Juxtamedullary Nephron

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Edward W Inscho - One of the best experts on this subject based on the ideXlab platform.

  • avian erythroblastosis virus e26 oncogene homolog 1 ets 1 plays a role in renal microvascular pathophysiology in the dahl salt sensitive rat
    Kidney International, 2020
    Co-Authors: Wenguang Feng, Edward W Inscho, Zhengrong Guan, Dongqi Xing, Xingsheng Li, Weizhong Ying, Colton E Remedies, Paul W Sanders
    Abstract:

    Prior studies reported that haploinsufficiency of the transcription factor ETS-1 is renoprotective in Dahl salt-sensitive rats, but the mechanism is unclear. Here, we tested whether ETS-1 is involved in hypertension-induced renal microvascular pathology and autoregulatory impairment. Hypertension was induced in salt-sensitive rats and salt-sensitive rats that are heterozygous with 1 wild-type or reference allele of Ets1 (SSEts1+/-) by feeding a diet containing 4% sodium chloride for 1 week. Increases in blood pressure did not differ. However, phosphorylated ETS-1 increased in afferent arterioles of hypertensive salt-sensitive rats, but not in hypertensive SSEts1+/- rats. Afferent arterioles of hypertensive salt-sensitive rats showed increased monocyte chemotactic protein-1 expression and infiltration of CD68 positive monocytes/macrophages. Isolated kidney microvessels showed increased mRNA expression of vascular cell adhesion molecule, intercellular adhesion molecule, P-selectin, fibronectin, transforming growth factor-β, and collagen I in hypertensive salt-sensitive rats compared with hypertensive SSEts1+/- rats. Using the in vitro blood-perfused Juxtamedullary Nephron preparation, pressure-mediated afferent arteriolar responses were significantly blunted in hypertensive salt-sensitive rats compared to hypertensive SSEts1+/- rats. Over a 65-170 mm Hg pressure range tested baseline arteriolar diameters averaged 15.1 μm and remained between 107% and 89% of baseline diameter in hypertensive salt-sensitive rats vs. 114% and 73% in hypertensive SSEts1+/- rats (significantly different). Thus, ETS-1 participates in renal arteriolar pathology and autoregulation and thereby is involved in hypertension-mediated kidney injury in salt-sensitive rats.

  • Afferent arteriole responsiveness to endothelin receptor activation: does sex matter?
    Biology of Sex Differences, 2019
    Co-Authors: Eman Y. Gohar, Anthony K. Cook, David M. Pollock, Edward W Inscho
    Abstract:

    Background The pathogenesis of hypertension is distinct between men and women. Endothelin-1 (ET-1) is a potential contributor to sex differences in the pathophysiology of hypertension. ET-1 participates in blood pressure regulation through activation of endothelin A (ET_A) and endothelin B (ET_B) receptors including those in the vasculature. Previous studies demonstrated that sex and sex hormones evoke discrepancies in ET-1-mediated control of vascular tone in different vascular beds. However, little is known about sex- and sex hormone-related differences in ET-1-dependent renal microvascular reactivity. Accordingly, we hypothesized that loss of sex hormones impairs afferent arteriole reactivity to ET-1. Methods Male and female Sprague Dawley rats were subjected to gonadectomy or sham surgery ( n  = 6/group). After 3 weeks, kidneys from those rats were prepared for assessment of renal microvascular responses to ET-1 (ET_A and ET_B agonist, 10^−12 to 10^−8 M) and sarafotoxin 6c (S6c, ET_B agonist, 10^−12 to 10^−8 M) using the blood-perfused Juxtamedullary Nephron preparation. Results Control afferent arteriole diameters at 100 mmHg were similar between sham male and female rats averaging 14.6 ± 0.3 and 15.3 ± 0.3 μm, respectively. Gonadectomy had no significant effect on control arteriole diameter. In sham males, ET-1 produced significant concentration-dependent decreases in afferent arteriole diameter, with 10^−8 M ET-1 decreasing diameter by 84 ± 1%. ET-1 induced similar concentration-dependent vasoconstrictor responses in sham female rats, with 10^−8 M ET-1 decreasing the diameter by 82 ± 1%. The afferent arteriolar vasoconstrictor responses to ET-1 were unchanged by ovariectomy or orchiectomy. Selective ET_B receptor activation by S6c induced a concentration-dependent decline in afferent arteriole diameter, with 10^−8 M S6c decreasing diameter by 77 ± 3 and 76 ± 3% in sham male and female rats, respectively. Notably, ovariectomy augmented the vasoconstrictor response to S6c (10^−12 to 10^−9 M), whereas orchiectomy had no significant impact on the responsiveness to ET_B receptor activation. Conclusion These data demonstrate that sex does not significantly influence afferent arteriole reactivity to ET receptor activation. Gonadectomy potentiated the responsiveness of the afferent arteriole to ET_B-induced vasoconstriction in females, but not males, suggesting that female sex hormones influence ET_B-mediated vasoconstriction in the renal microcirculation.

  • Afferent arteriole responsiveness to endothelin receptor activation: does sex matter?
    Biology of sex differences, 2019
    Co-Authors: Eman Y. Gohar, Anthony K. Cook, David M. Pollock, Edward W Inscho
    Abstract:

