Role of Fas (CD95) in tubulointerstitial disease induced by unilateral ureteric obstruction.
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Murine renal tubular epithelial cells and interstitial fibroblasts may express both Fas (CD95) death receptor and Fas ligand and are vulnerable to Fas-mediated death in vitro. We therefore hypothesized that an absence of renal Fas may protect resident cells from undergoing apoptosis. We performed unilateral ureteric ligation [producing unilateral ureteral obstruction (UUO)] in 6-wk-old normal control mice and C57Bl6/lpr mice, which express a nonfunctional Fas receptor. Obstructed kidneys were removed at days 3, 7, and 14 (n = 6 per group). Tubular cell apoptosis at day 7 was significantly reduced in lpr mice [21.8 +/- 5.8 vs. 45.7 +/- 7.6 cells/10 high-power fields (hpf), P < 0.02]. Importantly, there was no difference in tubular cell proliferation between normal and lpr mice at any time point studied. Interestingly, double labeling with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and the proximal tubule-specific antibody Fx1A indicated that the absence of Fas reduced distal but not proximal tubular death at day 7. In addition, there was no difference in interstitial cell apoptosis or proliferation, suggesting that Fas does not play a significant role in interstitial cell death. Importantly, inflammatory macrophage infiltration and ultimate collagen I deposition was unchanged in lpr mice. In conclusion, the absence of functional cell surface Fas in UUO provides distal tubular cells with partial protection from apoptosis but does not affect interstitial cell fate in this model of tubulointerstitial injury. (+info)
Renal cellular response to ureteral obstruction: role of maturation and angiotensin II.
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Renal angiotensin II (ANG II) is increased as a result of unilateral ureteral obstruction (UUO), and angiotensin AT(2) receptors predominate over AT(1) receptors in the early postnatal period. To examine the renal cellular response to 3-day UUO in the neonatal and adult rat, AT(1) and AT(2) receptors were inhibited by losartan and PD-123319, respectively. Additional rats received exogenous ANG II, 0.5 mg. kg(-1). day(-1). Renal cellular proliferation and apoptosis were quantitated by proliferating cell nuclear antigen and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling technique, respectively. In the neonate, UUO reduced proliferation and increased tubular apoptosis. Losartan had no detectable cellular effect, whereas PD-123319 increased cellular proliferation and suppressed apoptosis, and exogenous ANG II stimulated apoptosis. In the adult, UUO increased cellular proliferation as well as apoptosis, whereas losartan, PD-123319, and exogenous ANG II did not alter the cellular response. In conclusion, UUO impairs renal growth in the neonate by reducing proliferation and stimulating apoptosis, at least in part through angiotensin AT(2) receptors. UUO stimulates both renal cellular proliferation and apoptosis in the adult, but these effects are independent of ANG II. We speculate that the unique early responses of the developing kidney to urinary tract obstruction are mediated by a highly activated renin-angiotensin system and preponderance of AT(2) receptors. (+info)
Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis.
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BACKGROUND: Osteopontin is a macrophage adhesive protein that is expressed by renal tubules in tubulointerstitial disease. METHODS: To investigate the function of OPN, we induced tubulointerstitial disease in OPN null mutant (OPN-/-) and wild-type (OPN+/+) mice by unilateral ureteral ligation. Tissue was analyzed for macrophages (ED-1), types I and IV collagen deposition, TGF-beta expression, and for tubular and interstitial cell apoptosis. RESULTS: Obstructed kidneys from both OPN-/- and OPN+/+ mice developed hydronephrosis, tubular atrophy, interstitial inflammation and fibrosis. OPN was absent in OPN-/- kidneys but was increased in obstructed OPN+/+ kidneys. Macrophage influx, measured by computer-assisted quantitative immunostaining, was less in OPN-/- mice compared to OPN+/+ mice at day 4 (threefold, P < 0.02), day 7 (fivefold, P < 0.02), but not at day 14. Interstitial deposition of types I and IV collagen were also two- to fourfold less in obstructed OPN-/- kidneys (P < 0.02). There was also a reduction of TGF-beta mRNA expression in the interstitium at day 7 (by in situ hybridization) and a near significant 34% reduction in cortical TGF-beta activity (P = 0.06) compared to obstructed OPN+/+ kidneys at day 14. Obstructed kidneys from OPN-/- mice also had more interstitial and tubular apoptotic cells (TUNEL assay) compared to obstructed OPN+/+ mice at all time points. The ability of OPN to act as a cell survival factor was also documented by showing that the apoptosis of serum-starved NRK52E renal epithelial cells was markedly enhanced in the presence of neutralizing anti-OPN antibody. CONCLUSION: OPN mediates early interstitial macrophage influx and interstitial fibrosis in unilateral ureteral obstruction. OPN may also function as a survival factor for renal tubulointerstitial cells. (+info)
Increased oxidative stress in mouse kidneys with unilateral ureteral obstruction.
