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Richard J Roman - One of the best experts on this subject based on the ideXlab platform.
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abstract p160 dual specificity protein phosphatase 5 regulates renal vessel Myogenic Response via direct modulating extracellular signal related kinase and protein kinase c
Hypertension, 2019Co-Authors: Wenjun Gao, Richard J Roman, Shaoxun Wang, Huawei Zhang, George W Booz, Fan FanAbstract:Dual-specificity protein phosphatase 5 (DUSP5) is a serine-threonine phosphatase that regulates intracellular signal transduction by dephosphorylating extracellular signal-related kinase (ERK1/2) a...
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knockdown of add3 impairs the Myogenic Response of renal afferent arterioles and middle cerebral arteries
American Journal of Physiology-renal Physiology, 2017Co-Authors: Fan Fan, Mallikarjuna R Pabbidi, Shaoxun Wang, Paige N Mims, Richard J RomanAbstract:We have reported that the Myogenic Response of the renal afferent arteriole (Af-art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow are impaired in Fawn-Hooded...
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impaired Myogenic Response of the afferent arteriole contributes to the increased susceptibility to renal disease in milan normotensive rats
Physiological Reports, 2017Co-Authors: Ying Ge, Sean P Didion, Richard J RomanAbstract:Abstract Milan normotensive (MNS) rats are more susceptible to the development of renal disease than Milan hypertensive (MHS) rats, but the genes and pathways involved are unknown. This study compared the Myogenic Response of isolated perfused afferent arterioles (Af‐Art) and autoregulation of renal blood flow (RBF) and glomerular capillary pressure (Pgc) in 6–9‐week‐old MNS and MHS rats. The diameter of the Af‐Art of MHS rats decreased significantly from 14.3 ± 0.5 to 11.5 ± 0.6 μ m when perfusion pressure was elevated from 60 to 120 mmHg. In contrast, the diameter of Af‐Art of MNS rats did not decrease. RBF was well autoregulated in MHS rats, but it increased by 26% in MNS rats. Pgc rose by 11 mmHg when renal perfusion pressure (RPP) was increased from 100 to 140 mmHg in MNS but not in MHS rats. Protein excretion increased from 10 ± 1 to 245 ± 36 mg/day in MNS rats as they aged from 3 to 11 months but it did not increase in MHS rats. We also compared the development of proteinuria in MNS and MHS rats following the induction of diabetes with streptozotocin. Protein excretion rose from 16 ± 3 to 234 ± 43 mg/day in MNS rats, but it remained unaltered in MHS rats. These data indicate that the Myogenic Response of the Af‐art is impaired in MNS rats and increased transmission of pressure to the glomerulus may contribute to renal injury in MNS rats similar to what is seen in fawn‐hooded hypertensive and Dahl salt‐sensitive rats.
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Molecular Mechanisms of Renal Blood Flow Autoregulation
2016Co-Authors: Marilyn Burke, Mallikarjuna R Pabbidi, Jerry Farley, Richard J RomanAbstract:Abstract: Diabetes and hypertension are the leading causes of chronic kidney disease and their incidence is increasing at an alarming rate. Both are associated with impairments in the autoregulation of renal blood flow (RBF) and greater trans-mission of fluctuations in arterial pressure to the glomerular capillaries. The ability of the kidney to maintain relatively constant blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure is mediated by the Myogenic re-sponse of afferent arterioles working in concert with tubuloglomerular feedback that adjusts the tone of the afferent arteri-ole in Response to changes in the delivery of sodium chloride to the macula densa. Despite intensive investigation, the fac-tors initiating the Myogenic Response and the signaling pathways involved in the Myogenic Response and tubuloglomerular feedback remain uncertain. This review focuses on current thought regarding the molecular mechanisms underlying myo-genic control of renal vascular tone, the interrelationships between the Myogenic Response and tubuloglomerular feedback, the evidence that alterations in autoregulation of RBF contributes to hypertension and diabetes-induced nephropathy and the identification of vascular therapeutic targets for improved renoprotection in hypertensive and diabetic patients
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impaired Myogenic Response and autoregulation of cerebral blood flow is rescued in cyp4a1 transgenic dahl salt sensitive rat