    The pathogenesis of hypertension is distinct between men and women. Endothelin-1 (ET-1) is a potential contributor to sex differences in the pathophysiology of hypertension. ET-1 participates in blood pressure regulation through activation of endothelin A (ETA) and endothelin B (ETB) receptors including those in the vasculature. Previous studies demonstrated that sex and sex hormones evoke discrepancies in ET-1-mediated control of vascular tone in different vascular beds. However, little is known about sex- and sex hormone-related differences in ET-1-dependent renal microvascular reactivity. Accordingly, we hypothesized that loss of sex hormones impairs afferent arteriole reactivity to ET-1. Male and female Sprague Dawley rats were subjected to gonadectomy or sham surgery (n = 6/group). After 3 weeks, kidneys from those rats were prepared for assessment of renal microvascular responses to ET-1 (ETA and ETB agonist, 10−12 to 10−8 M) and sarafotoxin 6c (S6c, ETB agonist, 10−12 to 10−8 M) using the blood-perfused Juxtamedullary Nephron preparation. Control afferent arteriole diameters at 100 mmHg were similar between sham male and female rats averaging 14.6 ± 0.3 and 15.3 ± 0.3 μm, respectively. Gonadectomy had no significant effect on control arteriole diameter. In sham males, ET-1 produced significant concentration-dependent decreases in afferent arteriole diameter, with 10−8 M ET-1 decreasing diameter by 84 ± 1%. ET-1 induced similar concentration-dependent vasoconstrictor responses in sham female rats, with 10−8 M ET-1 decreasing the diameter by 82 ± 1%. The afferent arteriolar vasoconstrictor responses to ET-1 were unchanged by ovariectomy or orchiectomy. Selective ETB receptor activation by S6c induced a concentration-dependent decline in afferent arteriole diameter, with 10−8 M S6c decreasing diameter by 77 ± 3 and 76 ± 3% in sham male and female rats, respectively. Notably, ovariectomy augmented the vasoconstrictor response to S6c (10−12 to 10−9 M), whereas orchiectomy had no significant impact on the responsiveness to ETB receptor activation. These data demonstrate that sex does not significantly influence afferent arteriole reactivity to ET receptor activation. Gonadectomy potentiated the responsiveness of the afferent arteriole to ETB-induced vasoconstriction in females, but not males, suggesting that female sex hormones influence ETB-mediated vasoconstriction in the renal microcirculation.

  • Afferent arteriole responsiveness to endothelin receptor activation: does sex matter?
    Biology of Sex Differences, 2019
    Co-Authors: Eman Y. Gohar, Anthony K. Cook, David M. Pollock, Edward W Inscho
    Abstract:

    Background The pathogenesis of hypertension is distinct between men and women. Endothelin-1 (ET-1) is a potential contributor to sex differences in the pathophysiology of hypertension. ET-1 participates in blood pressure regulation through activation of endothelin A (ET_A) and endothelin B (ET_B) receptors including those in the vasculature. Previous studies demonstrated that sex and sex hormones evoke discrepancies in ET-1-mediated control of vascular tone in different vascular beds. However, little is known about sex- and sex hormone-related differences in ET-1-dependent renal microvascular reactivity. Accordingly, we hypothesized that loss of sex hormones impairs afferent arteriole reactivity to ET-1. Methods Male and female Sprague Dawley rats were subjected to gonadectomy or sham surgery ( n  = 6/group). After 3 weeks, kidneys from those rats were prepared for assessment of renal microvascular responses to ET-1 (ET_A and ET_B agonist, 10^−12 to 10^−8 M) and sarafotoxin 6c (S6c, ET_B agonist, 10^−12 to 10^−8 M) using the blood-perfused Juxtamedullary Nephron preparation. Results Control afferent arteriole diameters at 100 mmHg were similar between sham male and female rats averaging 14.6 ± 0.3 and 15.3 ± 0.3 μm, respectively. Gonadectomy had no significant effect on control arteriole diameter. In sham males, ET-1 produced significant concentration-dependent decreases in afferent arteriole diameter, with 10^−8 M ET-1 decreasing diameter by 84 ± 1%. ET-1 induced similar concentration-dependent vasoconstrictor responses in sham female rats, with 10^−8 M ET-1 decreasing the diameter by 82 ± 1%. The afferent arteriolar vasoconstrictor responses to ET-1 were unchanged by ovariectomy or orchiectomy. Selective ET_B receptor activation by S6c induced a concentration-dependent decline in afferent arteriole diameter, with 10^−8 M S6c decreasing diameter by 77 ± 3 and 76 ± 3% in sham male and female rats, respectively. Notably, ovariectomy augmented the vasoconstrictor response to S6c (10^−12 to 10^−9 M), whereas orchiectomy had no significant impact on the responsiveness to ET_B receptor activation. Conclusion These data demonstrate that sex does not significantly influence afferent arteriole reactivity to ET receptor activation. Gonadectomy potentiated the responsiveness of the afferent arteriole to ET_B-induced vasoconstriction in females, but not males, suggesting that female sex hormones influence ET_B-mediated vasoconstriction in the renal microcirculation.

  • Mechanisms of sphingosine-1-phosphate-mediated vasoconstriction of rat afferent arterioles.
    Acta physiologica (Oxford England), 2017
    Co-Authors: Zhengrong Guan, Fuchenchu Wang, Xiangqin Cui, Edward W Inscho
    Abstract:

    Aim Sphingosine-1-phosphate (S1P) influences resistance vessel function and is implicated in renal pathological processes. Previous studies revealed that S1P evoked potent vasoconstriction of the pre-glomerular microvasculature, but the underlying mechanisms remain incompletely defined. We postulated that S1P-mediated pre-glomerular microvascular vasoconstriction involves activation of voltage-dependent L-type calcium channels (L-VDCC) and the rho/rho kinase pathway. Methods Afferent arteriolar reactivity was assessed in vitro using the blood-perfused rat Juxtamedullary Nephron preparation, and diameter was measured during exposure to physiological and pharmacological agents. Results Exogenous S1P (10-9 -10-5 mol L-1 ) evoked concentration-dependent vasoconstriction of afferent arterioles. Superfusion with nifedipine, a L-VDCC blocker, increased arteriolar diameter by 39 ± 18% of baseline and significantly attenuated the S1P-induced vasoconstriction. Superfusion with the rho kinase inhibitor, Y-27632, increased diameter by 60 ± 12% of baseline and also significantly blunted vasoconstriction by S1P. Combined nifedipine and Y-27632 treatment significantly inhibited S1P-induced vasoconstriction over the entire concentration range tested. In contrast, depletion of intracellular Ca2+ stores with the Ca2+ -ATPase inhibitors, thapsigargin or cyclopiazonic acid, did not alter the S1P-mediated vasoconstrictor profile. Scavenging reactive oxygen species (ROS) or inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity significantly attenuated S1P-mediated vasoconstriction. Conclusion Exogenous S1P elicits potent vasoconstriction of rat afferent arterioles. These data also demonstrate that S1P-mediated pre-glomerular vasoconstriction involves activation of L-VDCC, the rho/rho kinase pathway and ROS. Mobilization of Ca2+ from intracellular stores is not required for S1P-mediated vasoconstriction. These studies reveal a potential role for S1P in the modulation of renal microvascular tone.

