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Tadashi Inagami - One of the best experts on this subject based on the ideXlab platform.
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effects on blood pressure and exploratory behaviour of mice lacking Angiotensin II type 2 receptor
Nature, 1995Co-Authors: Toshihiro Ichiki, Agnes B. Fogo, Iekuni Ichikawa, Patricia A Labosky, Chiyo Shiota, Shigeru Okuyama, Yasuko Imagawa, F Niimura, Brigid L M Hogan, Tadashi InagamiAbstract:THERE are two major Angiotensin II receptor isoforms, AT1 and AT2. AT1 mediates the well-known pressor and mitogenic effects of Angiotensin II (refs 1-5), but the signalling mechanism and physiological role of AT2 (refs 6-11) has not been established. Its abundant expression in fetal tissues12 and certain brain nuclei13 suggest possible roles in growth, development and neuronal functions. Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of Angiotensin II. Thus AT2 mediates a depressor effect and antagonizes the AT1-mediated pressor action of Angiotensin II. In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature. Our results show that Angiotensin II activates AT1 and AT2, which have mutually counteracting haemo-dynamic effects, and that AT2 regulates central nervous system functions, including behaviour.
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effects on blood pressure and exploratory behaviour of mice lacking Angiotensin II type 2 receptor
Nature, 1995Co-Authors: Toshihiro Ichiki, Agnes B. Fogo, Iekuni Ichikawa, Patricia A Labosky, Chiyo Shiota, Shigeru Okuyama, Yasuko Imagawa, F Niimura, Brigid L M Hogan, Tadashi InagamiAbstract:There are two major Angiotensin II receptor isoforms, AT1 and AT2. AT1 mediates the well-known pressor and mitogenic effects of Angiotensin II, but the signalling mechanism and physiological role of AT2 has not been established. Its abundant expression in fetal tissues and certain brain nuclei suggest possible roles in growth, development and neuronal functions. Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of Angiotensin II. Thus AT2 mediates a depressor effect and antagonizes the AT1-mediated pressor action of Angiotensin II. In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature. Our results show that Angiotensin II activates AT1 and AT2, which have mutually counteracting haemodynamic effects, and that AT2 regulates central nervous system functions, including behaviour.
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steroid hormones upregulate rat Angiotensin II type 1a receptor gene role of glucocorticoid responsive elements in rat Angiotensin II type 1a promoter
The Journal of Steroid Biochemistry and Molecular Biology, 1995Co-Authors: Tadashi InagamiAbstract:Abstract The transcription of the rat Angiotensin II type 1A receptor gene is stimulated by glucocorticoids. To clarify the molecular mechanism for glucocorticoid action in rat vascular smooth muscle cells, we investigated the effects of dexamethasone on the promoter activity of the Angiotensin II type 1A receptor by using promoter/luciferase reporter gene constructs and heterologous context constructs (containing the thymidine kinase promoter) in transfected vascular smooth muscle cells. There are three putative glucocorticoid responsive elements in the promoter. However, only one glucocorticoid responsive element was found to respond to dexamethasone (1 μM). The region was located at positions, −756 to −770 bp upstream of the transcription initiation site. A glucocorticoid antagonist, RU38486, completely blocked the induction by dexamethasone, suggesting that the glucocorticoid responsive element was functional through a specific glucocorticoid receptor. Compared with the angiotension II type 1A receptor promoter, no effect by dexamethasone was observed in vascular smooth muscle cells transfected with the Angiotensin II type 1B receptor promoter/luciferase reporter gene constructs. We concluded that the dexamethasone-induced increase in the transcription of the Angiotensin II type 1A receptor gene occurred through the binding to GRE up the glucocorticoid-specific receptor.
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cloning and expression of a complementary dna encoding a bovine adrenal Angiotensin II type 1 receptor
Nature, 1991Co-Authors: Kazuyuki Sasaki, Y Yamano, S Bardhan, Naoharu Iwai, J J Murray, M Hasegawa, Y Matsuda, Tadashi InagamiAbstract:Angiotensin II elicits different responses which affect cardiovascular, neuronal and electrolyte transport regulation. To understand the mechanisms responsible for its various actions, the receptor for Angiotensin II has long been sought, but numerous attempts to purify the receptor have been unsuccessful owing to its instability and low concentration. We report here the expression cloning of a complementary DNA encoding a bovine Angiotensin II receptor to overcome these difficulties. The receptor cDNA encodes a protein of 359 amino-acid residues with a transmembrane topology similar to that of other G protein-coupled receptors. COS-7 cells transfected with the cDNA expressed specific and high-affinity binding sites for Angiotensin II, Angiotensin II antagonist and a non-peptide specific antagonist for type-1 receptor. Dithiothreitol inhibited ligand binding. The concentration of intracellular Ca2+ and of inositol-1,4,5-trisphosphate increased in the transfected COS-7 cells in response to Angiotensin II or Angiotensin III, indicating that this receptor is the type-1 receptor for Angiotensin II. Northern blot analysis revealed that the messenger RNA for this receptor is expressed in bovine adrenal medulla, cortex and kidney.