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2015Co-Authors: Aron M Geurts, Mallikarjuna R Pabbidi, Howard J Jacob, Sydney R Murphy, Richard J RomanAbstract:We have reported that a reduction in renal production of 20-HETE contributes to development of hypertension in Dahl salt-sensitive (SS) rats. The present study examined whether 20-HETE production is also reduced in the cerebral vasculature of SS rats and whether this impairs the Myogenic Response and autoregulation of cerebral blood flow (CBF). The production of 20-HETE, the Myogenic Response of middle cerebral arteries (MCA), and autoregulation of CBF were compared in SS, SS-5BN rats and a newly generated CYP4A1 transgenic rat. 20-HETE production was 6-fold higher in cerebral arteries of CYP4A1 and SS-5BN than in SS rats. The diameter of the MCA decreased to 70 ± 3% to 65 ± 6% in CYP4A1 and SS-5BN rats when pressure was increased from 40 to 140 mmHg. In contrast, the Myogenic Response of MCA isolated from SS rats did not constrict. Administration of a 20-HETE synthesis inhibitor, HET0016, abolished the Myogenic Response of MCA in CYP4A1 and SS-5BN rats but had no effect in SS rats. Autoregulation of CBF was impaired in SS rats compared with CYP4A1 and SS-5BN rats. Blood-brain barrier leakage was 5-fold higher in the brain of SS rats than in SS-5BN and SS.CYP4A1 rats. These findings indicate that a genetic deficiency in the formation of 20-HETE contributes to an impaired Myogenic Response in MCA and autoregulation of CBF in SS rats and this may contribute to vascular remodeling and cerebral injury following the onset of hypertension.
Anita T. Layton - One of the best experts on this subject based on the ideXlab platform.
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theoretical assessment of the ca2 oscillations in the afferent arteriole smooth muscle cell of the rat kidney
International Journal of Biomathematics, 2018Co-Authors: Anita T. LaytonAbstract:The afferent arteriole (AA) of rat kidney exhibits the Myogenic Response, in which the vessel constricts in Response to an elevation in blood pressure and dilates in Response to a pressure reductio...
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introduction to mathematical modeling of blood flow control in the kidney
2017Co-Authors: Anita T. Layton, Aurelie EdwardsAbstract:Besides its best known role in the excretion of metabolic wastes and toxins, the kidney also plays an indispensable role in regulating the balance of water, electrolytes, acid–base species, blood volume, and blood pressure. To properly fulfill its functions, it is crucial for the kidney to exercise hemodynamic control. In this review, we describe representative mathematical models that have been developed to better understand the kidney’s autoregulatory processes. In particular, we consider mathematical models that simulate renal blood flow regulation by means of key autoregulatory mechanisms: the Myogenic Response and tubuloglomerular feedback. We discuss the extent to which these modeling efforts have expanded the understanding of renal functions in health and diseases.
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Modeling the effects of positive and negative feedback in kidney blood flow control.
Bellman Prize in Mathematical Biosciences, 2016Co-Authors: Anita T. LaytonAbstract:Abstract Blood flow in the mammalian kidney is tightly autoregulated. One of the important autoregulation mechanisms is the Myogenic Response, which is activated by perturbations in blood pressure along the afferent arteriole. Another is the tubuloglomerular feedback, which is a negative feedback that responds to variations in tubular fluid [Cl − ] at the macula densa. 1 When initiated, both the Myogenic Response and the tubuloglomerular feedback adjust the afferent arteriole muscle tone. A third mechanism is the connecting tubule glomerular feedback, which is a positive feedback mechanism located at the connecting tubule, downstream of the macula densa. The connecting tubule glomerular feedback is much less well studied. The goal of this study is to investigate the interactions among these feedback mechanisms and to better understand the effects of their interactions. To that end, we have developed a mathematical model of solute transport and blood flow control in the rat kidney. The model represents the Myogenic Response, tubuloglomerular feedback, and connecting tubule glomerular feedback. By conducting a bifurcation analysis, we studied the stability of the system under a range of physiologically-relevant parameters. The bifurcation results were confirmed by means of a comparison with numerical simulations. Additionally, we conducted numerical simulations to test the hypothesis that the interactions between the tubuloglomerular feedback and the connecting tubule glomerular feedback may give rise to a yet-to-be-explained low-frequency oscillation that has been observed in experimental records.