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BACKGROUND: Unilateral ureteral obstruction (UUO) is a well-established experimental model of renal injury leading to interstitial fibrosis. The molecular and cellular mechanism(s) of interstitial fibrosis in UUO kidney is beginning to be elucidated. Oxidative stress has been implicated in the pathogenesis of various forms of renal injury; however, little is known about its involvement in the setting of ureteral obstruction. METHODS: To investigate the possible involvement of oxidative stress in the obstructive nephropathy, we studied the occurrence and distribution of Nepsilon-carboxymethyl-lysine (CML) in the kidneys after ureteral obstruction. CML is an integrative biomarker of the cumulative protein damage induced by glycoxidation. Heme oxygenase-1 (HO-1) mRNA and protein expression, which is a sensitive and reliable indicator of oxidative stress, were also examined. RESULTS: CML immunoreactivity was found in the interstitium of UUO kidneys 10 days after the onset ureteral obstruction. HO-1 mRNA was up-regulated as early as 12 hours after ureteral obstruction. HO-1 immunoreactivity was observed in the periglomerular and peritubular interstitium two days after ureteral obstruction. CONCLUSIONS: These results strongly suggested the presence of increased oxidative stress in the interstitium of UUO kidneys. The oxidative stress and the formation of various kind of biological active oxidative products in the interstitium are supposed to play significant roles in UUO kidney. (+info)
How they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT.
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CAKUT are problems that often require surgical intervention or, in the worst case, lead to renal failure and the need for dialysis and/or renal transplantation. It is believed that these anomalies share a common genetic cause and to date there has been no good animal model with which to study these abnormalities. Although the abnormal interaction between the ureteral bud and metanephric blastema leads to renal hypodysplasia, vesicoureteral reflux, and ectopic ureters to name a few, the genetic and biochemical modulation of urinary tract development is not understood. Studies using the mouse strain mutant for angiotensin type 2 (AT2) receptors have given new insight into this mystery. The animals show defective apoptosis of undifferentiated mesenchymal cells in the area surrounding the developing kidney and urinary tract. This abnormal apoptosis may well interfere with the normal interaction between the ureteral bud and metanephric blastema resulting in CAKUT. This abnormal interaction would theoretically lead to preexisting intrinsic abnormalities of the kidney, which are programmed and take effect early in embryonic development. In the worst cases, the renal abnormalities would lead to progressive deterioration of renal function. Undoubtedly, there are more genes and biochemical modulators involved in this process other than the RAS and AT2 receptors. Our current animal model gives new and unique possibilities with which to study development of the kidney and urinary tract and ultimately seek ways of preventing an often debilitating disease process. (+info)
Obstructive nephropathy as a result of retroperitoneal fibrosis: a review of its pathogenesis and associations.
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Retroperitoneal fibrosis is a rare disease, typically with an insidious clinical course. It is thought that this disease process is perhaps an exaggerated reaction to an inciting inflammatory event. In this study, a case of retroperitoneal fibrosis is reported, in which the patient presented with typical symptoms of retroperitoneal fibrosis, along with some atypical vasculitic symptomatology. Retroperitoneal fibrosis is a disease process with an unknown etiology, which has been observed to be associated with a number of different possible inciting factors. Two factors that have been documented in the literature as being associated with retroperitoneal fibrosis include the use of beta-blocking agents, and connective tissue disease processes such as systemic lupus erythematosus. The patient discussed was using beta-blocker medication and also had signs and symptoms suggestive of a lupus syndrome. There are no reported cases of the combined association of beta-blocker usage, lupus, and retroperitoneal fibrosis. (+info)
Role of TNFR1 and TNFR2 receptors in tubulointerstitial fibrosis of obstructive nephropathy.