K U Malik - One of the best experts on this subject based on the ideXlab platform.
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6β hydroxytestosterone a cytochrome p450 1b1 testosterone metabolite mediates Angiotensin II induced renal dysfunction in male mice
Hypertension, 2016Co-Authors: Ajeeth K Pingili, Mehmet Kara, Shyamala Thirunavukkarasu, Akemi Katsurada, Dewan S A Majid, Gabriel L Navar, David D Brand, Frank J Gonzalez, K U MalikAbstract:6β-Hydroxytestosterone, a cytochrome P450 1B1–derived metabolite of testosterone, contributes to the development of Angiotensin II–induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of Angiotensin II in the maintenance of renal homeostasis, development of hypertension, and end-organ damage, this study was conducted to determine the contribution of 6β-hydroxytestosterone to Angiotensin II actions on water consumption and renal function in male Cyp1b1 +/+ and Cyp1b1 −/− mice. Castration of Cyp1b1 +/+ mice or Cyp1b1 −/− gene disruption minimized the Angiotensin II–induced increase in water consumption, urine output, proteinuria, and sodium excretion and decreases in urine osmolality. 6β-Hydroxytestosterone did not alter Angiotensin II–induced increases in water intake, urine output, proteinuria, and sodium excretion or decreases in osmolality in Cyp1b1 +/+ mice, but restored these effects of Angiotensin II in Cyp1b1 −/− or castrated Cyp1b1 +/+ mice. Cyp1b1 gene disruption or castration prevented Angiotensin II–induced renal fibrosis, oxidative stress, inflammation, urinary excretion of Angiotensinogen, expression of Angiotensin II type 1 receptor, and Angiotensin-converting enzyme. 6β-Hydroxytestosterone did not alter Angiotensin II–induced renal fibrosis, inflammation, oxidative stress, urinary excretion of Angiotensinogen, expression of Angiotensin II type 1 receptor, or Angiotensin-converting enzyme in Cyp1b1 +/+ mice. However, in Cyp1b1 −/− or castrated Cyp1b1 +/+ mice, it restored these effects of Angiotensin II. These data indicate that 6β-hydroxytestosterone contributes to increased thirst, impairment of renal function, and end-organ injury associated with Angiotensin II–induced hypertension in male mice and that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension in male mice.
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cytochrome p450 1b1 contributes to renal dysfunction and damage caused by Angiotensin II in mice
Hypertension, 2012Co-Authors: Brett L Jennings, Xiao R Fang, Fariborz A Yaghini, Larry J Anderson, Jason Porter, William B. Campbell, Anne M. Estes, Frank J Gonzalez, K U MalikAbstract:Cytochrome P450 1B1 contributes to the development of Angiotensin II–induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of Angiotensin II in the kidney, as well as in salt and water homeostasis, and blood pressure regulation, we determined the contribution of cytochrome P450 1B1 to renal dysfunction and injury associated with Angiotensin II–induced hypertension in male Cyp1b1 +/+ and Cyp1b1 − / − mice. Angiotensin II infusion (700 ng/kg per minute) given by miniosmotic pumps for 13 and 28 days increased systolic blood pressure in Cyp1b1 +/+ mice; this increase was significantly reduced in Cyp1b1 − / − mice. Angiotensin II increased renal Cyp1b1 activity, vascular resistance, and reactivity to vasoconstrictor agents and caused endothelial dysfunction in Cyp1b1 +/+ but not Cyp1b1 − / − mice. Angiotensin II increased water consumption and urine output, decreased urine osmolality, increased urinary Na + and K + excretion, and caused proteinuria and albuminuria in Cyp1b1 +/+ mice that was diminished in Cyp1b1 − / − mice. Infusion of Angiotensin II for 28 but not 13 days caused renal fibrosis, tubular damage, and inflammation in Cyp1b1 +/+ mice, which was minimized in Cyp1b1 − / − mice. Angiotensin II increased levels of 12- and 20-hydroxyeicosatetraenoic acids; reactive oxygen species; and activity of NADPH oxidase, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src in the kidneys of Cyp1b1 +/+ but not Cyp1b1 − / − mice. These data suggest that increased thirst, renal dysfunction, and injury and inflammation associated with Angiotensin II–induced hypertension in mice depend on cytochrome P450 1B1 activity, thus indicating that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension.