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conduction of feedback mediated signal in a computational model of coupled nephrons
Mathematical Medicine and Biology-a Journal of The Ima, 2016Co-Authors: Ioannis Sgouralis, Anita T. LaytonAbstract:The nephron in the kidney regulates its fluid flow by several autoregulatory mechanisms. Two primary mechanisms are the Myogenic Response and the tubuloglomerular feedback (TGF). The Myogenic Response is a property of the pre-glomerular vasculature in which a rise in intravascular pressure elicits vasoconstriction that generates a compensatory increase in vascular resistance. TGF is a negative feedback Response that balances glomerular filtration with tubular reabsorptive capacity. While each nephron has its own autoregulatory Response, the Responses of the kidney's many nephrons do not act autonomously but are instead coupled through the pre-glomerular vasculature. To better understand the conduction of these signals along the pre-glomerular arterioles and the impacts of internephron coupling on nephron flow dynamics, we developed a mathematical model of renal haemodynamics of two neighbouring nephrons that are coupled in that their afferent arterioles arise from a common cortical radial artery. Simulations were conducted to estimate internephron coupling strength, determine its dependence on vascular properties and to investigate the effect of coupling on TGF-mediated flow oscillations. Simulation results suggest that reduced gap-junctional conductances may yield stronger internephron TGF coupling and highly irregular TGF-mediated oscillations in nephron dynamics, both of which experimentally have been associated with hypertensive rats.
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mathematical modeling of renal hemodynamics in physiology and pathophysiology
Bellman Prize in Mathematical Biosciences, 2015Co-Authors: Ioannis Sgouralis, Anita T. LaytonAbstract:In addition to the excretion of metabolic waste and toxin, the kidney plays an indispensable role in regulating the balance of water, electrolyte, acid-base, and blood pressure. For the kidney to maintain proper functions, hemodynamic control is crucial. In this review, we describe representative mathematical models that have been developed to better understand the kidney's autoregulatory processes. We consider mathematical models that simulate glomerular filtration, and renal blood flow regulation by means of the Myogenic Response and tubuloglomerular feedback. We discuss the extent to which these modeling efforts have expanded the understanding of renal functions in health and disease.
Fan Fan - One of the best experts on this subject based on the ideXlab platform.
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a mutation in γ adducin impairs autoregulation of renal blood flow and promotes the development of kidney disease
Journal of The American Society of Nephrology, 2020Co-Authors: Fan Fan, Aron M Geurts, Mallikarjuna R Pabbidi, Shaoxun Wang, Wenjun Gao, Chao Zhang, Yedan Liu, Ya Guo, Yoshikazu Muroya, Takashi HirataAbstract:BACKGROUND The genes and mechanisms involved in the association between diabetes or hypertension and CKD risk are unclear. Previous studies have implicated a role for γ-adducin (ADD3), a cytoskeletal protein encoded by Add3. METHODS We investigated renal vascular function in vitro and in vivo and the susceptibility to CKD in rats with wild-type or mutated Add3 and in genetically modified rats with overexpression or knockout of ADD3. We also studied glomeruli and primary renal vascular smooth muscle cells isolated from these rats. RESULTS This study identified a K572Q mutation in ADD3 in fawn-hooded hypertensive (FHH) rats-a mutation previously reported in Milan normotensive (MNS) rats that also develop kidney disease. Using molecular dynamic simulations, we found that this mutation destabilizes a critical ADD3-ACTIN binding site. A reduction of ADD3 expression in membrane fractions prepared from the kidney and renal vascular smooth muscle cells of FHH rats was associated with the disruption of the F-actin cytoskeleton. Compared with renal vascular smooth muscle cells from Add3 transgenic rats, those from FHH rats had elevated membrane expression of BKα and BK channel current. FHH and Add3 knockout rats exhibited impairments in the Myogenic Response of afferent arterioles and in renal blood flow autoregulation, which were rescued in Add3 transgenic rats. We confirmed these findings in a genetic complementation study that involved crossing FHH and MNS rats that share the ADD3 mutation. Add3 transgenic rats showed attenuation of proteinuria, glomerular injury, and kidney fibrosis with aging and mineralocorticoid-induced hypertension. CONCLUSIONS This is the first report that a mutation in ADD3 that alters ACTIN binding causes renal vascular dysfunction and promotes the susceptibility to kidney disease.