Pamela K. Carmines - One of the best experts on this subject based on the ideXlab platform.

  • Renal Arteriolar Angiotensin Responses During Varied Adenosine Receptor Activation
    2016
    Co-Authors: Pamela K. Carmines, Edward W Inscho
    Abstract:

    Abstract We performed experiments to test the hypothesis that endogenous adenosine acts as an essential cofactor re-quired for eliciting angiotensin II (Ang II)-induced afferent and/or efferent arteriolar vasoconstriction. Enalaprilat (2 mg IV) was administered to anesthetized rats to reduce endoge-nous Ang II levels. Kidneys and blood were harvested from these animals and used for study of renal microvascular function using the in vitro blood-perfused Juxtamedullary Nephron technique. Arteriolar inside diameter was monitored videomicroscopically in (1) normal kidneys, (2) kidneys sub-jected to adenosine receptor blockade (100 ^imol/L 1,3-dipro-pyl-8-p-sulfophenylxanthine), and (3) kidneys continuously exposed to 1 /wnol/L adenosine. Under resting conditions, arteriolar diameters were similar in all three groups of kidneys, averaging 24.8 ±1.0 jun (n=23) in afferent arterioles an

  • Afferent Arteriolar Responsiveness to Altered Perfusion Pressure in Renal Hypertension
    2016
    Co-Authors: Edward W Inscho, Anthony K. Cook, Pamela K. Carmines, Gabriel L. Navar
    Abstract:

    The present study was performed to determine the role of afferent arterioles in the impaired autoregulatory response shown to occur in the contralateral kidney of Goldblatt hypertensive rats. The responsiveness of Juxtamedullary afferent arterioles to alterations in perfusion pressure was studied in the nonclipped kidney of two-kidney, one clip hypertensive and sham-operated rats. Systolic pressure, 5-6 weeks after clipping, averaged 184±6 mm Hg in the hypertensive rats (n=16) and 121±3 mm Hg in the sham-operated control rats (n=7). By using the in vitro blood-perfused Juxtamedullary Nephron technique, afferent arterioles were directly visualized, and their inside diameters were measured by videomicroscopic methods. In sham-operated kidneys perfused with blood from normotensive rats, afferent arteriolar diameter averaged 22.8 ±1.8 fim at a renal arterial perfusion pressure of 151±1 mm Hg and increased to 24.8±1.8 fim when perfusion pressure was reduced to 110±2 mm Hg. Conversely, in hypertensive kidneys perfused with blood from either hypertensive or normotensive rats, the afferent arterioles failed to vasodilate and actually exhibited a slight decrease in diameter from 24.6 ±1.3 to 23.0 ±2.3 fim in response to the same reduction in perfusion pressure. Vasodilator capability, however, could be demonstrated in response to verapamil and sodium nitroprusside

  • Tempol Prevents Altered K+ Channel Regulation of Afferent Arteriolar Tone in Diabetic Rat Kidney
    Hypertension (Dallas Tex. : 1979), 2012
    Co-Authors: Carmen M. Troncoso Brindeiro, Pascale H. Lane, Pamela K. Carmines
    Abstract:

    Experiments were performed to test the hypothesis that oxidative stress underlies the enhanced tonic dilator impact of inward-rectifier K + channels on renal afferent arterioles of rats with streptozotocin-induced diabetes mellitus. Sham and diabetic rats were left untreated or provided Tempol in their drinking water for 26±1 days, after which afferent arteriolar lumen diameter and its responsiveness to K + channel blockade were measured using the in vitro blood-perfused Juxtamedullary Nephron technique. Afferent diameter averaged 19.4±0.8 μm in sham rats and 24.4±0.8 μm in diabetic rats ( P 2+ (inward-rectifier K + channel blocker) was 3 times greater in diabetic rats than in sham rats. Glibenclamide (K ATP channel blocker) and tertiapin-Q (Kir1.1/Kir3.x channel blocker) decreased afferent diameter in diabetic rats but had no effect on arterioles from sham rats. Chronic Tempol treatment prevented diabetes mellitus–induced increases in both renal vascular dihydroethidium staining and baseline afferent arteriolar diameter. Moreover, Tempol prevented the exaggeration of afferent arteriolar responses to Ba 2+ , tertiapin-Q, and glibenclamide otherwise evident in diabetic rats. Preglomerular microvascular smooth muscle cells expressed mRNA encoding Kir1.1, Kir2.1, and Kir6.1. Neither diabetes mellitus nor Tempol altered Kir1.1, Kir2.1, Kir6.1, or SUR2B protein levels in renal cortical microvessels. To the extent that the effects of Tempol reflect its antioxidant actions, our observations indicate that oxidative stress contributes to the exaggerated impact of Kir1.1, Kir2.1, and K ATP channels on afferent arteriolar tone during diabetes mellitus and that this phenomenon involves posttranslational modulation of channel function.

  • Basal nitric oxide production curtails arteriolar vasoconstrictor responses to ANG II in rat kidney.
    American Journal of Physiology-Renal Physiology, 1996
    Co-Authors: Hideki Ikenaga, Rachel W. Fallet, Pamela K. Carmines
    Abstract:

    Experiments were performed to test the hypothesis that renal arteriolar vasoconstrictor responses to angiotensin II (ANG II) are curtailed through a mechanism that involves stimulation of endogenous nitric oxide (NO) synthesis. The in vitro blood-perfused Juxtamedullary Nephron technique was exploited to monitor arteriolar lumen diameter responses to exogenous ANG II before and during treatment with the NO synthase inhibitor N omega-nitro-L-arginine (L-NNA). Under control conditions, 1 nM ANG II reduced afferent and efferent arteriolar diameters by 13 and 11%, respectively. In the presence of L-NNA, 1 nM ANG II decreased afferent diameter by 26% and efferent diameter by 35%. This augmentation could not be attributed to the L-NNA-induced decrease in baseline diameter. L-NNA also augmented vasopressin responses, indicating a lack of agonist specificity in this interaction. ANG II reactivity during L-NNA treatment was not enhanced when tissue NO activity was fixed at basal levels (exposure to 1 microM sodium nitroprusside). These results indicate that endogenous NO modulates the vasoconstrictive impact of ANG II on both afferent and efferent arterioles of Juxtamedullary Nephrons and that this process does not require stimulation of NO synthesis.