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cytochrome p450 1b1 contributes to Angiotensin II induced hypertension and associated pathophysiology
Hypertension, 2010Co-Authors: Brett L Jennings, Seyhan Sahanfirat, Nasreen Farjana, Xiao R Fang, Anne M. Estes, Frank J Gonzalez, K U MalikAbstract:Hypertension is the leading cause of cardiovascular diseases, and Angiotensin II is one of the major components of the mechanisms that contribute to the development of hypertension. However, the precise mechanisms for the development of hypertension are unknown. Our recent study showing that Angiotensin II–induced vascular smooth muscle cell growth depends on cytochrome P450 1B1 led us to investigate its contribution to hypertension caused by this peptide. Angiotensin II was infused via miniosmotic pump into rats (150 ng/kg per minute) or mice (1000 μg/kg per day) for 13 days resulting in increased blood pressure, increased cardiac and vascular hypertrophy, increased vascular reactivity to vasoconstrictor agents, increased vascular reactive oxygen species production, and endothelial dysfunction in both species. The increase in blood pressure and associated pathophysiological changes were minimized by the cytochrome P450 1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene in both species and was markedly reduced in Cyp1b1 −/− mice. These data suggest that cytochrome P450 1B1 contributes to Angiotensin II–induced hypertension and associated pathophysiological changes. Moreover, 2,3′,4,5′-tetramethoxystilbene, which prevents both cytochrome P450 1B1–dependent and –independent components of Angiotensin II–induced hypertension and inhibits associated pathophysiological changes could be clinically useful in the treatment of hypertension and associated cardiovascular and inflammatory diseases.
Iekuni Ichikawa - One of the best experts on this subject based on the ideXlab platform.
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podocyte injury enhances filtration of liver derived Angiotensinogen and renal Angiotensin II generation
Kidney International, 2014Co-Authors: Taiji Matsusaka, Akira Nishiyama, Fumio Niimura, Ira Pastan, Iekuni Ichikawa, Ayumi ShintaniAbstract:Intrarenal Angiotensin II is increased in kidney diseases independently of plasma Angiotensin II and is thought to promote progressive deterioration of renal architecture. Here we investigated the mechanism of enhanced renal Angiotensin II generation in kidney glomerular diseases. For this, kidney- or liver-specific Angiotensinogen gene (Agt) knockout was superimposed on the mouse model of inducible podocyte injury (NEP25). Seven days after induction of podocyte injury, renal Angiotensin II was increased ninefold in NEP25 mice with intact Agt, accompanied by increases in urinary albumin and Angiotensinogen excretion, renal Angiotensinogen protein, and its mRNA. Kidney Agt knockout attenuated renal Agt mRNA but not renal Angiotensin II, renal, or urinary Angiotensinogen protein. In contrast, liver Agt knockout markedly reduced renal Angiotensin II to 18.7% of that of control NEP25 mice, renal and urinary Angiotensinogen protein, but not renal Agt mRNA. Renal Angiotensin II had no relationship with renal Agt mRNA, or with renal renin mRNA, which was elevated in liver Agt knockouts. Kidney and liver dual Agt knockout mice showed phenotypes comparable to those of liver Agt knockout mice. Thus, increased renal Angiotensin II generation upon severe podocyte injury is attributed to increased filtered Angiotensinogen of liver origin resulting from loss of macromolecular barrier function of the glomerular capillary wall that occurs upon severe podocyte injury.