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abstract p160 dual specificity protein phosphatase 5 regulates renal vessel Myogenic Response via direct modulating extracellular signal related kinase and protein kinase c
Hypertension, 2019Co-Authors: Wenjun Gao, Richard J Roman, Shaoxun Wang, Huawei Zhang, George W Booz, Fan FanAbstract:Dual-specificity protein phosphatase 5 (DUSP5) is a serine-threonine phosphatase that regulates intracellular signal transduction by dephosphorylating extracellular signal-related kinase (ERK1/2) a...
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knockdown of add3 impairs the Myogenic Response of renal afferent arterioles and middle cerebral arteries
American Journal of Physiology-renal Physiology, 2017Co-Authors: Fan Fan, Mallikarjuna R Pabbidi, Shaoxun Wang, Paige N Mims, Richard J RomanAbstract:We have reported that the Myogenic Response of the renal afferent arteriole (Af-art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow are impaired in Fawn-Hooded...
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zinc finger nuclease knockout of dual specificity protein phosphatase 5 enhances the Myogenic Response and autoregulation of cerebral blood flow in fhh 1bn rats
PLOS ONE, 2014Co-Authors: Fan Fan, Aron M Geurts, Mallikarjuna R Pabbidi, Stanley V Smith, David R Harder, Howard J Jacob, Richard J RomanAbstract:We recently reported that the Myogenic Responses of the renal afferent arteriole (Af-Art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow (RBF and CBF) were impaired in Fawn Hooded hypertensive (FHH) rats and were restored in a FHH.1BN congenic strain in which a small segment of chromosome 1 from the Brown Norway (BN) containing 15 genes including dual-specificity protein phosphatase-5 (Dusp5) were transferred into the FHH genetic background. We identified 4 single nucleotide polymorphisms in the Dusp5 gene in FHH as compared with BN rats, two of which altered CpG sites and another that caused a G155R mutation. To determine whether Dusp5 contributes to the impaired Myogenic Response in FHH rats, we created a Dusp5 knockout (KO) rat in the FHH.1BN genetic background using a zinc-finger nuclease that introduced an 11 bp frame-shift deletion and a premature stop codon at AA121. The expression of Dusp5 was decreased and the levels of its substrates, phosphorylated ERK1/2 (p-ERK1/2), were enhanced in the KO rats. The diameter of the MCA decreased to a greater extent in Dusp5 KO rats than in FHH.1BN and FHH rats when the perfusion pressure was increased from 40 to 140 mmHg. CBF increased markedly in FHH rats when MAP was increased from 100 to 160 mmHg, and CBF was better autoregulated in the Dusp5 KO and FHH.1BN rats. The expression of Dusp5 was higher at the mRNA level but not at the protein level and the levels of p-ERK1/2 and p-PKC were lower in cerebral microvessels and brain tissue isolated from FHH than in FHH.1BN rats. These results indicate that Dusp5 modulates Myogenic reactivity in the cerebral circulation and support the view that a mutation in Dusp5 may enhance Dusp5 activity and contribute to the impaired Myogenic Response in FHH rats.