  • Contribution of tubuloglomerular feedback to renal arteriolar angiotensin II responsiveness
    Kidney international, 1996
    Co-Authors: Hideki Ikenaga, Rachel W. Fallet, Pamela K. Carmines
    Abstract:

    Contribution of tubuloglomerular feedback to renal arteriolar angiotensin II responsiveness. The purpose of the present study was to test the hypothesis that a component of the afferent arteriolar vasoconstrictor response to angiotensin II (Ang II) requires an intact tubuloglomerular feedback (TGF) mechanism. Enalaprilat-treated male Sprague-Dawley rats served as tissue donors for study of renal microvascular function using the in vitro blood-perfused Juxtamedullary Nephron technique. Arteriolar lumen diameter responses to exogenous Ang II were determined before and after TGF blockade (papillectomy or 50 µ m furosemide). Before TGF blockade, 10nm Ang II significantly reduced diameters of both midafferent (53 ± 5%) and efferent (43 ± 9%) arterioles. TGF blockade did not alter baseline diameter of either arteriole, but significantly blunted the mid-afferent vasoconstriction evoked by 10nm Ang II (44 ± 7% inhibition by papillectomy; 43 ± 10% inhibition by furosemide). Similar behavior was observed at afferent arteriolar sites near the glomerulus; however, efferent arteriolar Ang II responsiveness was not altered by papillectomy. The impact of TGF blockade on afferent arteriolar Ang II responsiveness was most prominent at high peptide concentrations (10nm), while not significantly influencing the response to 1nm Ang II. In contrast, the afferent vasoconstrictor effect of norepinephrine was unaffected by papillectomy. These data indicate that the vasoconstrictor influence of exogenous Ang II on afferent, but not efferent, arterioles of intact Juxtamedullary Nephrons includes both TGF-dependent and TGF-independent components.

Zhengrong Guan - One of the best experts on this subject based on the ideXlab platform.

  • avian erythroblastosis virus e26 oncogene homolog 1 ets 1 plays a role in renal microvascular pathophysiology in the dahl salt sensitive rat
    Kidney International, 2020
    Co-Authors: Wenguang Feng, Edward W Inscho, Zhengrong Guan, Dongqi Xing, Xingsheng Li, Weizhong Ying, Colton E Remedies, Paul W Sanders
    Abstract:

    Prior studies reported that haploinsufficiency of the transcription factor ETS-1 is renoprotective in Dahl salt-sensitive rats, but the mechanism is unclear. Here, we tested whether ETS-1 is involved in hypertension-induced renal microvascular pathology and autoregulatory impairment. Hypertension was induced in salt-sensitive rats and salt-sensitive rats that are heterozygous with 1 wild-type or reference allele of Ets1 (SSEts1+/-) by feeding a diet containing 4% sodium chloride for 1 week. Increases in blood pressure did not differ. However, phosphorylated ETS-1 increased in afferent arterioles of hypertensive salt-sensitive rats, but not in hypertensive SSEts1+/- rats. Afferent arterioles of hypertensive salt-sensitive rats showed increased monocyte chemotactic protein-1 expression and infiltration of CD68 positive monocytes/macrophages. Isolated kidney microvessels showed increased mRNA expression of vascular cell adhesion molecule, intercellular adhesion molecule, P-selectin, fibronectin, transforming growth factor-β, and collagen I in hypertensive salt-sensitive rats compared with hypertensive SSEts1+/- rats. Using the in vitro blood-perfused Juxtamedullary Nephron preparation, pressure-mediated afferent arteriolar responses were significantly blunted in hypertensive salt-sensitive rats compared to hypertensive SSEts1+/- rats. Over a 65-170 mm Hg pressure range tested baseline arteriolar diameters averaged 15.1 μm and remained between 107% and 89% of baseline diameter in hypertensive salt-sensitive rats vs. 114% and 73% in hypertensive SSEts1+/- rats (significantly different). Thus, ETS-1 participates in renal arteriolar pathology and autoregulation and thereby is involved in hypertension-mediated kidney injury in salt-sensitive rats.

  • Mechanisms of sphingosine-1-phosphate-mediated vasoconstriction of rat afferent arterioles.
    Acta physiologica (Oxford England), 2017
    Co-Authors: Zhengrong Guan, Fuchenchu Wang, Xiangqin Cui, Edward W Inscho
    Abstract:

    Aim Sphingosine-1-phosphate (S1P) influences resistance vessel function and is implicated in renal pathological processes. Previous studies revealed that S1P evoked potent vasoconstriction of the pre-glomerular microvasculature, but the underlying mechanisms remain incompletely defined. We postulated that S1P-mediated pre-glomerular microvascular vasoconstriction involves activation of voltage-dependent L-type calcium channels (L-VDCC) and the rho/rho kinase pathway. Methods Afferent arteriolar reactivity was assessed in vitro using the blood-perfused rat Juxtamedullary Nephron preparation, and diameter was measured during exposure to physiological and pharmacological agents. Results Exogenous S1P (10-9 -10-5 mol L-1 ) evoked concentration-dependent vasoconstriction of afferent arterioles. Superfusion with nifedipine, a L-VDCC blocker, increased arteriolar diameter by 39 ± 18% of baseline and significantly attenuated the S1P-induced vasoconstriction. Superfusion with the rho kinase inhibitor, Y-27632, increased diameter by 60 ± 12% of baseline and also significantly blunted vasoconstriction by S1P. Combined nifedipine and Y-27632 treatment significantly inhibited S1P-induced vasoconstriction over the entire concentration range tested. In contrast, depletion of intracellular Ca2+ stores with the Ca2+ -ATPase inhibitors, thapsigargin or cyclopiazonic acid, did not alter the S1P-mediated vasoconstrictor profile. Scavenging reactive oxygen species (ROS) or inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity significantly attenuated S1P-mediated vasoconstriction. Conclusion Exogenous S1P elicits potent vasoconstriction of rat afferent arterioles. These data also demonstrate that S1P-mediated pre-glomerular vasoconstriction involves activation of L-VDCC, the rho/rho kinase pathway and ROS. Mobilization of Ca2+ from intracellular stores is not required for S1P-mediated vasoconstriction. These studies reveal a potential role for S1P in the modulation of renal microvascular tone.