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Liver Angiotensinogen Is the Primary Source of Renal Angiotensin II
Journal of the American Society of Nephrology : JASN, 2012Co-Authors: Taiji Matsusaka, Hiroyuki Kobori, Akira Nishiyama, Fumio Niimura, Akihiro Shimizu, Ira Pastan, Akihiko Saito, Iekuni IchikawaAbstract:Angiotensin II content in the kidney is much higher than in the plasma, and it increases more in kidney diseases through an uncertain mechanism. Because the kidney abundantly expresses Angiotensinogen mRNA, transcriptional dysregulation of Angiotensinogen within the kidney is one potential cause of increased renal Angiotensin II in the setting of disease. Here, we observed that kidney-specific Angiotensinogen knockout mice had levels of renal Angiotensinogen protein and Angiotensin II that were similar to those levels of control mice. In contrast, liver-specific knockout of Angiotensinogen nearly abolished plasma and renal Angiotensinogen protein and renal tissue Angiotensin II. Immunohistochemical analysis in mosaic proximal tubules of megalin knockout mice revealed that Angiotensinogen protein was incorporated selectively in megalin-intact cells of the proximal tubule, indicating that the proximal tubule reabsorbs filtered Angiotensinogen through megalin. Disruption of the filtration barrier in a transgenic mouse model of podocyte-selective injury increased renal Angiotensin II content and markedly increased both tubular and urinary Angiotensinogen protein without an increase in renal renin activity, supporting the dependency of renal Angiotensin II generation on filtered Angiotensinogen. Taken together, these data suggest that liver-derived Angiotensinogen is the primary source of renal Angiotensinogen protein and Angiotensin II. Furthermore, an abnormal increase in the permeability of the glomerular capillary wall to Angiotensinogen, which characterizes proteinuric kidney diseases, enhances the synthesis of renal Angiotensin II.
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effects on blood pressure and exploratory behaviour of mice lacking Angiotensin II type 2 receptor
Nature, 1995Co-Authors: Toshihiro Ichiki, Agnes B. Fogo, Iekuni Ichikawa, Patricia A Labosky, Chiyo Shiota, Shigeru Okuyama, Yasuko Imagawa, F Niimura, Brigid L M Hogan, Tadashi InagamiAbstract:THERE are two major Angiotensin II receptor isoforms, AT1 and AT2. AT1 mediates the well-known pressor and mitogenic effects of Angiotensin II (refs 1-5), but the signalling mechanism and physiological role of AT2 (refs 6-11) has not been established. Its abundant expression in fetal tissues12 and certain brain nuclei13 suggest possible roles in growth, development and neuronal functions. Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of Angiotensin II. Thus AT2 mediates a depressor effect and antagonizes the AT1-mediated pressor action of Angiotensin II. In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature. Our results show that Angiotensin II activates AT1 and AT2, which have mutually counteracting haemo-dynamic effects, and that AT2 regulates central nervous system functions, including behaviour.
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effects on blood pressure and exploratory behaviour of mice lacking Angiotensin II type 2 receptor
Nature, 1995Co-Authors: Toshihiro Ichiki, Agnes B. Fogo, Iekuni Ichikawa, Patricia A Labosky, Chiyo Shiota, Shigeru Okuyama, Yasuko Imagawa, F Niimura, Brigid L M Hogan, Tadashi InagamiAbstract:There are two major Angiotensin II receptor isoforms, AT1 and AT2. AT1 mediates the well-known pressor and mitogenic effects of Angiotensin II, but the signalling mechanism and physiological role of AT2 has not been established. Its abundant expression in fetal tissues and certain brain nuclei suggest possible roles in growth, development and neuronal functions. Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of Angiotensin II. Thus AT2 mediates a depressor effect and antagonizes the AT1-mediated pressor action of Angiotensin II. In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature. Our results show that Angiotensin II activates AT1 and AT2, which have mutually counteracting haemodynamic effects, and that AT2 regulates central nervous system functions, including behaviour.
Frank J Gonzalez - One of the best experts on this subject based on the ideXlab platform.
