The Experts below are selected from a list of 192 Experts worldwide ranked by ideXlab platform
Yukiya Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and Pharmacodynamics of Bisoprolol in Rats with Bilateral Ureter Ligation-induced Renal Failure
Drug metabolism and pharmacokinetics, 2006Co-Authors: Katsutoshi Tahara, Katsuya Saigusa, Yuka Kagawa, Masato Taguchi, Yukiya HashimotoAbstract:The effect of renal failure on the pharmacokinetics and pharmacodynamics of bisoprolol was investigated in bilateral Ureter-ligated (BUL) rats. The blood bisoprolol concentrations following 30-min intravenous infusion at a rate of 60 microg/kg/min were higher in renal artery-occluded (RAO) rats than in control rats, and were higher in BUL rats than in RAO rats. Increased blood bisoprolol concentrations accompanied decreased mean systemic clearances: 50.7, 36.4, and 26.2 mL/min/kg in control, RAO, and BUL rats, respectively. The finding indicated that approximately 30% of administered bisoprolol was excreted via the kidney, and that not only the renal clearance but also non-renal clearance of bisoprolol was decreased in BUL rats. The beta-blocking action of bisoprolol was assessed by the reduction in isoproterenol-induced increases in the heart rate. The relationship between blood concentration and the beta-blocking action of bisoprolol in BUL rats was similar to that in control rats. These results suggested that renal excretion and hepatic metabolism of bisoprolol were significantly reduced in BUL rats, but that pharmacodynamics of bisoprolol was not altered by acute renal failure.
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Endogenous Uremic Substances are not Involved in the Reduced Hepatic Extraction of Metoprolol in Bilateral Ureter-Ligated Rats†
Drug metabolism and pharmacokinetics, 2006Co-Authors: Masato Taguchi, Misato Urai, Shigehiro Taira, Hiroko Tanabe, Yukiya HashimotoAbstract:The hepatic extraction of metoprolol is reduced in rats with bilateral Ureter Ligation (BUL)-induced renal failure. The aim of the present study was to evaluate the effect of uremic substances on the hepatic metabolism of metoprolol in rats with BUL. The metabolic rate in the liver microsomes of BUL rats was similar to that in sham rats, and there was no significant difference between sham and BUL rats in the effect of the supernatant of liver homogenates on the metabolism. The rate of metabolism in the liver microsomes in the presence of the plasma of BUL rats was also similar to that in the presence of the plasma of sham rats. These findings indicated that uremic substances which accumulate in BUL rats do not directly inhibit the activity of CYP2D2, which is responsible for the metabolism of metoprolol in the rat liver.
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Mechanism responsible for the decreased hepatic NADPH generation rate in rats with bilateral Ureter Ligation-induced renal failure.
Biological & pharmaceutical bulletin, 2005Co-Authors: Takashi Higashi, Masato Taguchi, Misato Urai, Yukiya HashimotoAbstract:We previously reported that a decrease in hepatic NADPH generation results in reduced hepatic first-pass clearance of propranolol in rats with bilateral Ureteral Ligation (BUL)-induced renal failure. The aim of the present study was to evaluate the mechanisms responsible for the reduced NADPH generation in the supernatant of liver homogenates (SUP) obtained from rats with BUL. The NADPH generation in the SUP in the presence of NADP(+) was decreased in BUL rats as compared with control rats. After the addition of glucose-6-phosphate or 6-phosphogluconic acid, the increase in NADPH in the SUP of BUL rats was similar to that in control rats. The NADPH generation in the SUP after the addition of the ultrafiltrate of BUL rat SUP was smaller than that after the addition of the ultrafiltrate of control rat SUP. These findings suggest that the enzymatic activities in the pentose phosphate pathway were not decreased significantly in BUL rats, and that the decrease in the generation of NADPH in BUL rats was mainly caused by the decreased concentration of endogenous substrate(s) and/or the increased concentration of endogenous inhibitor(s) for the pentose phosphate pathway.