  • abstract 491 activation of voltage dependent l type calcium channels and the rho kinase pathway are involved in s1p induced vasoconstriction in rat Juxtamedullary afferent arterioles
    Hypertension, 2012
    Co-Authors: Zhengrong Guan, Anthony K. Cook, Sean T Singletary, Edward W Inscho
    Abstract:

    Sphingosine-1-phosphate (S1P) is an important regulator of resistance vessels and is implicated in pathological processes including diabetic nephropathy and acute kidney injury. Previous studies show that S1P causes marked vasoconstriction in preglomerular but not postglomerular microvessels, however, the intracellular signaling pathways underlying S1P-mediated vasoconstriction are undefined. We postulated that S1P-mediated afferent arteriolar (AA) vasoconstriction involves activation of voltage-dependent L-type Ca2+ channels (L-VDCC) and the rho kinase pathway. Studies were conducted in vitro using the blood-perfused Juxtamedullary Nephron preparation. Superfusion of S1P (n=6) evoked concentration-dependent AA vasoconstriction. Control diameter averaged 13.8±0.9 μm and declined to 95±2, 85±4, 75±6, 60±5 and 46±5% of control diameter in response to S1P (from 10-9 to 10-5 M), respectively. Superfusion with nifedipine (10-6 M, n=6), a L-VDCC inhibitor, increased basal diameter by 39±18% (p 0.05), respectively. Similar results were obtained with CPA (10-5 M, n=6). S1P reduced diameter to 97±2, 93±2, 75±5, 53±6 and 36±5% of the control (p>0.05), respectively, suggesting that mobilization of intracellular Ca2+ store is not required for S1P-induced vasoconstriction. Overall, these data indicate that both L-VDCC and rho kinase pathways contribute to S1P-mediated AA vasoconstriction.

  • effect of epithelial sodium channel blockade on the myogenic response of rat Juxtamedullary afferent arterioles
    Hypertension, 2009
    Co-Authors: Zhengrong Guan, Anthony K. Cook, Jennifer S Pollock, Janet L Hobbs, Edward W Inscho
    Abstract:

    The mechanotransduction mechanism underlying the myogenic response is poorly understood, but evidence implicates participation of epithelial sodium channel (ENaC)-like proteins. Therefore, the role of ENaC on the afferent arteriolar myogenic response was investigated in vitro using the blood-perfused Juxtamedullary Nephron technique. Papillectomy was used to isolate myogenic influences by eliminating tubuloglomerular feedback signals. Autoregulatory responses were assessed by manipulating perfusion pressure in 30-mm Hg steps. Under control conditions, arteriolar diameter increased by 15% from 13.0+/-1.3 to 14.7+/-1.2 microm (P 0.05). Immunofluorescence revealed expression of the alpha, beta, and gamma subunits of ENaC in freshly isolated preglomerular microvascular smooth muscle cells. These results demonstrate that selective ENaC inhibitors attenuate afferent arteriolar myogenic responses and suggest that ENaC may function as mechanosensitive ion channels initiating pressure-dependent myogenic responses in rat Juxtamedullary afferent arterioles.

  • effect of epithelial sodium channel blockade on the myogenic response of rat Juxtamedullary afferent arterioles
    Hypertension, 2009
    Co-Authors: Zhengrong Guan, Anthony K. Cook, Jennifer S Pollock, Janet L Hobbs, Edward W Inscho
    Abstract:

    The mechanotransduction mechanism underlying the myogenic response is poorly understood, but evidence implicates participation of epithelial sodium channel (ENaC)-like proteins. Therefore, the role of ENaC on the afferent arteriolar myogenic response was investigated in vitro using the blood-perfused Juxtamedullary Nephron technique. Papillectomy was used to isolate myogenic influences by eliminating tubuloglomerular feedback signals. Autoregulatory responses were assessed by manipulating perfusion pressure in 30-mm Hg steps. Under control conditions, arteriolar diameter increased by 15% from 13.0±1.3 to 14.7±1.2 μm ( P P P >0.05). Immunofluorescence revealed expression of the α, β, and γ subunits of ENaC in freshly isolated preglomerular microvascular smooth muscle cells. These results demonstrate that selective ENaC inhibitors attenuate afferent arteriolar myogenic responses and suggest that ENaC may function as mechanosensitive ion channels initiating pressure-dependent myogenic responses in rat Juxtamedullary afferent arterioles.

Luis Gabriel Navar - One of the best experts on this subject based on the ideXlab platform.

  • Neuronal nitric oxide synthase modulates rat renal microvascular function
    American Journal of Physiology-Renal Physiology, 1998
    Co-Authors: Atsuhiro Ichihara, Edward W Inscho, John D. Imig, Luis Gabriel Navar
    Abstract:

    This study was performed to determine the influence of neuronal nitric oxide synthase (nNOS) on renal arteriolar tone under conditions of normal, interrupted, and increased volume delivery to the macula densa segment and on the microvascular responses to angiotensin II (ANG II). Experiments were performed in vitro on afferent (21.2 ± 0.2 μm) and efferent (18.5 ± 0.2 μm) arterioles of kidneys harvested from male Sprague-Dawley rats, using the blood-perfused Juxtamedullary Nephron technique. Superfusion with the specific nNOS inhibitor, S-methyl-l-thiocitrulline (l-SMTC), decreased afferent and efferent arteriolar diameters, and these decreases in arteriolar diameters were prevented by interruption of distal volume delivery by papillectomy. When 10 mM acetazolamide was added to the blood perfusate to increase volume delivery to the macula densa segment, afferent arteriolar vasoconstrictor responses tol-SMTC were enhanced, but this effect was again completely prevented after papillectomy. In contrast, the arteriolar diameter responses to the nonselective NOS inhibitor, N ω-nitro-l-arginine (l-NNA) were only attenuated by papillectomy.l-SMTC (10 μM) enhanced the efferent arteriolar vasoconstrictor response to ANG II but did not alter the afferent arteriolar vasoconstrictor responsiveness to ANG II. In contrast, l-NNA (100 μM) enhanced both afferent and efferent arteriolar vasoconstrictor responses to ANG II. These results indicate that the modulating influence of nNOS on afferent arteriolar tone of Juxtamedullary Nephrons is dependent on distal tubular fluid flow. Furthermore, nNOS exerts a differential modulatory action on the Juxtamedullary microvasculature by enhancing efferent, but not afferent, arteriolar responsiveness to ANG II.