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6β hydroxytestosterone a cytochrome p450 1b1 testosterone metabolite mediates Angiotensin II induced renal dysfunction in male mice
Hypertension, 2016Co-Authors: Ajeeth K Pingili, Mehmet Kara, Shyamala Thirunavukkarasu, Akemi Katsurada, Dewan S A Majid, Gabriel L Navar, David D Brand, Frank J Gonzalez, K U MalikAbstract:6β-Hydroxytestosterone, a cytochrome P450 1B1–derived metabolite of testosterone, contributes to the development of Angiotensin II–induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of Angiotensin II in the maintenance of renal homeostasis, development of hypertension, and end-organ damage, this study was conducted to determine the contribution of 6β-hydroxytestosterone to Angiotensin II actions on water consumption and renal function in male Cyp1b1 +/+ and Cyp1b1 −/− mice. Castration of Cyp1b1 +/+ mice or Cyp1b1 −/− gene disruption minimized the Angiotensin II–induced increase in water consumption, urine output, proteinuria, and sodium excretion and decreases in urine osmolality. 6β-Hydroxytestosterone did not alter Angiotensin II–induced increases in water intake, urine output, proteinuria, and sodium excretion or decreases in osmolality in Cyp1b1 +/+ mice, but restored these effects of Angiotensin II in Cyp1b1 −/− or castrated Cyp1b1 +/+ mice. Cyp1b1 gene disruption or castration prevented Angiotensin II–induced renal fibrosis, oxidative stress, inflammation, urinary excretion of Angiotensinogen, expression of Angiotensin II type 1 receptor, and Angiotensin-converting enzyme. 6β-Hydroxytestosterone did not alter Angiotensin II–induced renal fibrosis, inflammation, oxidative stress, urinary excretion of Angiotensinogen, expression of Angiotensin II type 1 receptor, or Angiotensin-converting enzyme in Cyp1b1 +/+ mice. However, in Cyp1b1 −/− or castrated Cyp1b1 +/+ mice, it restored these effects of Angiotensin II. These data indicate that 6β-hydroxytestosterone contributes to increased thirst, impairment of renal function, and end-organ injury associated with Angiotensin II–induced hypertension in male mice and that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension in male mice.
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cytochrome p450 1b1 contributes to renal dysfunction and damage caused by Angiotensin II in mice
Hypertension, 2012Co-Authors: Brett L Jennings, Xiao R Fang, Fariborz A Yaghini, Larry J Anderson, Jason Porter, William B. Campbell, Anne M. Estes, Frank J Gonzalez, K U MalikAbstract:Cytochrome P450 1B1 contributes to the development of Angiotensin II–induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of Angiotensin II in the kidney, as well as in salt and water homeostasis, and blood pressure regulation, we determined the contribution of cytochrome P450 1B1 to renal dysfunction and injury associated with Angiotensin II–induced hypertension in male Cyp1b1 +/+ and Cyp1b1 − / − mice. Angiotensin II infusion (700 ng/kg per minute) given by miniosmotic pumps for 13 and 28 days increased systolic blood pressure in Cyp1b1 +/+ mice; this increase was significantly reduced in Cyp1b1 − / − mice. Angiotensin II increased renal Cyp1b1 activity, vascular resistance, and reactivity to vasoconstrictor agents and caused endothelial dysfunction in Cyp1b1 +/+ but not Cyp1b1 − / − mice. Angiotensin II increased water consumption and urine output, decreased urine osmolality, increased urinary Na + and K + excretion, and caused proteinuria and albuminuria in Cyp1b1 +/+ mice that was diminished in Cyp1b1 − / − mice. Infusion of Angiotensin II for 28 but not 13 days caused renal fibrosis, tubular damage, and inflammation in Cyp1b1 +/+ mice, which was minimized in Cyp1b1 − / − mice. Angiotensin II increased levels of 12- and 20-hydroxyeicosatetraenoic acids; reactive oxygen species; and activity of NADPH oxidase, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src in the kidneys of Cyp1b1 +/+ but not Cyp1b1 − / − mice. These data suggest that increased thirst, renal dysfunction, and injury and inflammation associated with Angiotensin II–induced hypertension in mice depend on cytochrome P450 1B1 activity, thus indicating that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension.
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cytochrome p450 1b1 contributes to Angiotensin II induced hypertension and associated pathophysiology
Hypertension, 2010Co-Authors: Brett L Jennings, Seyhan Sahanfirat, Nasreen Farjana, Xiao R Fang, Anne M. Estes, Frank J Gonzalez, K U MalikAbstract:Hypertension is the leading cause of cardiovascular diseases, and Angiotensin II is one of the major components of the mechanisms that contribute to the development of hypertension. However, the precise mechanisms for the development of hypertension are unknown. Our recent study showing that Angiotensin II–induced vascular smooth muscle cell growth depends on cytochrome P450 1B1 led us to investigate its contribution to hypertension caused by this peptide. Angiotensin II was infused via miniosmotic pump into rats (150 ng/kg per minute) or mice (1000 μg/kg per day) for 13 days resulting in increased blood pressure, increased cardiac and vascular hypertrophy, increased vascular reactivity to vasoconstrictor agents, increased vascular reactive oxygen species production, and endothelial dysfunction in both species. The increase in blood pressure and associated pathophysiological changes were minimized by the cytochrome P450 1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene in both species and was markedly reduced in Cyp1b1 −/− mice. These data suggest that cytochrome P450 1B1 contributes to Angiotensin II–induced hypertension and associated pathophysiological changes. Moreover, 2,3′,4,5′-tetramethoxystilbene, which prevents both cytochrome P450 1B1–dependent and –independent components of Angiotensin II–induced hypertension and inhibits associated pathophysiological changes could be clinically useful in the treatment of hypertension and associated cardiovascular and inflammatory diseases.