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The Hepatic and Intestinal Metabolic Activities of P450 in Rats with Surgery- and Drug-Induced Renal Dysfunction
Pharmaceutical Research, 2003Co-Authors: Hiromi Okabe, Miyako Hasunuma, Yukiya HashimotoAbstract:Purpose. The hepatic and intestinal metabolic activities of P450 were evaluated in rats with surgery- and drug-induced renal dysfunction. Methods. Renal failure was induced by five-sixths nephrectomy (NR), bilateral Ureter Ligation (BUL), the intramuscular injection of glycerol (GL), and the intraperitoneal injection of cisplatin (CDDP). Phenytoin 4-hydroxylation, debrisoquine 4-hydroxylation, and testosterone 6β-hydroxylation were estimated to evaluate the metabolic activities of cytochrome P450 (CYP) 2C, 2D, and 3A, respectively. Results. The hepatic CYP3A metabolic activities were decreased by 65.9% and 60.2% in NR and GL rats, respectively. The hepatic CYP2C metabolic activity was decreased by 48.8% in CDDP rats. No alteration in hepatic drug-metabolizing activities was observed in BUL rats. On the other hand, the intestinal CYP3A metabolic activity was weakly increased in GL rats but not significantly altered in NR, CDDP, and BUL rats. Conclusions. This study suggested (a) that only selected P450 metabolic activity in the liver is decreased in renal failure, (b) that extent of the decrease in hepatic metabolic activities of P450 is dependent on the etiology of renal failure, and (c) that alteration of CYP3A metabolic activity in the intestine is not always correlated with that in the liver.
Luan D Truong - One of the best experts on this subject based on the ideXlab platform.
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renal cell apoptosis in chronic obstructive uropathy the roles of caspases
Kidney International, 2001Co-Authors: Luan D Truong, Chun Chui Tsao, George M Nassar, Gustavo Ayala, David Sheikhhamad, Yeong Jin Choi, Wadi N SukiAbstract:Renal cell apoptosis in chronic obstructive uropathy: The roles of caspases. Background Apoptosis of tubular and interstitial cells is well documented in kidneys with chronic obstructive uropathy (COU) and probably plays an important role in the pathogenesis of this condition. The molecular control of apoptosis in COU remains poorly understood. Apoptosis in general is known to proceed initially along distinct pathways, which later converge into a common arm characterized by orderly activation of caspases. Caspases are cytosolic enzymes that belong to a 12-member family and serve as effector molecules for apoptosis. The role of individual caspases in mediating renal cell apoptosis in kidneys with COU is studied. Methods Kidneys were harvested from sham-operated mice and mice with COU created by left Ureter Ligation at days 4, 7, 15, 20, and 30. The following studies were performed: ( 1 ) determination of dried kidney weight; ( 2 ) in situ end labeling of fragmented DNA to detect apoptotic tubular and interstitial cells; ( 3 ) ribonuclease protection assay with specific anti-sense RNA probes for caspases 1, 2, 3, 6, 7, 8, 9, 11, and 12 to detect the expression of individual caspases; ( 4 ) immunostaining for caspases; and ( 5 ) assay for caspase 3. To assess the role of caspases in COU-associated renal cell apoptosis, the frequencies of apoptotic tubular and interstitial cells were separately quantitated for each experimental time point, and their patterns of variation were correlated with those of individual caspases. Results The obstructed kidneys showed progressive tissue loss (60% of control at day 15). Apoptosis of both tubular and interstitial cells was seen in obstructed kidneys. Tubular cell apoptosis peaked at four days after Ureter Ligation (13-fold of control), remained high between days 4 to 15, and thereafter decreased rapidly. Apoptotic interstitial cells were scanty initially, but gradually increased throughout the entire experiment. Apoptosis was minimal throughout the experiment in control and contralateral kidneys. In control and contralateral kidneys, caspases 2, 3, 6, 7, 8, and 9 mRNAs were expressed at low levels, whereas those for caspases 1, 11, and 12 were not detected. The obstructed kidneys displayed increased expression of all tested caspases. Caspases 1, 11, and 12 mRNAs were detected in obstructed kidneys in a common pattern characterized by a sharp increase at day 4, followed by a decrease until day 20, and a subsequent sharp increase until the end of the study at day 30. A similar pattern was noted for other caspases (2, 3, 6, 7, 8, and 9), which maximally reached twofold to fourfold that of controls. Immunostaining for caspases 1, 2, 3, 6, 7, 8, and 9 showed the same pattern characterized by focal and weak expression in proximal tubules of control or contralateral kidney, contrasting with increased staining in atrophic or dilated tubules of obstructed kidneys. Interstitial cells also displayed staining for several caspases, which paralleled the increasing density of interstitial cells toward the end of the experiment. Caspase-3 assay showed a marked increased activity in obstructed kidneys that reached fourfold and sevenfold of control at days 4 and 30, respectively. The rise and fall of caspase mRNAs between days 4 and 30 paralleled a similar fluctuation in tubular cell apoptosis. The subsequent increase of mRNAs was correlated with a continuous rise of interstitial cell apoptosis. Conclusions Urinary obstruction in mice induces apoptosis of both tubular and interstitial cells in the affected kidney in a distinctive pattern that parallels an increased expression of caspases. This correlation suggests that these caspases mediate COU-associated renal cell apoptosis. Among the evaluated caspases, increased renal caspase 3 activity implies its central role in renal cell apoptosis associated with urinary obstruction.