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abstract 223 zinc finger nuclease knockout of dual specificity protein phosphatase 5 enhances Myogenic Response in autoregulation of cerebral blood flow in fhh 1bn rats
Hypertension, 2014Co-Authors: Fan Fan, Aron M Geurts, Mallikarjuna R Pabbidi, David R Harder, Howard J Jacob, Richard J RomanAbstract:We recently reported that the pressure-induced Myogenic Responses of afferent arteries (Af-Art) and middle cerebral arteries (MCAs) were impaired in the fawn hooded hypertensive (FHH) rats and were restored in FHH.1BN congenic strain in which chromosome 1 from the Brown Norway (BN) rats containing 11 genes including dual-specificity protein phosphatase-5 (Dusp5) was transferred into FHH genetic background. There are 4 single nucleotide polymorphisms (SNP) in Dusp5 in FHH as compared with BN rats, one of which causes G155R mutation. To determine whether Dusp5 contributes to the impaired vascular Myogenic Response in FHH rats, we created a Dusp5 knockout (KO) rats in the FHH.1BN genetic background using zinc-finger nuclease (ZFN) that introduced a premature stop codon at amino acid (AA) 121. The expression of Dusp5 in KO rats were significantly decreased and the level of phosphorylated ERK2 (p-ERK2) was significantly increased in multiple organs including liver, spleen and white blood cells (WBCs). The luminal diameter of the MCAs in FHH.1BN rats (n=12) decreased 20 ± 2 % when the perfusion pressure was increased from 40 to 140 mmHg, whereas it decreased 34 ± 7 % in Dusp5 KO rats (n=6) and increased 10 ± 4% in FHH strain (n=8). Autoregulation was markedly impaired and CBF increased by 54 ± 6% in FHH rats when MAP was increased from 100 to 160 mmHg. CBF was better autoregulated in FHH.1BN strain and Dusp5 KO rats increased by only 26 ± 3% and 12 ± 3% when MAP was increased over the same range. However, the range of autoregulation of CBF was extended in the FHH rats (n=7) in that CBF rose to 107 ± 6% in FHH.1BN rats (n=7) when pressure was increased to 190 mmHg versus 33 ± 4% in the Dusp5 KO animals (n=6). These results suggest that Dusp5 plays an important role in modulating of Myogenic tone in the cerebral circulation. Unless the G155R mutation activates Dusp5 in FHH rats, it is unlikely that Dusp5 is responsible for the impaired Myogenic Response in FHH rats.
Mallikarjuna R Pabbidi - One of the best experts on this subject based on the ideXlab platform.
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a mutation in γ adducin impairs autoregulation of renal blood flow and promotes the development of kidney disease
Journal of The American Society of Nephrology, 2020Co-Authors: Fan Fan, Aron M Geurts, Mallikarjuna R Pabbidi, Shaoxun Wang, Wenjun Gao, Chao Zhang, Yedan Liu, Ya Guo, Yoshikazu Muroya, Takashi HirataAbstract:BACKGROUND The genes and mechanisms involved in the association between diabetes or hypertension and CKD risk are unclear. Previous studies have implicated a role for γ-adducin (ADD3), a cytoskeletal protein encoded by Add3. METHODS We investigated renal vascular function in vitro and in vivo and the susceptibility to CKD in rats with wild-type or mutated Add3 and in genetically modified rats with overexpression or knockout of ADD3. We also studied glomeruli and primary renal vascular smooth muscle cells isolated from these rats. RESULTS This study identified a K572Q mutation in ADD3 in fawn-hooded hypertensive (FHH) rats-a mutation previously reported in Milan normotensive (MNS) rats that also develop kidney disease. Using molecular dynamic simulations, we found that this mutation destabilizes a critical ADD3-ACTIN binding site. A reduction of ADD3 expression in membrane fractions prepared from the kidney and renal vascular smooth muscle cells of FHH rats was associated with the disruption of the F-actin cytoskeleton. Compared with renal vascular smooth muscle cells from Add3 transgenic rats, those from FHH rats had elevated membrane expression of BKα and BK channel current. FHH and Add3 knockout rats exhibited impairments in the Myogenic Response of afferent arterioles and in renal blood flow autoregulation, which were rescued in Add3 transgenic rats. We confirmed these findings in a genetic complementation study that involved crossing FHH and MNS rats that share the ADD3 mutation. Add3 transgenic rats showed attenuation of proteinuria, glomerular injury, and kidney fibrosis with aging and mineralocorticoid-induced hypertension. CONCLUSIONS This is the first report that a mutation in ADD3 that alters ACTIN binding causes renal vascular dysfunction and promotes the susceptibility to kidney disease.