Brett L Jennings - One of the best experts on this subject based on the ideXlab platform.
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cytochrome p450 1b1 contributes to renal dysfunction and damage caused by Angiotensin II in mice
Hypertension, 2012Co-Authors: Brett L Jennings, Xiao R Fang, Fariborz A Yaghini, Larry J Anderson, Jason Porter, William B. Campbell, Anne M. Estes, Frank J Gonzalez, K U MalikAbstract:Cytochrome P450 1B1 contributes to the development of Angiotensin II–induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of Angiotensin II in the kidney, as well as in salt and water homeostasis, and blood pressure regulation, we determined the contribution of cytochrome P450 1B1 to renal dysfunction and injury associated with Angiotensin II–induced hypertension in male Cyp1b1 +/+ and Cyp1b1 − / − mice. Angiotensin II infusion (700 ng/kg per minute) given by miniosmotic pumps for 13 and 28 days increased systolic blood pressure in Cyp1b1 +/+ mice; this increase was significantly reduced in Cyp1b1 − / − mice. Angiotensin II increased renal Cyp1b1 activity, vascular resistance, and reactivity to vasoconstrictor agents and caused endothelial dysfunction in Cyp1b1 +/+ but not Cyp1b1 − / − mice. Angiotensin II increased water consumption and urine output, decreased urine osmolality, increased urinary Na + and K + excretion, and caused proteinuria and albuminuria in Cyp1b1 +/+ mice that was diminished in Cyp1b1 − / − mice. Infusion of Angiotensin II for 28 but not 13 days caused renal fibrosis, tubular damage, and inflammation in Cyp1b1 +/+ mice, which was minimized in Cyp1b1 − / − mice. Angiotensin II increased levels of 12- and 20-hydroxyeicosatetraenoic acids; reactive oxygen species; and activity of NADPH oxidase, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src in the kidneys of Cyp1b1 +/+ but not Cyp1b1 − / − mice. These data suggest that increased thirst, renal dysfunction, and injury and inflammation associated with Angiotensin II–induced hypertension in mice depend on cytochrome P450 1B1 activity, thus indicating that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension.
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cytochrome p450 1b1 contributes to Angiotensin II induced hypertension and associated pathophysiology
Hypertension, 2010Co-Authors: Brett L Jennings, Seyhan Sahanfirat, Nasreen Farjana, Xiao R Fang, Anne M. Estes, Frank J Gonzalez, K U MalikAbstract:Hypertension is the leading cause of cardiovascular diseases, and Angiotensin II is one of the major components of the mechanisms that contribute to the development of hypertension. However, the precise mechanisms for the development of hypertension are unknown. Our recent study showing that Angiotensin II–induced vascular smooth muscle cell growth depends on cytochrome P450 1B1 led us to investigate its contribution to hypertension caused by this peptide. Angiotensin II was infused via miniosmotic pump into rats (150 ng/kg per minute) or mice (1000 μg/kg per day) for 13 days resulting in increased blood pressure, increased cardiac and vascular hypertrophy, increased vascular reactivity to vasoconstrictor agents, increased vascular reactive oxygen species production, and endothelial dysfunction in both species. The increase in blood pressure and associated pathophysiological changes were minimized by the cytochrome P450 1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene in both species and was markedly reduced in Cyp1b1 −/− mice. These data suggest that cytochrome P450 1B1 contributes to Angiotensin II–induced hypertension and associated pathophysiological changes. Moreover, 2,3′,4,5′-tetramethoxystilbene, which prevents both cytochrome P450 1B1–dependent and –independent components of Angiotensin II–induced hypertension and inhibits associated pathophysiological changes could be clinically useful in the treatment of hypertension and associated cardiovascular and inflammatory diseases.