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mechanism of chronic obstructive uropathy increased expression of apoptosis promoting molecules
Kidney International, 2000Co-Authors: Yeong Jin Choi, David Sheikhhamad, Wadi N Suki, Elzbieta Baranowskadaca, Vinh Nguyen, Takehiko Koji, Christie M Ballantyne, Luan D TruongAbstract:Mechanism of chronic obstructive uropathy: Increased expression of apoptosis-promoting molecules. Background We have demonstrated that renal tubular and interstitial cells undergo pronounced apoptosis during the course of chronic obstructive uropathy (COU). Apoptosis is a complex cellular process consisting of multiple steps, each of which is mediated by families of related molecules. These families may include receptor/ligand molecules such as Fas, Fas ligand, tumor necrosis factor receptor-1 (TNFR-1), and TNF-related apoptosis inducing ligand (TRAIL); signal transduction adapter molecules such as Fas-associated death domain (FADD), TNFR-1 associated death domain (TRADD), receptor-interacting protein (RIP), Fas-associated factor (FAF), and Fas-associated phosphatase (FAP); or effector molecules such as caspases. However, the mechanism of tubular cell apoptosis, as well as the pathogenetic relevance of these apoptosis-related molecules in COU, remains poorly understood. Methods Kidneys were harvested from sham-operated control mice and mice with COU created by left Ureter Ligation sacrificed in groups of three at days 4, 15, 30, and 45. To detect apoptotic tubular and interstitial cells, in situ end labeling of fragmented DNA was performed. To detect the expression of apoptosis-related molecules, ribonuclease protection assay was used with specific antisense RNA probes for Fas, Fas ligand, TNFR-1, TRAIL, FADD, TRADD, RIP, FAF, FAP, and caspase-8. Immunostaining for Fas, Fas ligand, TRAIL, TRADD, RIP, and caspase-8 was also performed. To assess the role of these molecules in COU-associated renal cell apoptosis, the frequencies of apoptotic tubular and interstitial cells were separately quantitated for each experimental time point, and their patterns of variation were correlated with those of apoptosis-related molecules. Results The obstructed kidneys displayed increased apoptosis of both tubular and interstitial cells. Tubular cell apoptosis appeared at day 4 after Ureter Ligation, peaked (fivefold of control) at day 15, and decreased gradually until the end of the experiment. In contrast, interstitial cell apoptosis sustained a progressive increase throughout the experiment. Apoptosis was minimal at all experimental time points for control and contralateral kidneys. Compared with control and contralateral kidneys, the ligated kidneys displayed a dynamic expression of mRNAs for many apoptosis-related molecules, which included an up to threefold increase for Fas, Fas ligand, TNF-R1, TRAIL, TRADD, RIP, and caspase-8, and an up to twofold increase for FADD and FAP, but there was little change for FAF. These mRNAs increased between days 4 and 15, decreased until day 30, but then increased again until day 45. The rise and fall of mRNAs between days 4 and 30 paralleled a similar fluctuation in tubular cell apoptosis in that period. The subsequent increase of mRNAs was correlated with a continuous rise of interstitial cell apoptosis. We demonstrated a positive immunostaining for Fas and Fas ligand in the tubular cells at early time points as well as in interstitial inflammatory cells at later time points. Although increased expression of TRAIL, TRADD, RIP, and caspase-8 was noted in tubular cells, there was no staining for these molecules in interstitial cells. Conclusion The current study documents a dynamic expression of several molecules that are known to mediate the most crucial steps of apoptosis. It implicates these molecules in COU-associated renal cell apoptosis and in the pathogenesis of this condition. It also lays the foundation for interventional studies, including genetic engineering, to evaluate the molecular control of apoptosis associated with COU.
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Expression of adhesion molecules in kidney with experimental chronic obstructive uropathy: the pathogenic role of ICAM-1 and VCAM-1.
