Rho-kinase inhibition reduces pressure-mediated autoregulatory adjustments in afferent arteriolar diameter

Inscho, Edward W.; Cook, Anthony K.; Webb, R.; Li, Jin

doi:10.1152/ajprenal.90703.2008

Cited by 30 publications

(41 citation statements)

References 73 publications

(126 reference statements)

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“…44 L-VDCCs play a prominent role in controlling RBF and GFR by maintaining basal renal vascular tone and regulating preglomerular microvascular responses to various vasoconstrictor stimuli. [23][24][25][26]45,46 Thus, the involvement of L-VDCCs in S1P-mediated vasoconstriction of preglomerular microvessels implies that S1P may play an important role in regulating renal vascular resistance and in controlling the renal microcirculation. Nevertheless, a small proportion of S1P-mediated afferent arteriolar vasoconstriction was retained in the presence of diltiazem or nifedipine, suggesting that other intracellular signaling pathways may also be involved.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine-1-Phosphate Evokes Unique Segment-Specific Vasoconstriction of the Renal Microvasculature

Guan¹,

Singletary²,

Cook³

et al. 2014

Journal of the American Society of Nephrology

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Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, has been implicated in regulating vascular tone and participating in chronic and acute kidney injury. However, little is known about the role of S1P in the renal microcirculation. Here, we directly assessed the vasoresponsiveness of preglomerular and postglomerular microvascular segments to exogenous S1P using the in vitro blood-perfused juxtamedullary nephron preparation. Superfusion of S1P (0.001-10 mM) evoked concentration-dependent vasoconstriction in preglomerular microvessels, predominantly afferent arterioles. After administration of 10 mM S1P, the diameter of afferent arterioles decreased to 35%65% of the control diameter, whereas the diameters of interlobular and arcuate arteries declined to 50%612% and 68%66% of the control diameter, respectively. Notably, efferent arterioles did not respond to S1P. The S1P receptor agonists FTY720 and FTY720-phosphate and the specific S1P1 receptor agonist SEW2871 each evoked modest afferent arteriolar vasoconstriction. Conversely, S1P2 receptor inhibition with JTE-013 significantly attenuated S1P-mediated afferent arteriolar vasoconstriction. Moreover, blockade of L-type voltage-dependent calcium channels with diltiazem or nifedipine attenuated S1P-mediated vasoconstriction. Intravenous injection of S1P in anesthetized rats reduced renal blood flow dose dependently. Western blotting and immunofluorescence revealed S1P1 and S1P2 receptor expression in isolated preglomerular microvessels and microvascular smooth muscle cells. These data demonstrate that S1P evokes segmentally distinct preglomerular vasoconstriction via activation of S1P1 and/or S1P2 receptors, partially via L-type voltagedependent calcium channels. Accordingly, S1P may have a novel function in regulating afferent arteriolar resistance under physiologic conditions. 25: 177425: -178525: , 201425: . doi: 10.1681 Sphingosine 1-phosphate (S1P) is recognized as an important signaling molecule in diverse biologic processes. 1,2 Growing evidence indicates that S1P plays an important role in regulating vascular reactivity. 3-5 S1P is a bioactive sphingolipid metabolite and is released from erythrocytes, platelets, and endothelial cells. 6,7 The majority of S1P effects are mediated via five distinct receptors (S1P1-S1P5 receptors), which represent a family of small G proteincoupled receptors (GPCRs) 5 ; however, S1P can also exist in the cytoplasm as a second messenger involved in Ca 2+ mobilization or cell survival and proliferation. 8,9 S1P1-S1P3 receptors are expressed by a wide variety of tissues, whereas S1P4 and S1P5 receptors are mainly expressed in cells of the immune and nervous systems. 4,10 In the vasculature, endothelial cells mainly express S1P1 and S1P3 with variable expression of S1P2, whereas vascular smooth muscle cells express S1P2 and S1P3 with variable expression of S1P1. [3][4][5] Studies in animals show that application of exogenous S1P J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 99%

Sphingosine-1-Phosphate Evokes Unique Segment-Specific Vasoconstriction of the Renal Microvasculature

Guan¹,

Singletary²,

Cook³

et al. 2014

Journal of the American Society of Nephrology

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“…Interesting- Calcium measurements were performed using fura 2. Data were modified from an earlier report [74] ly, the afferent arteriolar vasoconstriction elicited by α β-methylene ATP was completely eliminated [88]. Thus, P2 receptor activation involves induction of a number of second messenger systems that also play major roles in regulating pressure-dependent renal perfusion.…”

Section: P2 Receptors and The Renal Microcirculation: Single Vessel Smentioning

confidence: 98%

“…Inhibition of Rho-kinase in hydronephrotic kidneys vasodilates virtually every pre-and postglomerular artery/arteriole and attenuates endothelin-or adenosine-induced renal microvascular vasoconstriction [87]. Similarly, preliminary in vitro studies revealed that Rho-kinase inhibition with Y-27632 produced a rapid, concentration-dependent afferent arteriolar vasodilation and inhibited renal autoregulatory responses [88]. In addition, vasoconstrictor responses induced by angiotensin II or ATP were markedly attenuated [88].…”

