The Experts below are selected from a list of 837 Experts worldwide ranked by ideXlab platform
Yufeng Huang - One of the best experts on this subject based on the ideXlab platform.
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receptor mediated nonproteolytic activation of prorenin and induction of tgf β1 and pai 1 expression in renal mesangial cells
American Journal of Physiology-renal Physiology, 2012Co-Authors: Jiandong Zhang, Nancy A Noble, Wayne A Border, Yufeng HuangAbstract:While elevated plasma prorenin levels are commonly found in diabetic patients and correlate with diabetic nephropathy, the pathological role of prorenin, if any, remains unclear. Prorenin binding to the (pro)renin receptor [(p)RR] unmasks prorenin catalytic activity. We asked whether elevated prorenin could be activated at the site of renal mesangial cells (MCs) through receptor binding without being proteolytically converted to renin. Recombinant inactive rat prorenin and a mutant prorenin that is noncleavable, i.e., cannot be activated proteolytically, are produced in 293 cells. After MCs were incubated with 10−7 M native or mutant prorenin for 6 h, cultured supernatant acquired the ability to generate angiotensin I (ANG I) from angiotensinogen, indicating both prorenins were activated. Small interfering RNA (siRNA) against the (p)RR blocked their activation. Furthermore, either native or mutant rat prorenin at 10−7 M alone similarly and significantly induced transforming growth factor-β1, plasminogen activator inhibitor-1 (PAI-1), and fibronectin mRNA expression, and these effects were blocked by (p)RR siRNA, but not by the ANG II receptor antagonist, Saralasin. When angiotensinogen was also added to cultured MCs with inactive native or mutant prorenin, PAI-1 and fibronectin were further increased significantly compared with prorenin or mutant prorenin alone. This effect was blocked partially by treatment with (p)RR siRNA or Saralasin. We conclude that prorenin binds the (p)RR on renal MCs and is activated nonproteolytically. This activation leads to increased expression of PAI-1 and transforming growth factor-β1 via ANG II-independent and ANG II-dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may play a role in the development of diabetic nephropathy.
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receptor dependent prorenin activation and induction of pai 1 expression in vascular smooth muscle cells
American Journal of Physiology-endocrinology and Metabolism, 2008Co-Authors: Jiandong Zhang, Nancy A Noble, Wayne A Border, Rick T Owens, Yufeng HuangAbstract:Although elevated plasma prorenin levels are commonly found in diabetic patients and correlate with microvascular complications, the pathological role of these increases, if any, remains unclear. Prorenin/renin binding to the prorenin/renin receptor [(p)RR] enhances the efficiency of angiotensinogen cleavage by renin and unmasks prorenin catalytic activity. We asked whether plasma prorenin could be activated in local vascular tissue through receptor binding. Immunohistochemical staining showing localization of the (p)RR in the aorta to vascular smooth muscle cells (VSMCs). After cultured rat VSMCs were incubated with 10−7 M inactive prorenin, cultured supernatant acquired the ability to generate ANG I from angiotensinogen, indicating that prorenin had been activated. Activated prorenin facilitated angiotensin generation in cultured VSMCs when exogenous angiotensinogen was added. Small interfering RNA (siRNA) against the (p)RR blocked this activation and subsequent angiotensin generation. Prorenin alone induced dose- and time-dependent increases in mRNA and protein for the profibrotic molecule plasminogen activator inhibitor (PAI)-1, effects that were blocked by siRNA, but not by the ANG II receptor antagonist Saralasin. When inactive prorenin and angiotensinogen were incubated with cells, PAI-1 mRNA increased a striking 54-fold, 8-fold higher than the increase seen with prorenin alone. PAI-1 protein increased 2.75-fold. These effects were blocked by treatment with siRNA + Saralasin. We conclude that prorenin at high concentration binds the (p)RR on VSMCs and is activated. This activation leads to increased expression of PAI-1 via ANG II-independent and -dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may contribute to the progression of fibrotic disease.