Nephron, 2000Co-Authors: S.b. Shappell, Wadi N Suki, Leonardo Mendoza, Tayfun Gurpinar, C. W. Smith, Luan D TruongAbstract:Background: Chronic obstructive uropathy induced by maintained unilateral Ureter Ligation in the rat is characterized morphologically by interstitial inflammation, interstitial fibr
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cell apoptosis and proliferation in obstructive uropathy
Seminars in Nephrology, 1998Co-Authors: Luan D Truong, David Sheikhhamad, Subhendu Chakraborty, Wadi N SukiAbstract:: Distinct patterns of cell proliferation and apoptosis have been recognized for tubular, interstitial, and glomerular cells in chronic obstructive uropathy (OU). In many experimental models of OU, tubular cell apoptosis develops quickly after Ureter Ligation, peaks between 7 and 24 days postobtruction (about 30-fold of control), and tapers thereafter. Apoptosis initially involves the dilated collecting ducts, but subsequently spreads to other tubules. Tubular cell apoptosis probably accounts for renal tissue loss in OU because a direct correlation between its degree and the decline in dry kidney weight is well-documented. Pronounced tubular cell proliferation occurs shortly after Ureter Ligation, peaks at about day 6 (60-fold above control), and quickly subsides to baseline. Because the peak of tubular cell proliferation immediately precedes the onset of tubular cell apoptosis, a pathogenetic link may exist between these two processes. Interstitial cell apoptosis occurs with an increasing frequency throughout the course of OU (up to 35-fold above control). Interstitial cell proliferation appears in a bimodal pattern with the early peak coinciding with that of tubular cell proliferation and consisting mostly of fibroblasts, whereas the later peak consists mostly of inflammatory cells. Glomerular cell apoptosis and proliferation are not different from control, which explains, in part, the structural integrity of the glomeruli throughout the disease course. Although the general pathways of cell apoptosis and proliferation are well known, the molecular control of these processes in OU is poorly understood. In addition, whether apoptosis or proliferation of tubular and interstitial cells is differentially regulated remains to be studied. However, several molecules known to be activated or overexpressed in kidney with OU may modulate cell apoptosis and proliferation. The relevant functions of these molecules include induction of apoptosis (angiotensin II, reactive oxygen species, jun-N-terminal kinase, p53), inhibition of the cell cycle (transforming growth factor-beta, p21), inhibition of apoptosis (clusterin, epidermal growth factor, insulin-like growth factor, bcl-2, osteopontin), or promotion of interstitial fibroblast proliferation (platelet-derived growth factor).
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Chronic obstructive uropathy in severe combined immunodeficient (SCID) mice: Lymphocyte infiltration is not required for progressive tubulointerstitial injury
Journal of the American Society of Nephrology : JASN, 1998Co-Authors: Scott B. Shappell, Tayfun Gurpinar, Wadi N Suki, Juan Lechago, Luan D TruongAbstract:Progressive renal injury in humans and experimental animal models is characterized by tubular atrophy, infiltration of mononuclear inflammatory cells, and interstitial fibrosis. Permanent unilateral Ureter Ligation represents a reproducible model for investigating mechanisms of progressive kidney injury, and in the rat is characterized by tubular epithelial cell proliferation followed by apoptosis and progressive infiltration of monocytes and lymphocytes. Nevertheless, whether monocytes or lymphocytes play a dominant role in causing tubulointerstitial damage remains to be elucidated. In the current study, a model of chronic obstructive uropathy in the mouse is established and the role of lymphocyte infiltration in the evolution of the tubule and interstitial alterations is investigated. Permanent Ligation of the left Ureter in wild-type (C3H/HeJ) mice resulted in progressive atrophy of tubules and interstitial fibrosis compared with the contralateral kidney over a 30-d period. Immunoperoxidase studies on frozen sections taken from kidneys at 0, 3, 10, 20, and 30 d after Ureter Ligation showed that the tubulointerstitial injury was accompanied by a marked and progressive increase in interstitial macrophages and T lymphocytes, with no appreciable increase in B lymphocytes. No increase in inflammatory cells was detected in contralateral kidneys over the same time frame. The significance of T lymphocyte infiltration was examined by comparing the degree of tubular atrophy and interstitial fibrosis and the nature and quantity of the inflammatory infiltrate in wild-type mice and C3HSMn.C-Scid/J (SCID) mice subjected to permanent left Ureter Ligation. SCID mice have genetic defects in immunoglobulin and T cell receptor gene rearrangements and are devoid of circulating mature B and T lymphocytes. Wild-type and SCID mice developed tubular atrophy and interstitial volume expansion in the ligated kidney to the same degree and at the same rate. SCID mice developed a prominent and marked monocyte/macrophage infiltrate in the ligated kidney, which was essentially equal to that in wild-type mice. In contrast, consistent with the known absence of mature lymphocytes in SCID mice, there was essentially no T lymphocyte infiltration into the ligated kidney of SCID mice. These results demonstrate the effective establishment of the model of maintained unilateral Ureter Ligation in mice, which is readily applicable to genetic mutant strains thus allowing for specific investigation of the role of individual components of the inflammatory response in progressive tubulointerstitial injury. These studies further demonstrate that lymphocyte infiltration is not required for progressive tubular atrophy and increased interstitial fibrosis after maintained unilateral Ureter Ligation.