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peripheral anti angiogenic imbalance during pregnancy impairs Myogenic tone and increases cerebral edema in a rodent model of hellp syndrome
Brain Sciences, 2018Co-Authors: Cynthia Bean, Mallikarjuna R Pabbidi, Shaunakay Spencer, Jamie Szczepanski, Sarah Araji, Sellena Dixon, Kedra WallaceAbstract:Using an animal model of hemolysis elevated liver enzymes low platelets (HELLP) that has systemic inflammation and neuroinflammation we wanted to determine if blood brain barrier (BBB) permeability, cerebral edema, vascular tone, and occludin expression were altered in pregnant rats. Anti-angiogenic proteins sFlt-1 and sEng (4.7 and 7 µg/kg/day, respectively) were chronically infused into normal pregnant (NP) rats beginning on gestational day 12 via a mini-osmotic pump. On gestational day 19, blood pressure was measured via a carotid catheter and brains were collected. BBB permeability was assessed in select brain regions from rats infused with 0.5 mg/mL Texas Red Dextran and phenylephrine. Occludin, sFlt-1, and sEng were analyzed via western blot or ELISA. Infusion of sFlt-1 and sEng into NP rats increased hemolysis and liver enzymes, and decreased platelets and led to hypertension. HELLP rats had significant impairment in the Myogenic Response and increased BBB permeability in the posterior cortex and brainstem. Brain water content in the posterior cortex was increased and sEng protein expression in the brainstem was significantly increased in HELLP rats. The results from this study suggest that a peripheral anti-angiogenic imbalance during pregnancy is associated with decreased Myogenic tone, vasogenic edema, and an increase in BBB permeability, but not anti-angiogenic imbalance in the brain.
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knockdown of add3 impairs the Myogenic Response of renal afferent arterioles and middle cerebral arteries
American Journal of Physiology-renal Physiology, 2017Co-Authors: Fan Fan, Mallikarjuna R Pabbidi, Shaoxun Wang, Paige N Mims, Richard J RomanAbstract:We have reported that the Myogenic Response of the renal afferent arteriole (Af-art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow are impaired in Fawn-Hooded...
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Molecular Mechanisms of Renal Blood Flow Autoregulation
2016Co-Authors: Marilyn Burke, Mallikarjuna R Pabbidi, Jerry Farley, Richard J RomanAbstract:Abstract: Diabetes and hypertension are the leading causes of chronic kidney disease and their incidence is increasing at an alarming rate. Both are associated with impairments in the autoregulation of renal blood flow (RBF) and greater trans-mission of fluctuations in arterial pressure to the glomerular capillaries. The ability of the kidney to maintain relatively constant blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure is mediated by the Myogenic re-sponse of afferent arterioles working in concert with tubuloglomerular feedback that adjusts the tone of the afferent arteri-ole in Response to changes in the delivery of sodium chloride to the macula densa. Despite intensive investigation, the fac-tors initiating the Myogenic Response and the signaling pathways involved in the Myogenic Response and tubuloglomerular feedback remain uncertain. This review focuses on current thought regarding the molecular mechanisms underlying myo-genic control of renal vascular tone, the interrelationships between the Myogenic Response and tubuloglomerular feedback, the evidence that alterations in autoregulation of RBF contributes to hypertension and diabetes-induced nephropathy and the identification of vascular therapeutic targets for improved renoprotection in hypertensive and diabetic patients
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impaired Myogenic Response and autoregulation of cerebral blood flow is rescued in cyp4a1 transgenic dahl salt sensitive rat
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2015Co-Authors: Aron M Geurts, Mallikarjuna R Pabbidi, Howard J Jacob, Sydney R Murphy, Richard J RomanAbstract:We have reported that a reduction in renal production of 20-HETE contributes to development of hypertension in Dahl salt-sensitive (SS) rats. The present study examined whether 20-HETE production is also reduced in the cerebral vasculature of SS rats and whether this impairs the Myogenic Response and autoregulation of cerebral blood flow (CBF). The production of 20-HETE, the Myogenic Response of middle cerebral arteries (MCA), and autoregulation of CBF were compared in SS, SS-5BN rats and a newly generated CYP4A1 transgenic rat. 20-HETE production was 6-fold higher in cerebral arteries of CYP4A1 and SS-5BN than in SS rats. The diameter of the MCA decreased to 70 ± 3% to 65 ± 6% in CYP4A1 and SS-5BN rats when pressure was increased from 40 to 140 mmHg. In contrast, the Myogenic Response of MCA isolated from SS rats did not constrict. Administration of a 20-HETE synthesis inhibitor, HET0016, abolished the Myogenic Response of MCA in CYP4A1 and SS-5BN rats but had no effect in SS rats. Autoregulation of CBF was impaired in SS rats compared with CYP4A1 and SS-5BN rats. Blood-brain barrier leakage was 5-fold higher in the brain of SS rats than in SS-5BN and SS.CYP4A1 rats. These findings indicate that a genetic deficiency in the formation of 20-HETE contributes to an impaired Myogenic Response in MCA and autoregulation of CBF in SS rats and this may contribute to vascular remodeling and cerebral injury following the onset of hypertension.
