTRODUCTION & OBJECTIVES: Hepatocyte growth factor (HGF) is an important regulatory cytokine involved in renal injury response associated with chronic renal failure. There is little information as to its possible role in obstructive uropathy. We sought to investigate the potential involvement of HGF in a fetal model of partial ureteral obstruction and its relationships with TGF-bl and the renal renin-angiotensin system (RAS). MATERIAL & M E T H O D S : At 95 days gestation, bilateral PUO (BPUO) was created in 4 fetal sheep and unilateral PUO (UPUO) in 4 for 6 weeks; 3 agematched (135 days gestation) served as controls. Total renal mRNA was probed for HGF, renin, angiotensinogen, type 1 and 2 angiotensin II receptors (AT-1 and AT-2) and transforming growth factor- bl (TGF-bl) and assessed by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: All animals in BPUO group had moderate to severe hydronephrosis with enlarged kidneys while only 1 had so in UPUO group (mean weight 22.7 g. in BPUO group versus 9.4 g. in controls). HGF mRNA expression was significantly increased in BPUO kidneys when compared to normal controls (p=0.01). A positive correlation was identified between renal weight and expression levels of HGF mRNA (r = 0.713; p = 0.0028). Transforming growth factor- bl mRNA expression was similar in normal and obstructed animals and no correlation of HGF and TGF-b 1 was noted. Renal weight and expression levels of TGF-bl mRNA did not correlate. No significant difference was present in gene expression of any component of the renal RAS and TGF-bl among the groups. No correlation was present between renal weight and any of the components of renal RAS. CONCLUSIONS: This study clearly demonstrates HGF mRNA induction in the fetal sheep kidney in response to partial ureteral obstruction with hydronephrosis and associated with obstructive hypertrophy. Fetal obsmlction did not lead to a significant change in gene expression of renal RAS components assessed at term. HGF induction, independent from renal RAS, may be related to the complex regulation of the fetal renal response to obstruction.
INTRODUCTION & OBJECTIVES: Bladder outlet obstruction with intravesical pressures exceeding 40 cm-H20 can result in urinary tract deterioration. Anticholinergic medications represent one important means to oppose imminent injury by improving bladder dynamics and possibly inhibiting long term decreases in bladder wall compliance. Previous.reports have demonstrated a mitogenic effect of acetylcholine (Ach) in other organ systems. We evaluated whether hydrostatic pressure and/or acetylcholine increase human bladder smooth muscle cell (HBSMC) proliferation and subsequently determine whether highly selective anticholinergic medications have the ability to inhibit HBSMC growth. MATERIAL & METHODS: Cultured HBSMC were exposed to varying concentrations (10nM-100pM) of Ach in the presence and absence of 40 cm-H20 hydrostatic pressure. DNA synthesis was measured using a radio-labeled thymidine incorporation assay. Thereafter, cells exposed to hydrostatic pressure were treated with either l~tM AF-DX 16 (M2 antagonist), 1 gM 4-DAMP (M3 antagonist) or 1 ~M atropine (Both M2 and M s antagonist) and the effect on proliferation evaluated. RESULTS: Although there was a trend towards increased incorporation of thymidine at the higher concentrations ofAch (10gM and 100 ~M), at no point did the differences reach statistical significance. Cells maintained at 40 cm- H20 also demonstrated an increase in growth rate but this likewise failed to reach statistical significance, to both stimuli a statistically significant increase in thymidine incorporation was appreciated at Ach concentrations of > 1 gM. Antimuscarinic agents had no apparent effect on proliferative rate in cells grown at atmospheric pressure. However, there was a dramatic decrease in thymidine incorporation for cells that were simultaneously exposed to increased hydrostatic pressure. This effect was most pronounced when the combined M2/M3 receptor antagonist was applied. , CONCLUSIONS: Ach acts as a mitogen for HBSMC. This effect is most pronounced at hydrostatic pressures known to increase muscarinic receptor expression. In addition muscarinic receptor inhibition results in a profound decrease in HBSMC growth. This data suggests that anti-muscarinic drugs may prove beneficial in inhibiting long term bladder injury observed in bladder outlet obstruction and neurogenic bladder.
European Urology Supplements 4 (2005) No. 3, pp. 31