Michel Burnier - One of the best experts on this subject based on the ideXlab platform.
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angiotensin ii type 1 receptor blockers
Circulation, 2001Co-Authors: Michel BurnierAbstract:In the 1970s, a series of observations demonstrated that angiotensin II has deleterious effects on the heart and kidney and that patients with high levels of plasma renin activity are at a higher risk of developing stroke or myocardial infarction than those with low plasma renin activity.1 2 Thereafter, the development of pharmacological probes that block the renin-angiotensin system helped define the contribution of this system to blood pressure control and to the pathogenesis of diseases such as hypertension, congestive heart failure, and chronic renal failure. Thus, the concept of treating hypertension and congestive heart failure by a specific blockade of the renin-angiotensin system was first established with the use of Saralasin, a nonselective peptidic antagonist of angiotensin II receptors.3 4 5 6 7 8 9 With Saralasin, it became possible to demonstrate that angiotensin II receptor blockade, alone or in combination with salt depletion, lowers blood pressure in hypertensive patients and improves systemic hemodynamics in patients with congestive heart failure.3 4 5 6 7 8 9 10 However, Saralasin had many drawbacks. Because it is a peptide, it had to be administered intravenously. This characteristic limited its use to hours or a few days at maximum. In addition, at higher doses, Saralasin had some partial agonist, angiotensin II–like effects. The next major breakthrough in the understanding of the renin-angiotensin system was triggered by the development of orally active angiotensin-converting enzyme (ACE) inhibitors.10 11 12 13 14 15 Studies performed with these agents rapidly confirmed and reinforced the seminal clinical observations made with Saralasin. ACE inhibitors are now recognized as an important therapeutic step to control blood pressure in hypertensive patients and to reduce morbidity and mortality in patients with congestive heart failure.16 In addition, because of their ability to lower proteinuria, ACE inhibitors have …
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Angiotensin II antagonists.
Clinical and experimental hypertension (New York N.Y. : 1993), 1993Co-Authors: Hans R. Brunner, Michel Burnier, Jürg Nussberger, Bernard WaeberAbstract:Acute blockade of the renin-angiotensin system with the parenterally active angiotensin II antagonist Saralasin has been shown to effectively lower blood pressure in a large fraction of patients with essential hypertension and to improve hemodynamics in some patients with congestive heart failure. It is now possible to antagonize chronically angiotensin II at its receptor using the non-peptide angiotensin II inhibitor losartan (DuP 753, MK 954). When administered by mouth, this compound induces a dose-dependent inhibition of the pressor response to exogenous angiotensin II. This effect is closely related to circulating levels of the active metabolite E3174. Preliminary studies performed in hypertensive patients suggest that losartan has a blood pressure lowering action equivalent to that of an ACE inhibitor. Whether this compound will compare favorably with ACE inhibitors requires however further investigation.
Jiandong Zhang - One of the best experts on this subject based on the ideXlab platform.
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receptor mediated nonproteolytic activation of prorenin and induction of tgf β1 and pai 1 expression in renal mesangial cells
American Journal of Physiology-renal Physiology, 2012Co-Authors: Jiandong Zhang, Nancy A Noble, Wayne A Border, Yufeng HuangAbstract:While elevated plasma prorenin levels are commonly found in diabetic patients and correlate with diabetic nephropathy, the pathological role of prorenin, if any, remains unclear. Prorenin binding to the (pro)renin receptor [(p)RR] unmasks prorenin catalytic activity. We asked whether elevated prorenin could be activated at the site of renal mesangial cells (MCs) through receptor binding without being proteolytically converted to renin. Recombinant inactive rat prorenin and a mutant prorenin that is noncleavable, i.e., cannot be activated proteolytically, are produced in 293 cells. After MCs were incubated with 10−7 M native or mutant prorenin for 6 h, cultured supernatant acquired the ability to generate angiotensin I (ANG I) from angiotensinogen, indicating both prorenins were activated. Small interfering RNA (siRNA) against the (p)RR blocked their activation. Furthermore, either native or mutant rat prorenin at 10−7 M alone similarly and significantly induced transforming growth factor-β1, plasminogen activator inhibitor-1 (PAI-1), and fibronectin mRNA expression, and these effects were blocked by (p)RR siRNA, but not by the ANG II receptor antagonist, Saralasin. When angiotensinogen was also added to cultured MCs with inactive native or mutant prorenin, PAI-1 and fibronectin were further increased significantly compared with prorenin or mutant prorenin alone. This effect was blocked partially by treatment with (p)RR siRNA or Saralasin. We conclude that prorenin binds the (p)RR on renal MCs and is activated nonproteolytically. This activation leads to increased expression of PAI-1 and transforming growth factor-β1 via ANG II-independent and ANG II-dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may play a role in the development of diabetic nephropathy.