  • Neuronal nitric oxide synthase modulates rat renal microvascular function.
    The American journal of physiology, 1998
    Co-Authors: A Ichihara, Edward W Inscho, John D. Imig, Luis Gabriel Navar
    Abstract:

    This study was performed to determine the influence of neuronal nitric oxide synthase (nNOS) on renal arteriolar tone under conditions of normal, interrupted, and increased volume delivery to the macula densa segment and on the microvascular responses to angiotensin II (ANG II). Experiments were performed in vitro on afferent (21.2 +/- 0.2 microns) and efferent (18.5 +/- 0.2 microns) arterioles of kidneys harvested from male Sprague-Dawley rats, using the blood-perfused Juxtamedullary Nephron technique. Superfusion with the specific nNOS inhibitor, S-methyl-L-thiocitrulline (L-SMTC), decreased afferent and efferent arteriolar diameters, and these decreases in arteriolar diameters were prevented by interruption of distal volume delivery by papillectomy. When 10 mM acetazolamide was added to the blood perfusate to increase volume delivery to the macula densa segment, afferent arteriolar vasoconstrictor responses to L-SMTC were enhanced, but this effect was again completely prevented after papillectomy. In contrast, the arteriolar diameter responses to the nonselective NOS inhibitor, N omega-nitro-L-arginine (L-NNA) were only attenuated by papillectomy. L-SMTC (10 microM) enhanced the efferent arteriolar vasoconstrictor response to ANG II but did not alter the afferent arteriolar vasoconstrictor responsiveness to ANG II. In contrast, L-NNA (100 microM) enhanced both afferent and efferent arteriolar vasoconstrictor responses to ANG II. These results indicate that the modulating influence of nNOS on afferent arteriolar tone of Juxtamedullary Nephrons is dependent on distal tubular fluid flow. Furthermore, nNOS exerts a differential modulatory action on the Juxtamedullary micro-vasculature by enhancing efferent, but not afferent, arteriolar responsiveness to ANG II.

  • Pressure-mediated vasoconstriction of Juxtamedullary afferent arterioles involves P2-purinoceptor activation.
    The American journal of physiology, 1996
    Co-Authors: Edward W Inscho, A K Cook, Luis Gabriel Navar
    Abstract:

    This study was conducted to examine the hypothesis that P2 purinoceptors contribute to pressure-induced autoregulatory adjustments of afferent arteriolar caliber. Experiments were performed in vitro using the blood-perfused Juxtamedullary Nephron technique. Afferent arteriolar diameter averaged 19.2 +/- 0.6 microns (n = 51) at control perfusion pressure of 100 mmHg and decreased when perfusion pressure was increased. Desensitization of P2 purinoceptors abolished the alpha, beta-methylene ATP-mediated afferent vasoconstriction and prevented pressure-dependent autoregulatory adjustments in afferent diameter. P2-purinoceptor saturation significantly decreased afferent caliber and attenuated pressure-induced autoregulatory responses. To block P2 receptors, afferent arterioles were treated with the P2-purinoceptor antagonists, pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid or suramin. P2-receptor blockade prevented the afferent arteriolar vasoconstriction evoked by increasing perfusion pressure from 100 to 130 and 160 mmHg. These data demonstrate that inhibition of P2 purinoceptor-dependent responses through receptor desensitization, receptor saturation, or purinoceptor blockade impairs normal autoregulatory behavior in rat Juxtamedullary afferent arterioles. The results are consistent with the hypothesis that P2 purinoceptors participate in mediating autoregulatory adjustments in afferent arteriolar diameter.

  • autoregulation of afferent arteriolar blood flow in Juxtamedullary Nephrons
    American Journal of Physiology-renal Physiology, 1994
    Co-Authors: T Takenaka, Edward W Inscho, Pamela K. Carmines, Lisa M Harrisonbernard, Luis Gabriel Navar
    Abstract:

    Utilizing the in vitro blood-perfused Juxtamedullary Nephron preparation, we examined the effects of alterations in renal arterial pressure on afferent arteriolar blood flow. With video microscopy and cross-correlation techniques, arteriolar inside diameters and centerline erythrocyte velocity were measured to estimate single afferent arteriolar blood flow. In response to random changes in perfusion pressure, afferent arteriolar diameter (n = 8) varied inversely (-0.53 +/- 0.02%/mmHg), and erythrocyte velocity was directly related (1.4 +/- 0.1%/mmHg). Above 95 mmHg, the slope of the relationship between perfusion pressure and afferent arteriolar blood flow did not differ from zero (0.081 +/- 0.053%/mmHg), suggesting efficient autoregulation. When the tubuloglomerular feedback pathway was interrupted by the addition of furosemide (n = 9) or papillectomy (n = 7), there was attenuation of pressure-induced afferent arteriolar constriction, with impairment in blood flow autoregulation (0.60 +/- 0.05%/mmHg). Superfusion with diltiazem abolished autoregulatory responses in afferent arteriolar diameter and blood flow (1.5 +/- 0.2%/mmHg). These data demonstrate the autoregulation of blood flow of individual afferent arterioles in Juxtamedullary Nephrons and suggest that both tubuloglomerular feedback-dependent and -independent mechanisms are required for autoregulatory responses.