Wadi N Suki - One of the best experts on this subject based on the ideXlab platform.
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renal cell apoptosis in chronic obstructive uropathy the roles of caspases
Kidney International, 2001Co-Authors: Luan D Truong, Chun Chui Tsao, George M Nassar, Gustavo Ayala, David Sheikhhamad, Yeong Jin Choi, Wadi N SukiAbstract:Renal cell apoptosis in chronic obstructive uropathy: The roles of caspases. Background Apoptosis of tubular and interstitial cells is well documented in kidneys with chronic obstructive uropathy (COU) and probably plays an important role in the pathogenesis of this condition. The molecular control of apoptosis in COU remains poorly understood. Apoptosis in general is known to proceed initially along distinct pathways, which later converge into a common arm characterized by orderly activation of caspases. Caspases are cytosolic enzymes that belong to a 12-member family and serve as effector molecules for apoptosis. The role of individual caspases in mediating renal cell apoptosis in kidneys with COU is studied. Methods Kidneys were harvested from sham-operated mice and mice with COU created by left Ureter Ligation at days 4, 7, 15, 20, and 30. The following studies were performed: ( 1 ) determination of dried kidney weight; ( 2 ) in situ end labeling of fragmented DNA to detect apoptotic tubular and interstitial cells; ( 3 ) ribonuclease protection assay with specific anti-sense RNA probes for caspases 1, 2, 3, 6, 7, 8, 9, 11, and 12 to detect the expression of individual caspases; ( 4 ) immunostaining for caspases; and ( 5 ) assay for caspase 3. To assess the role of caspases in COU-associated renal cell apoptosis, the frequencies of apoptotic tubular and interstitial cells were separately quantitated for each experimental time point, and their patterns of variation were correlated with those of individual caspases. Results The obstructed kidneys showed progressive tissue loss (60% of control at day 15). Apoptosis of both tubular and interstitial cells was seen in obstructed kidneys. Tubular cell apoptosis peaked at four days after Ureter Ligation (13-fold of control), remained high between days 4 to 15, and thereafter decreased rapidly. Apoptotic interstitial cells were scanty initially, but gradually increased throughout the entire experiment. Apoptosis was minimal throughout the experiment in control and contralateral kidneys. In control and contralateral kidneys, caspases 2, 3, 6, 7, 8, and 9 mRNAs were expressed at low levels, whereas those for caspases 1, 11, and 12 were not detected. The obstructed kidneys displayed increased expression of all tested caspases. Caspases 1, 11, and 12 mRNAs were detected in obstructed kidneys in a common pattern characterized by a sharp increase at day 4, followed by a decrease until day 20, and a subsequent sharp increase until the end of the study at day 30. A similar pattern was noted for other caspases (2, 3, 6, 7, 8, and 9), which maximally reached twofold to fourfold that of controls. Immunostaining for caspases 1, 2, 3, 6, 7, 8, and 9 showed the same pattern characterized by focal and weak expression in proximal tubules of control or contralateral kidney, contrasting with increased staining in atrophic or dilated tubules of obstructed kidneys. Interstitial cells also displayed staining for several caspases, which paralleled the increasing density of interstitial cells toward the end of the experiment. Caspase-3 assay showed a marked increased activity in obstructed kidneys that reached fourfold and sevenfold of control at days 4 and 30, respectively. The rise and fall of caspase mRNAs between days 4 and 30 paralleled a similar fluctuation in tubular cell apoptosis. The subsequent increase of mRNAs was correlated with a continuous rise of interstitial cell apoptosis. Conclusions Urinary obstruction in mice induces apoptosis of both tubular and interstitial cells in the affected kidney in a distinctive pattern that parallels an increased expression of caspases. This correlation suggests that these caspases mediate COU-associated renal cell apoptosis. Among the evaluated caspases, increased renal caspase 3 activity implies its central role in renal cell apoptosis associated with urinary obstruction.