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receptor dependent prorenin activation and induction of pai 1 expression in vascular smooth muscle cells
American Journal of Physiology-endocrinology and Metabolism, 2008Co-Authors: Jiandong Zhang, Nancy A Noble, Wayne A Border, Rick T Owens, Yufeng HuangAbstract:Although elevated plasma prorenin levels are commonly found in diabetic patients and correlate with microvascular complications, the pathological role of these increases, if any, remains unclear. Prorenin/renin binding to the prorenin/renin receptor [(p)RR] enhances the efficiency of angiotensinogen cleavage by renin and unmasks prorenin catalytic activity. We asked whether plasma prorenin could be activated in local vascular tissue through receptor binding. Immunohistochemical staining showing localization of the (p)RR in the aorta to vascular smooth muscle cells (VSMCs). After cultured rat VSMCs were incubated with 10−7 M inactive prorenin, cultured supernatant acquired the ability to generate ANG I from angiotensinogen, indicating that prorenin had been activated. Activated prorenin facilitated angiotensin generation in cultured VSMCs when exogenous angiotensinogen was added. Small interfering RNA (siRNA) against the (p)RR blocked this activation and subsequent angiotensin generation. Prorenin alone induced dose- and time-dependent increases in mRNA and protein for the profibrotic molecule plasminogen activator inhibitor (PAI)-1, effects that were blocked by siRNA, but not by the ANG II receptor antagonist Saralasin. When inactive prorenin and angiotensinogen were incubated with cells, PAI-1 mRNA increased a striking 54-fold, 8-fold higher than the increase seen with prorenin alone. PAI-1 protein increased 2.75-fold. These effects were blocked by treatment with siRNA + Saralasin. We conclude that prorenin at high concentration binds the (p)RR on VSMCs and is activated. This activation leads to increased expression of PAI-1 via ANG II-independent and -dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may contribute to the progression of fibrotic disease.
Adebayo Oyekan - One of the best experts on this subject based on the ideXlab platform.
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vascular responses to endothelin 1 angiotensin ii and u46619 in glycerol induced acute renal failure
Journal of Cardiovascular Pharmacology, 2001Co-Authors: Mohammad Newaz, Adebayo OyekanAbstract:Angiotensin II and endothelin-1, major endogenous vasoconstrictors in acute renal failure (ARF), can modulate the effects of each other. This study aimed to evaluate the interaction between these vasoconstrictors in glycerol-induced ARF by evaluating their effects in the isolated perfused kidney in the presence of their respective antagonists. In ARF, angiotensin II (2.5-25 ng) caused an increase in perfusion pressure. Saralasin, 1 microM, a nonselective angiotensin receptor antagonist, reduced these responses by 61+/- 6% (p 0.05). BQ610 and BQ788 combination further reduced vasoconstriction by 89 +/- 3% (p < 0.05). Responses to U46619 were not changed in ARF. However, Saralasin and BQ788, but not BQ610, attenuated its vasoconstrictor action. We conclude that vascular responses in ARF may be attributed to enhanced responses to angiotensin II through activation of ETB and/or PGH2 /thromboxane A2 receptors. We also suggest that the vasoconstrictor response to endothelin-1 in ARF is predominantly ETB receptor-mediated.