  • edrf angiotensin ii interactions in rat Juxtamedullary afferent and efferent arterioles
    American Journal of Physiology-renal Physiology, 1992
    Co-Authors: K Ohishi, Edward W Inscho, Pamela K. Carmines, Luis Gabriel Navar
    Abstract:

    The in vitro blood-perfused Juxtamedullary Nephron technique was utilized to determine the contribution of endothelium-derived relaxing factor (EDRF) to resting renal arteriolar caliber and to evaluate the interaction between EDRF and angiotensin II (ANG II) in renal microvascular control. Video microscopy was employed to visualize rat afferent and efferent arterioles and to measure their responses to blockade of nitric oxide (NO), which has been shown to account for much of the biological action of EDRF. The NO synthesis inhibitor, N omega-nitro-L-arginine (L-NNA), elicited vasoconstriction in a concentration-dependent manner, with 1,000 microM L-NNA significantly reducing both afferent (16 +/- 3%) and efferent (13 +/- 1%) diameters. This concentration of L-NNA also blocked the vasodilator response to 10 microM acetylcholine, while responsiveness to sodium nitroprusside was maintained. Vasoconstrictor responses to 1,000 microM L-NNA were attenuated in kidneys from rats pretreated with enalaprilat or losartan, reducing afferent diameter by 7 +/- 1 (n = 8) and 3 +/- 1% (n = 10) of control, respectively. Efferent arteriolar responses to L-NNA were similarly attenuated by losartan. The constrictor response to 10 nM ANG II was not exaggerated by L-NNA, suggesting that ANG II does not stimulate EDRF synthesis. These observations indicate that EDRF is continuously released in a quantity sufficient to affect both afferent and efferent arterioles of Juxtamedullary Nephrons in vitro. Furthermore, ANG II blockade attenuates the vasoconstriction elicited by L-NNA, suggesting that EDRF interacts with the renin-angiotensin system to control Juxtamedullary afferent and efferent arteriolar resistance.

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  • Afferent arteriole responsiveness to endothelin receptor activation: does sex matter?
    Biology of Sex Differences, 2019
    Co-Authors: Eman Y. Gohar, Anthony K. Cook, David M. Pollock, Edward W Inscho
    Abstract:

    Background The pathogenesis of hypertension is distinct between men and women. Endothelin-1 (ET-1) is a potential contributor to sex differences in the pathophysiology of hypertension. ET-1 participates in blood pressure regulation through activation of endothelin A (ET_A) and endothelin B (ET_B) receptors including those in the vasculature. Previous studies demonstrated that sex and sex hormones evoke discrepancies in ET-1-mediated control of vascular tone in different vascular beds. However, little is known about sex- and sex hormone-related differences in ET-1-dependent renal microvascular reactivity. Accordingly, we hypothesized that loss of sex hormones impairs afferent arteriole reactivity to ET-1. Methods Male and female Sprague Dawley rats were subjected to gonadectomy or sham surgery ( n  = 6/group). After 3 weeks, kidneys from those rats were prepared for assessment of renal microvascular responses to ET-1 (ET_A and ET_B agonist, 10^−12 to 10^−8 M) and sarafotoxin 6c (S6c, ET_B agonist, 10^−12 to 10^−8 M) using the blood-perfused Juxtamedullary Nephron preparation. Results Control afferent arteriole diameters at 100 mmHg were similar between sham male and female rats averaging 14.6 ± 0.3 and 15.3 ± 0.3 μm, respectively. Gonadectomy had no significant effect on control arteriole diameter. In sham males, ET-1 produced significant concentration-dependent decreases in afferent arteriole diameter, with 10^−8 M ET-1 decreasing diameter by 84 ± 1%. ET-1 induced similar concentration-dependent vasoconstrictor responses in sham female rats, with 10^−8 M ET-1 decreasing the diameter by 82 ± 1%. The afferent arteriolar vasoconstrictor responses to ET-1 were unchanged by ovariectomy or orchiectomy. Selective ET_B receptor activation by S6c induced a concentration-dependent decline in afferent arteriole diameter, with 10^−8 M S6c decreasing diameter by 77 ± 3 and 76 ± 3% in sham male and female rats, respectively. Notably, ovariectomy augmented the vasoconstrictor response to S6c (10^−12 to 10^−9 M), whereas orchiectomy had no significant impact on the responsiveness to ET_B receptor activation. Conclusion These data demonstrate that sex does not significantly influence afferent arteriole reactivity to ET receptor activation. Gonadectomy potentiated the responsiveness of the afferent arteriole to ET_B-induced vasoconstriction in females, but not males, suggesting that female sex hormones influence ET_B-mediated vasoconstriction in the renal microcirculation.

  • Afferent arteriole responsiveness to endothelin receptor activation: does sex matter?
    Biology of sex differences, 2019
    Co-Authors: Eman Y. Gohar, Anthony K. Cook, David M. Pollock, Edward W Inscho
    Abstract:

    The pathogenesis of hypertension is distinct between men and women. Endothelin-1 (ET-1) is a potential contributor to sex differences in the pathophysiology of hypertension. ET-1 participates in blood pressure regulation through activation of endothelin A (ETA) and endothelin B (ETB) receptors including those in the vasculature. Previous studies demonstrated that sex and sex hormones evoke discrepancies in ET-1-mediated control of vascular tone in different vascular beds. However, little is known about sex- and sex hormone-related differences in ET-1-dependent renal microvascular reactivity. Accordingly, we hypothesized that loss of sex hormones impairs afferent arteriole reactivity to ET-1. Male and female Sprague Dawley rats were subjected to gonadectomy or sham surgery (n = 6/group). After 3 weeks, kidneys from those rats were prepared for assessment of renal microvascular responses to ET-1 (ETA and ETB agonist, 10−12 to 10−8 M) and sarafotoxin 6c (S6c, ETB agonist, 10−12 to 10−8 M) using the blood-perfused Juxtamedullary Nephron preparation. Control afferent arteriole diameters at 100 mmHg were similar between sham male and female rats averaging 14.6 ± 0.3 and 15.3 ± 0.3 μm, respectively. Gonadectomy had no significant effect on control arteriole diameter. In sham males, ET-1 produced significant concentration-dependent decreases in afferent arteriole diameter, with 10−8 M ET-1 decreasing diameter by 84 ± 1%. ET-1 induced similar concentration-dependent vasoconstrictor responses in sham female rats, with 10−8 M ET-1 decreasing the diameter by 82 ± 1%. The afferent arteriolar vasoconstrictor responses to ET-1 were unchanged by ovariectomy or orchiectomy. Selective ETB receptor activation by S6c induced a concentration-dependent decline in afferent arteriole diameter, with 10−8 M S6c decreasing diameter by 77 ± 3 and 76 ± 3% in sham male and female rats, respectively. Notably, ovariectomy augmented the vasoconstrictor response to S6c (10−12 to 10−9 M), whereas orchiectomy had no significant impact on the responsiveness to ETB receptor activation. These data demonstrate that sex does not significantly influence afferent arteriole reactivity to ET receptor activation. Gonadectomy potentiated the responsiveness of the afferent arteriole to ETB-induced vasoconstriction in females, but not males, suggesting that female sex hormones influence ETB-mediated vasoconstriction in the renal microcirculation.