Jonathan H Jaggar - One of the best experts on this subject based on the ideXlab platform.
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smooth muscle cell transient receptor potential polycystin 2 trpp2 channels contribute to the Myogenic Response in cerebral arteries
The Journal of Physiology, 2013Co-Authors: Damodaran Narayanan, Simon Bulley, Dennis M Leo, Sarah K Burris, Kyle S Gabrick, Frederick A Boop, Jonathan H JaggarAbstract:Key points • Intravascular pressure is reported to activate several mechanosensitive ion channels, leading to smooth muscle cell (SMC) depolarization, voltage-dependent Ca2+ channel activation and vasoconstriction; a process known as the ‘Myogenic Response’. • Polycystin-1 and -2 (TRPP1 and -2) have been shown to differentially regulate the mesenteric artery Myogenic Response, with TRPP2 expression attenuating vasoconstriction. • We show that TRPP2 is the major TRPP isoform expressed and that TRPP2 is located primarily in the plasma membrane in cerebral artery SMCs. • Selective TRPP2 knockdown reduced swelling-induced non-selective cation currents (ICat) in SMCs and Myogenic tone in cerebral arteries. • These data indicate that TRPP2 activation contributes to the cerebral artery Myogenic Response and suggest that TRPP2 performs differential functions in different vascular beds. Abstract Intravascular pressure-induced vasoconstriction is a smooth muscle cell-specific mechanism that controls systemic blood pressure and organ regional blood flow. Smooth muscle cell polycystin-1 and -2 (TRPP1 and -2) proteins modulate the Myogenic Response in mesenteric arteries, but involvement in other vascular beds is unclear. Here, we examined TRPP2 expression, cellular distribution, cation currents (ICat), and physiological functions in smooth muscle cells of rat and human cerebral arteries. We demonstrate that TRPP2 is the major TRPP isoform expressed in cerebral artery smooth muscle cells, with message levels higher than those of TRPP1. Arterial biotinylation and immunofluorescence indicated that TRPP2 is located primarily (∼88%) in the smooth muscle cell plasma membrane. RNA interference reduced TRPP2 expression by ∼55% compared to control, but did not alter levels of TRPP1, TRPC1, TRPC3, TRPC6, TRPM4, ANO1/TMEM16A, or voltage-dependent Ca2+ (CaV1.2) channels, other ion channel proteins that modulate Myogenic tone. Cell swelling induced by hyposmotic (250 osmol (l solution)−1) bath solution stimulated Gd3+-sensitive ICat in smooth muscle cells that were reduced by selective TRPP2 knockdown. TRPP2 knockdown did not alter Myogenic tone at 20 mmHg but reduced tone between ∼28 and 39% over an intravascular pressure range between 40 and 100 mmHg. In contrast, TRPP2 knockdown did not alter depolarization-induced (60 mmol l K+) vasoconstriction. In summary, we show that TRPP2 is expressed in smooth muscle cells of resistance-size cerebral arteries, resides primarily in the plasma membrane, and contributes to the Myogenic Response. Data also suggest that TRPP2 differentially regulates the Myogenic Response in cerebral and mesenteric arteries.