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mechanism of chronic obstructive uropathy increased expression of apoptosis promoting molecules
Kidney International, 2000Co-Authors: Yeong Jin Choi, David Sheikhhamad, Wadi N Suki, Elzbieta Baranowskadaca, Vinh Nguyen, Takehiko Koji, Christie M Ballantyne, Luan D TruongAbstract:Mechanism of chronic obstructive uropathy: Increased expression of apoptosis-promoting molecules. Background We have demonstrated that renal tubular and interstitial cells undergo pronounced apoptosis during the course of chronic obstructive uropathy (COU). Apoptosis is a complex cellular process consisting of multiple steps, each of which is mediated by families of related molecules. These families may include receptor/ligand molecules such as Fas, Fas ligand, tumor necrosis factor receptor-1 (TNFR-1), and TNF-related apoptosis inducing ligand (TRAIL); signal transduction adapter molecules such as Fas-associated death domain (FADD), TNFR-1 associated death domain (TRADD), receptor-interacting protein (RIP), Fas-associated factor (FAF), and Fas-associated phosphatase (FAP); or effector molecules such as caspases. However, the mechanism of tubular cell apoptosis, as well as the pathogenetic relevance of these apoptosis-related molecules in COU, remains poorly understood. Methods Kidneys were harvested from sham-operated control mice and mice with COU created by left Ureter Ligation sacrificed in groups of three at days 4, 15, 30, and 45. To detect apoptotic tubular and interstitial cells, in situ end labeling of fragmented DNA was performed. To detect the expression of apoptosis-related molecules, ribonuclease protection assay was used with specific antisense RNA probes for Fas, Fas ligand, TNFR-1, TRAIL, FADD, TRADD, RIP, FAF, FAP, and caspase-8. Immunostaining for Fas, Fas ligand, TRAIL, TRADD, RIP, and caspase-8 was also performed. To assess the role of these molecules in COU-associated renal cell apoptosis, the frequencies of apoptotic tubular and interstitial cells were separately quantitated for each experimental time point, and their patterns of variation were correlated with those of apoptosis-related molecules. Results The obstructed kidneys displayed increased apoptosis of both tubular and interstitial cells. Tubular cell apoptosis appeared at day 4 after Ureter Ligation, peaked (fivefold of control) at day 15, and decreased gradually until the end of the experiment. In contrast, interstitial cell apoptosis sustained a progressive increase throughout the experiment. Apoptosis was minimal at all experimental time points for control and contralateral kidneys. Compared with control and contralateral kidneys, the ligated kidneys displayed a dynamic expression of mRNAs for many apoptosis-related molecules, which included an up to threefold increase for Fas, Fas ligand, TNF-R1, TRAIL, TRADD, RIP, and caspase-8, and an up to twofold increase for FADD and FAP, but there was little change for FAF. These mRNAs increased between days 4 and 15, decreased until day 30, but then increased again until day 45. The rise and fall of mRNAs between days 4 and 30 paralleled a similar fluctuation in tubular cell apoptosis in that period. The subsequent increase of mRNAs was correlated with a continuous rise of interstitial cell apoptosis. We demonstrated a positive immunostaining for Fas and Fas ligand in the tubular cells at early time points as well as in interstitial inflammatory cells at later time points. Although increased expression of TRAIL, TRADD, RIP, and caspase-8 was noted in tubular cells, there was no staining for these molecules in interstitial cells. Conclusion The current study documents a dynamic expression of several molecules that are known to mediate the most crucial steps of apoptosis. It implicates these molecules in COU-associated renal cell apoptosis and in the pathogenesis of this condition. It also lays the foundation for interventional studies, including genetic engineering, to evaluate the molecular control of apoptosis associated with COU.
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Expression of adhesion molecules in kidney with experimental chronic obstructive uropathy: the pathogenic role of ICAM-1 and VCAM-1.
Nephron, 2000Co-Authors: S.b. Shappell, Wadi N Suki, Leonardo Mendoza, Tayfun Gurpinar, C. W. Smith, Luan D TruongAbstract:Background: Chronic obstructive uropathy induced by maintained unilateral Ureter Ligation in the rat is characterized morphologically by interstitial inflammation, interstitial fibr
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cell apoptosis and proliferation in obstructive uropathy
Seminars in Nephrology, 1998Co-Authors: Luan D Truong, David Sheikhhamad, Subhendu Chakraborty, Wadi N SukiAbstract:: Distinct patterns of cell proliferation and apoptosis have been recognized for tubular, interstitial, and glomerular cells in chronic obstructive uropathy (OU). In many experimental models of OU, tubular cell apoptosis develops quickly after Ureter Ligation, peaks between 7 and 24 days postobtruction (about 30-fold of control), and tapers thereafter. Apoptosis initially involves the dilated collecting ducts, but subsequently spreads to other tubules. Tubular cell apoptosis probably accounts for renal tissue loss in OU because a direct correlation between its degree and the decline in dry kidney weight is well-documented. Pronounced tubular cell proliferation occurs shortly after Ureter Ligation, peaks at about day 6 (60-fold above control), and quickly subsides to baseline. Because the peak of tubular cell proliferation immediately precedes the onset of tubular cell apoptosis, a pathogenetic link may exist between these two processes. Interstitial cell apoptosis occurs with an increasing frequency throughout the course of OU (up to 35-fold above control). Interstitial cell proliferation appears in a bimodal pattern with the early peak coinciding with that of tubular cell proliferation and consisting mostly of fibroblasts, whereas the later peak consists mostly of inflammatory cells. Glomerular cell apoptosis and proliferation are not different from control, which explains, in part, the structural integrity of the glomeruli throughout the disease course. Although the general pathways of cell apoptosis and proliferation are well known, the molecular control of these processes in OU is poorly understood. In addition, whether apoptosis or proliferation of tubular and interstitial cells is differentially regulated remains to be studied. However, several molecules known to be activated or overexpressed in kidney with OU may modulate cell apoptosis and proliferation. The relevant functions of these molecules include induction of apoptosis (angiotensin II, reactive oxygen species, jun-N-terminal kinase, p53), inhibition of the cell cycle (transforming growth factor-beta, p21), inhibition of apoptosis (clusterin, epidermal growth factor, insulin-like growth factor, bcl-2, osteopontin), or promotion of interstitial fibroblast proliferation (platelet-derived growth factor).