  • Afferent arteriole responsiveness to endothelin receptor activation: does sex matter?
    Biology of Sex Differences, 2019
    Co-Authors: Eman Y. Gohar, Anthony K. Cook, David M. Pollock, Edward W Inscho
    Abstract:

    Background The pathogenesis of hypertension is distinct between men and women. Endothelin-1 (ET-1) is a potential contributor to sex differences in the pathophysiology of hypertension. ET-1 participates in blood pressure regulation through activation of endothelin A (ET_A) and endothelin B (ET_B) receptors including those in the vasculature. Previous studies demonstrated that sex and sex hormones evoke discrepancies in ET-1-mediated control of vascular tone in different vascular beds. However, little is known about sex- and sex hormone-related differences in ET-1-dependent renal microvascular reactivity. Accordingly, we hypothesized that loss of sex hormones impairs afferent arteriole reactivity to ET-1. Methods Male and female Sprague Dawley rats were subjected to gonadectomy or sham surgery ( n  = 6/group). After 3 weeks, kidneys from those rats were prepared for assessment of renal microvascular responses to ET-1 (ET_A and ET_B agonist, 10^−12 to 10^−8 M) and sarafotoxin 6c (S6c, ET_B agonist, 10^−12 to 10^−8 M) using the blood-perfused Juxtamedullary Nephron preparation. Results Control afferent arteriole diameters at 100 mmHg were similar between sham male and female rats averaging 14.6 ± 0.3 and 15.3 ± 0.3 μm, respectively. Gonadectomy had no significant effect on control arteriole diameter. In sham males, ET-1 produced significant concentration-dependent decreases in afferent arteriole diameter, with 10^−8 M ET-1 decreasing diameter by 84 ± 1%. ET-1 induced similar concentration-dependent vasoconstrictor responses in sham female rats, with 10^−8 M ET-1 decreasing the diameter by 82 ± 1%. The afferent arteriolar vasoconstrictor responses to ET-1 were unchanged by ovariectomy or orchiectomy. Selective ET_B receptor activation by S6c induced a concentration-dependent decline in afferent arteriole diameter, with 10^−8 M S6c decreasing diameter by 77 ± 3 and 76 ± 3% in sham male and female rats, respectively. Notably, ovariectomy augmented the vasoconstrictor response to S6c (10^−12 to 10^−9 M), whereas orchiectomy had no significant impact on the responsiveness to ET_B receptor activation. Conclusion These data demonstrate that sex does not significantly influence afferent arteriole reactivity to ET receptor activation. Gonadectomy potentiated the responsiveness of the afferent arteriole to ET_B-induced vasoconstriction in females, but not males, suggesting that female sex hormones influence ET_B-mediated vasoconstriction in the renal microcirculation.

  • Afferent Arteriolar Responsiveness to Altered Perfusion Pressure in Renal Hypertension
    2016
    Co-Authors: Edward W Inscho, Anthony K. Cook, Pamela K. Carmines, Gabriel L. Navar
    Abstract:

    The present study was performed to determine the role of afferent arterioles in the impaired autoregulatory response shown to occur in the contralateral kidney of Goldblatt hypertensive rats. The responsiveness of Juxtamedullary afferent arterioles to alterations in perfusion pressure was studied in the nonclipped kidney of two-kidney, one clip hypertensive and sham-operated rats. Systolic pressure, 5-6 weeks after clipping, averaged 184±6 mm Hg in the hypertensive rats (n=16) and 121±3 mm Hg in the sham-operated control rats (n=7). By using the in vitro blood-perfused Juxtamedullary Nephron technique, afferent arterioles were directly visualized, and their inside diameters were measured by videomicroscopic methods. In sham-operated kidneys perfused with blood from normotensive rats, afferent arteriolar diameter averaged 22.8 ±1.8 fim at a renal arterial perfusion pressure of 151±1 mm Hg and increased to 24.8±1.8 fim when perfusion pressure was reduced to 110±2 mm Hg. Conversely, in hypertensive kidneys perfused with blood from either hypertensive or normotensive rats, the afferent arterioles failed to vasodilate and actually exhibited a slight decrease in diameter from 24.6 ±1.3 to 23.0 ±2.3 fim in response to the same reduction in perfusion pressure. Vasodilator capability, however, could be demonstrated in response to verapamil and sodium nitroprusside

  • abstract 491 activation of voltage dependent l type calcium channels and the rho kinase pathway are involved in s1p induced vasoconstriction in rat Juxtamedullary afferent arterioles
    Hypertension, 2012
    Co-Authors: Zhengrong Guan, Anthony K. Cook, Sean T Singletary, Edward W Inscho
    Abstract:

    Sphingosine-1-phosphate (S1P) is an important regulator of resistance vessels and is implicated in pathological processes including diabetic nephropathy and acute kidney injury. Previous studies show that S1P causes marked vasoconstriction in preglomerular but not postglomerular microvessels, however, the intracellular signaling pathways underlying S1P-mediated vasoconstriction are undefined. We postulated that S1P-mediated afferent arteriolar (AA) vasoconstriction involves activation of voltage-dependent L-type Ca2+ channels (L-VDCC) and the rho kinase pathway. Studies were conducted in vitro using the blood-perfused Juxtamedullary Nephron preparation. Superfusion of S1P (n=6) evoked concentration-dependent AA vasoconstriction. Control diameter averaged 13.8±0.9 μm and declined to 95±2, 85±4, 75±6, 60±5 and 46±5% of control diameter in response to S1P (from 10-9 to 10-5 M), respectively. Superfusion with nifedipine (10-6 M, n=6), a L-VDCC inhibitor, increased basal diameter by 39±18% (p 0.05), respectively. Similar results were obtained with CPA (10-5 M, n=6). S1P reduced diameter to 97±2, 93±2, 75±5, 53±6 and 36±5% of the control (p>0.05), respectively, suggesting that mobilization of intracellular Ca2+ store is not required for S1P-induced vasoconstriction. Overall, these data indicate that both L-VDCC and rho kinase pathways contribute to S1P-mediated AA vasoconstriction.

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