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smooth muscle cell transient receptor potential polycystin 2 trpp2 channels contribute to the Myogenic Response in cerebral arteries
The Journal of Physiology, 2013Co-Authors: Damodaran Narayanan, Simon Bulley, Dennis M Leo, Sarah K Burris, Kyle S Gabrick, Frederick A Boop, Jonathan H JaggarAbstract:Intravascular pressure-induced vasoconstriction is a smooth muscle cell-specific mechanism that controls systemic blood pressure and organ regional blood flow. Smooth muscle cell polycystin-1 and -2 (TRPP1 and -2) proteins modulate the Myogenic Response in mesenteric arteries, but involvement in other vascular beds is unclear. Here, we examined TRPP2 expression, cellular distribution, cation currents (ICat), and physiological functions in smooth muscle cells of rat and human cerebral arteries. We demonstrate that TRPP2 is the major TRPP isoform expressed in cerebral artery smooth muscle cells, with message levels higher than those of TRPP1. Arterial biotinylation and immunofluorescence indicated that TRPP2 is located primarily (∼88%) in the smooth muscle cell plasma membrane. RNA interference reduced TRPP2 expression by ∼55% compared to control, but did not alter levels of TRPP1, TRPC1, TRPC3, TRPC6, TRPM4, ANO1/TMEM16A, or voltage-dependent Ca(2+) (CaV1.2) channels, other ion channel proteins that modulate Myogenic tone. Cell swelling induced by hyposmotic (250 osmol (l solution)(-1)) bath solution stimulated Gd(3+)-sensitive ICat in smooth muscle cells that were reduced by selective TRPP2 knockdown. TRPP2 knockdown did not alter Myogenic tone at 20 mmHg but reduced tone between ∼28 and 39% over an intravascular pressure range between 40 and 100 mmHg. In contrast, TRPP2 knockdown did not alter depolarization-induced (60 mmol l K(+)) vasoconstriction. In summary, we show that TRPP2 is expressed in smooth muscle cells of resistance-size cerebral arteries, resides primarily in the plasma membrane, and contributes to the Myogenic Response. Data also suggest that TRPP2 differentially regulates the Myogenic Response in cerebral and mesenteric arteries.
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tmem16a ano1 channels contribute to the Myogenic Response in cerebral arteries
Circulation Research, 2012Co-Authors: Simon Bulley, Sarah K Burris, Zachary P Neeb, John P Bannister, Candice M Thomasgatewood, Wanchana Jangsangthong, Jonathan H JaggarAbstract:Rationale: Pressure-induced arterial depolarization and constriction (the Myogenic Response) is a smooth muscle cell (myocyte)-specific mechanism that controls regional organ blood flow and systemic blood pressure. Several different nonselective cation channels contribute to pressure-induced depolarization, but signaling mechanisms involved are unclear. Similarly uncertain is the contribution of anion channels to the Myogenic Response and physiological functions and mechanisms of regulation of recently discovered transmembrane 16A (TMEM16A), also termed Anoctamin 1, chloride (Cl − ) channels in arterial myocytes. Objective: To investigate the hypothesis that myocyte TMEM16A channels control membrane potential and contractility and contribute to the Myogenic Response in cerebral arteries. Methods and Results: Cell swelling induced by hyposmotic bath solution stimulated Cl − currents in arterial myocytes that were blocked by TMEM16A channel inhibitory antibodies, RNAi-mediated selective TMEM16A channel knockdown, removal of extracellular calcium (Ca 2+ ), replacement of intracellular EGTA with BAPTA, a fast Ca 2+ chelator, and Gd 3+ and SKF-96365, nonselective cation channel blockers. In contrast, nimodipine, a voltage-dependent Ca 2+ channel inhibitor, or thapsigargin, which depletes intracellular Ca 2+ stores, did not alter swelling-activated TMEM16A currents. Pressure-induced (−40 mm Hg) membrane stretch activated ion channels in arterial myocyte cell–attached patches that were inhibited by TMEM16A antibodies and were of similar amplitude to recombinant TMEM16A channels. TMEM16A knockdown reduced intravascular pressure-induced depolarization and vasoconstriction but did not alter depolarization-induced (60 mmol/L K + ) vasoconstriction. Conclusions: Membrane stretch activates arterial myocyte TMEM16A channels, leading to membrane depolarization and vasoconstriction. Data also provide a mechanism by which a local Ca 2+ signal generated by nonselective cation channels stimulates TMEM16A channels to induce Myogenic constriction.