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Chronic obstructive uropathy in severe combined immunodeficient (SCID) mice: Lymphocyte infiltration is not required for progressive tubulointerstitial injury
Journal of the American Society of Nephrology : JASN, 1998Co-Authors: Scott B. Shappell, Tayfun Gurpinar, Wadi N Suki, Juan Lechago, Luan D TruongAbstract:Progressive renal injury in humans and experimental animal models is characterized by tubular atrophy, infiltration of mononuclear inflammatory cells, and interstitial fibrosis. Permanent unilateral Ureter Ligation represents a reproducible model for investigating mechanisms of progressive kidney injury, and in the rat is characterized by tubular epithelial cell proliferation followed by apoptosis and progressive infiltration of monocytes and lymphocytes. Nevertheless, whether monocytes or lymphocytes play a dominant role in causing tubulointerstitial damage remains to be elucidated. In the current study, a model of chronic obstructive uropathy in the mouse is established and the role of lymphocyte infiltration in the evolution of the tubule and interstitial alterations is investigated. Permanent Ligation of the left Ureter in wild-type (C3H/HeJ) mice resulted in progressive atrophy of tubules and interstitial fibrosis compared with the contralateral kidney over a 30-d period. Immunoperoxidase studies on frozen sections taken from kidneys at 0, 3, 10, 20, and 30 d after Ureter Ligation showed that the tubulointerstitial injury was accompanied by a marked and progressive increase in interstitial macrophages and T lymphocytes, with no appreciable increase in B lymphocytes. No increase in inflammatory cells was detected in contralateral kidneys over the same time frame. The significance of T lymphocyte infiltration was examined by comparing the degree of tubular atrophy and interstitial fibrosis and the nature and quantity of the inflammatory infiltrate in wild-type mice and C3HSMn.C-Scid/J (SCID) mice subjected to permanent left Ureter Ligation. SCID mice have genetic defects in immunoglobulin and T cell receptor gene rearrangements and are devoid of circulating mature B and T lymphocytes. Wild-type and SCID mice developed tubular atrophy and interstitial volume expansion in the ligated kidney to the same degree and at the same rate. SCID mice developed a prominent and marked monocyte/macrophage infiltrate in the ligated kidney, which was essentially equal to that in wild-type mice. In contrast, consistent with the known absence of mature lymphocytes in SCID mice, there was essentially no T lymphocyte infiltration into the ligated kidney of SCID mice. These results demonstrate the effective establishment of the model of maintained unilateral Ureter Ligation in mice, which is readily applicable to genetic mutant strains thus allowing for specific investigation of the role of individual components of the inflammatory response in progressive tubulointerstitial injury. These studies further demonstrate that lymphocyte infiltration is not required for progressive tubular atrophy and increased interstitial fibrosis after maintained unilateral Ureter Ligation.
Hermann Josef Gröne - One of the best experts on this subject based on the ideXlab platform.
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a chemokine receptor ccr 1 antagonist reduces renal fibrosis after unilateral Ureter Ligation
Journal of Clinical Investigation, 2002Co-Authors: Hans-joachim Anders, Yvonne Linde, Simone M Blattner, Volker Vielhauer, Clemens D Cohen, Frank Strutz, Matthias Mack, Michael Frink, Matthias Kretzler, Hermann Josef GröneAbstract:The expression of chemokines and their receptors is thought to contribute to leukocyte infiltration and progressive renal fibrosis after unilateral Ureter obstruction (UUO). We hypothesized that blocking the chemokine receptor CCR1 using the nonpeptide antagonist BX471 could reduce leukocyte infiltration and renal fibrosis after UUO. UUO kidneys from BX471-treated mice (day 0–10 and day 6–10) revealed a 40–60% reduction of interstitial macrophage and lymphocyte infiltrate compared with controls. Treated mice also showed a marked reduction of CCR1 and CCR5 mRNA levels, and FACS analysis showed a comparable reduction of CD8+/CCR5+ T cells. Markers of renal fibrosis, such as interstitial fibroblasts, interstitial volume, mRNA and protein expression for collagen I, were all significantly reduced by BX471-treatment compared with vehicle controls. By contrast treatment was ineffective when the drug was supplied only from days 0 to 5. In summary, blockade of CCR1 substantially reduces cell accumulation and renal fibrosis after UUO. Most interestingly, late onset of treatment is also effective. We therefore conclude that CCR1 blockade may represent a new therapeutic strategy for reducing cellular infiltration and renal fibrosis as major factors in the progression to end-stage renal failure.