Section: P2 Receptors and The Renal Microcirculation: Single Vessel Smentioning

confidence: 99%

“…Similarly, preliminary in vitro studies revealed that Rho-kinase inhibition with Y-27632 produced a rapid, concentration-dependent afferent arteriolar vasodilation and inhibited renal autoregulatory responses [88]. In addition, vasoconstrictor responses induced by angiotensin II or ATP were markedly attenuated [88]. Interesting- Calcium measurements were performed using fura 2.…”

Section: P2 Receptors and The Renal Microcirculation: Single Vessel Smentioning

confidence: 99%

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ATP, P2 receptors and the renal microcirculation

Inscho

2009

Purinergic Signalling

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Purinoceptors are rapidly becoming recognised as important regulators of tissue and organ function. Renal expression of P2 receptors is broad and diverse, as reflected by the fact that P2 receptors have been identified in virtually every major tubular/vascular element. While P2 receptor expression by these renal structures is recognised, the physiological functions that they serve remains to be clarified. Renal vascular P2 receptor expression is complex and poorly understood. Evidence suggests that different complements of P2 receptors are expressed by individual renal vascular segments. This unique distribution has given rise to the postulate that P2 receptors are important for renal vascular function, including regulation of preglomerular resistance and autoregulatory behaviour. More recent studies have also uncovered evidence that hypertension reduces renal vascular reactivity to P2 receptor stimulation in concert with compromised autoregulatory capability. This review will consolidate findings related to the role of P2 receptors in regulating renal microvascular function and will present areas of controversy related to the respective roles of ATP and adenosine in autoregulatory resistance adjustments.

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“…Studies using local administration of inhibitors in intact rats have reported ROCK inhibitor-induced dose-dependent increases renal blood flow (Bauer and Parekh, 2003;Cavarape et al, 2003b). At the glomerular level, measurements utilizing videomicroscopy in isolated split rat hydronephrotic kidneys or the in vitro blood-perfused juxtamedullary nephron technique have determined that ROCK inhibitors induce predominantly afferent and lesser efferent, arteriolar dilation (Cavarape et al, 2003b;Nakamura et al, 2003;Inscho et al, 2009). In the present studies, the whole kidney haemodynamic pattern induced by ROCK inhibitors in diabetic rats suggests not only afferent but also an important efferent effect of these compounds in diabetic rats.…”

Section: Figurementioning

confidence: 99%

Effects of systemic inhibition of Rho kinase on blood pressure and renal haemodynamics in diabetic rats

Komers

Oyama

Beard

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSE The RhoA/Rho associated kinases (ROCK) pathway has been implicated in the pathophysiology of diabetic nephropathy (DN). Early stages of diabetes are associated with renal haemodynamic changes, contributing to later development of DN. However, the role of RhoA/ROCK, known regulators of vascular tone, in this process has not been studied.EXPERIMENTAL APPROACH Blood pressure (BP), glomerular filtration (GFR), effective renal plasma flow and filtration fraction (FF) in response to the ROCK inhibitors Y27632 (0.1 and 0.5 mg·kg−1) and fasudil (0.3 and 1.5 mg·kg−1) were examined in streptozotocin‐diabetic rats and non‐diabetic controls.KEY RESULTS Diabetic rats demonstrated baseline increases in GFR and FF. In contrast to similar decreases in BP in diabetic and control rats, renal vasodilator effects and a decrease in FF, following ROCK inhibition were observed only in diabetic rats. The vasodilator effects of Y27632 and a further decrease in FF, were also detected in diabetic rats pretreated with the angiotensin antagonist losartan. The effects of ROCK inhibitors in diabetic rats were modulated by prior protein kinase C (PKC)β inhibition with ruboxistaurin, which abolished their effects on FF. Consistent with the renal vasodilator effects, the ROCK inhibitors reduced phosphorylation of myosin light chain in diabetic kidneys.CONCLUSIONS AND IMPLICATIONS The results indicate greater dependence of renal haemodynamics on RhoA/ROCK and beneficial haemodynamic effects of ROCK inhibitors in diabetes, which were additive to the effects of losartan. In this process, the RhoA/ROCK pathway operated downstream of or interacted with, PKCβ in some segments of the renal vascular tree.

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Rho-kinase inhibition reduces pressure-mediated autoregulatory adjustments in afferent arteriolar diameter

Cited by 30 publications

References 73 publications

Sphingosine-1-Phosphate Evokes Unique Segment-Specific Vasoconstriction of the Renal Microvasculature

Sphingosine-1-Phosphate Evokes Unique Segment-Specific Vasoconstriction of the Renal Microvasculature

ATP, P2 receptors and the renal microcirculation

Effects of systemic inhibition of Rho kinase on blood pressure and renal haemodynamics in diabetic rats

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