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Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the obstructed kidney. In this study, we report the contribution of tumor necrosis factor-alpha (TNF-alpha) to the fibrosis that develops after ureteral obstruction. Mice in which individual TNF-alpha receptors TNFR1 or TNFR2 had been genetically knocked out were used, and results were compared with mice of C57Bl/6 background after 5 days UUO. Both kidneys were removed and examined histologically for changes in interstitial volume (Vv(int)), collagen IV deposition, alpha-smooth muscle actin (alpha-SMA) matrix score, nuclear factor-kappaB (NF-kappaB) activity, and TNF-alpha mRNA levels. We found that the Vv(int) of contralateral unobstructed kidneys averaged approximately 7% and was indistinguishable among the three genotypes of mice. Vv(int) of ureteral obstructed kidney of C57Bl/6 mice averaged 33 +/- 3.9% after 5 days of UUO. Vv(int) of obstructed kidneys of TNFR1 mice was significantly reduced to 19.4 +/- 3.1%, whereas that of TNFR2 mice was significantly decreased to 25.4% +/- 4.8%. There was a modest but significant difference between Vv(int) of TNFR1 and TNFR2 (P < 0. 047). Both collagen IV and alpha-SMA matrix scores were decreased significantly in obstructed kidney of TNFR1 mouse compared with that of C57Bl/6 and TNFR2 mice. Nuclear extracts prepared from kidney cortex were found to have a significant increase in NF-kappaB binding activity in obstructed kidney compared with contralateral kidney. Individual knockout of the TNFR1 or TNFR2 genes resulted in significantly less NF-kappaB activation compared with the wild type, with TNFR1 being less than TNFR2 knockout. There was a significant increase in TNF-alpha mRNA in the kidney with ureteral obstruction in all three genotypes. TNFR1 knockout displayed a significant reduction in amount of TNF-alpha mRNA induced compared with wild-type or TNFR2 knockout mice. Treatment of TNFR1 knockout mice with an angiotensin converting enzyme inhibitor further decreased Vv(int) and TNF-alpha mRNA induction, suggesting an interaction of ANG II and TNF-alpha systems. These results suggest that TNF-alpha contributes, in part, to changes in interstitial volume, myofibroblast differentiation, and NF-kappaB activation in the kidney during ureteral obstruction. These changes appear to be mediated through both TNFR1 and TNFR2 gene products with effects through the TNFR1 receptor predominating. Furthermore, ANG II appears to stimulate TNF-alpha pathophysiological events leading to renal fibrosis. (+info)
F+0 diuresis renography in infants and children.
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The purpose of this study was to evaluate the feasibility of modifying diuresis renography by the simultaneous administration of 99mTc-mercaptoacetyltriglycine (MAG3) and furosemide in the investigation of hydronephrosis and hydroureteronephrosis in infants and children. Two parameters were assessed: the diuretic response in normal kidneys and the ability of the F+0 study to differentiate between renal obstruction and nonobstruction and to identify the level of obstruction in cases of renal obstruction. METHODS: Seventy-two patients (48 males, 24 females; age 2 d to 7 y; median age 6 wk) with sonographic diagnoses of hydronephrosis or hydroureteronephrosis were reviewed prospectively over a 3-y period. All patients had prior sonographic studies and micturating cystourethrography. Bladder catheterization was not routinely performed and was undertaken only if the child had suspected vesicoureteric junction (VUJ) obstruction or grade II or more vesicoureteric reflux. A weight-adjusted dose of 99mTc-MAG3 (maximum 200 MBq, minimum 20 MBq) and 1 mg/kg of furosemide (maximum 40 mg) were administered intravenously at the same time. Posterior imaging of the kidneys and bladder was performed for 20 min and followed by gravity-assisted drainage or imaging after voiding. All patients were followed-up for 6-12 mo, and the final diagnoses were based on either surgery or conservative management with repeated sonography or follow-up 99mTc-MAG3 studies (or both). The results of the F+0 diuresis renography were then compared with the final diagnoses. RESULTS: A renal unit was defined as a kidney and its ureter. There were 151 renal units with 1 patient having bilateral duplex kidneys, 6 patients having unilateral duplex kidneys and 1 patient having a solitary kidney. Fifty-five normal renal units and 96 abnormal renal units on the basis of sonographic findings were assessed. The furosemide clearance half-time for the 55 normal renal units was 1.3-6.3 min (mean 3.8 min). Of the 96 abnormal renal units, 53 were classified as nonobstructed and 43 were classified as obstructed. Of the 53 renal units classified as nonobstructed, there were 48 true-negative studies and 5 false-negative studies; of the 43 renal units classified as obstructed, there were 40 true-positive studies and 3 false-positive studies. The sensitivity was 88.9%, specificity was 94.1% and accuracy was 91.7%. The level of obstruction, either pelviureteric junction or VUJ, was also correctly identified. CONCLUSION: F+0 diuresis renography shows excellent diuretic responses in normal kidneys and is a valid method for the investigation of hydronephrosis and hydroureteronephrosis in infants and children. (+info)