Masato Taguchi - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and Pharmacodynamics of Bisoprolol in Rats with Bilateral Ureter Ligation-induced Renal Failure
Drug metabolism and pharmacokinetics, 2006Co-Authors: Katsutoshi Tahara, Katsuya Saigusa, Yuka Kagawa, Masato Taguchi, Yukiya HashimotoAbstract:The effect of renal failure on the pharmacokinetics and pharmacodynamics of bisoprolol was investigated in bilateral Ureter-ligated (BUL) rats. The blood bisoprolol concentrations following 30-min intravenous infusion at a rate of 60 microg/kg/min were higher in renal artery-occluded (RAO) rats than in control rats, and were higher in BUL rats than in RAO rats. Increased blood bisoprolol concentrations accompanied decreased mean systemic clearances: 50.7, 36.4, and 26.2 mL/min/kg in control, RAO, and BUL rats, respectively. The finding indicated that approximately 30% of administered bisoprolol was excreted via the kidney, and that not only the renal clearance but also non-renal clearance of bisoprolol was decreased in BUL rats. The beta-blocking action of bisoprolol was assessed by the reduction in isoproterenol-induced increases in the heart rate. The relationship between blood concentration and the beta-blocking action of bisoprolol in BUL rats was similar to that in control rats. These results suggested that renal excretion and hepatic metabolism of bisoprolol were significantly reduced in BUL rats, but that pharmacodynamics of bisoprolol was not altered by acute renal failure.
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Endogenous Uremic Substances are not Involved in the Reduced Hepatic Extraction of Metoprolol in Bilateral Ureter-Ligated Rats†
Drug metabolism and pharmacokinetics, 2006Co-Authors: Masato Taguchi, Misato Urai, Shigehiro Taira, Hiroko Tanabe, Yukiya HashimotoAbstract:The hepatic extraction of metoprolol is reduced in rats with bilateral Ureter Ligation (BUL)-induced renal failure. The aim of the present study was to evaluate the effect of uremic substances on the hepatic metabolism of metoprolol in rats with BUL. The metabolic rate in the liver microsomes of BUL rats was similar to that in sham rats, and there was no significant difference between sham and BUL rats in the effect of the supernatant of liver homogenates on the metabolism. The rate of metabolism in the liver microsomes in the presence of the plasma of BUL rats was also similar to that in the presence of the plasma of sham rats. These findings indicated that uremic substances which accumulate in BUL rats do not directly inhibit the activity of CYP2D2, which is responsible for the metabolism of metoprolol in the rat liver.
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Mechanism responsible for the decreased hepatic NADPH generation rate in rats with bilateral Ureter Ligation-induced renal failure.
Biological & pharmaceutical bulletin, 2005Co-Authors: Takashi Higashi, Masato Taguchi, Misato Urai, Yukiya HashimotoAbstract:We previously reported that a decrease in hepatic NADPH generation results in reduced hepatic first-pass clearance of propranolol in rats with bilateral Ureteral Ligation (BUL)-induced renal failure. The aim of the present study was to evaluate the mechanisms responsible for the reduced NADPH generation in the supernatant of liver homogenates (SUP) obtained from rats with BUL. The NADPH generation in the SUP in the presence of NADP(+) was decreased in BUL rats as compared with control rats. After the addition of glucose-6-phosphate or 6-phosphogluconic acid, the increase in NADPH in the SUP of BUL rats was similar to that in control rats. The NADPH generation in the SUP after the addition of the ultrafiltrate of BUL rat SUP was smaller than that after the addition of the ultrafiltrate of control rat SUP. These findings suggest that the enzymatic activities in the pentose phosphate pathway were not decreased significantly in BUL rats, and that the decrease in the generation of NADPH in BUL rats was mainly caused by the decreased concentration of endogenous substrate(s) and/or the increased concentration of endogenous inhibitor(s) for the pentose phosphate pathway.