Nancy A Noble - One of the best experts on this subject based on the ideXlab platform.
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receptor mediated nonproteolytic activation of prorenin and induction of tgf β1 and pai 1 expression in renal mesangial cells
American Journal of Physiology-renal Physiology, 2012Co-Authors: Jiandong Zhang, Nancy A Noble, Wayne A Border, Yufeng HuangAbstract:While elevated plasma prorenin levels are commonly found in diabetic patients and correlate with diabetic nephropathy, the pathological role of prorenin, if any, remains unclear. Prorenin binding to the (pro)renin receptor [(p)RR] unmasks prorenin catalytic activity. We asked whether elevated prorenin could be activated at the site of renal mesangial cells (MCs) through receptor binding without being proteolytically converted to renin. Recombinant inactive rat prorenin and a mutant prorenin that is noncleavable, i.e., cannot be activated proteolytically, are produced in 293 cells. After MCs were incubated with 10−7 M native or mutant prorenin for 6 h, cultured supernatant acquired the ability to generate angiotensin I (ANG I) from angiotensinogen, indicating both prorenins were activated. Small interfering RNA (siRNA) against the (p)RR blocked their activation. Furthermore, either native or mutant rat prorenin at 10−7 M alone similarly and significantly induced transforming growth factor-β1, plasminogen activator inhibitor-1 (PAI-1), and fibronectin mRNA expression, and these effects were blocked by (p)RR siRNA, but not by the ANG II receptor antagonist, Saralasin. When angiotensinogen was also added to cultured MCs with inactive native or mutant prorenin, PAI-1 and fibronectin were further increased significantly compared with prorenin or mutant prorenin alone. This effect was blocked partially by treatment with (p)RR siRNA or Saralasin. We conclude that prorenin binds the (p)RR on renal MCs and is activated nonproteolytically. This activation leads to increased expression of PAI-1 and transforming growth factor-β1 via ANG II-independent and ANG II-dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may play a role in the development of diabetic nephropathy.
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receptor dependent prorenin activation and induction of pai 1 expression in vascular smooth muscle cells
American Journal of Physiology-endocrinology and Metabolism, 2008Co-Authors: Jiandong Zhang, Nancy A Noble, Wayne A Border, Rick T Owens, Yufeng HuangAbstract:Although elevated plasma prorenin levels are commonly found in diabetic patients and correlate with microvascular complications, the pathological role of these increases, if any, remains unclear. Prorenin/renin binding to the prorenin/renin receptor [(p)RR] enhances the efficiency of angiotensinogen cleavage by renin and unmasks prorenin catalytic activity. We asked whether plasma prorenin could be activated in local vascular tissue through receptor binding. Immunohistochemical staining showing localization of the (p)RR in the aorta to vascular smooth muscle cells (VSMCs). After cultured rat VSMCs were incubated with 10−7 M inactive prorenin, cultured supernatant acquired the ability to generate ANG I from angiotensinogen, indicating that prorenin had been activated. Activated prorenin facilitated angiotensin generation in cultured VSMCs when exogenous angiotensinogen was added. Small interfering RNA (siRNA) against the (p)RR blocked this activation and subsequent angiotensin generation. Prorenin alone induced dose- and time-dependent increases in mRNA and protein for the profibrotic molecule plasminogen activator inhibitor (PAI)-1, effects that were blocked by siRNA, but not by the ANG II receptor antagonist Saralasin. When inactive prorenin and angiotensinogen were incubated with cells, PAI-1 mRNA increased a striking 54-fold, 8-fold higher than the increase seen with prorenin alone. PAI-1 protein increased 2.75-fold. These effects were blocked by treatment with siRNA + Saralasin. We conclude that prorenin at high concentration binds the (p)RR on VSMCs and is activated. This activation leads to increased expression of PAI-1 via ANG II-independent and -dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may contribute to the progression of fibrotic disease.
