renal auto regulation

8/8/2019 Renal Auto Regulation

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Renal autoregulation: newperspectives regarding the protectiveand regulatory roles of the underlying

mechanisms

Rodger Loutzenhiser,1 Karen Griffin,2Geoffrey Williamson,3 and Anil Bidani21Smooth Muscle Research Group, University of Calgary, Alberta, Canada; 2Department of Internal Medicine, Loyola University Medical Center and Edward Hines, Jr. Veterans AffairsHospital, Maywood, Illinois; and 3Department of Electrical and Computer Engineering, IllinoisInstitute of Technology, Chicago, Illinois


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ABSTRACT

When the kidney is subjected to acute increases in bloodpressure (BP), renal blood flow (RBF) and glomerular filtrationrate (GFR) are observed to remain relatively constant. Twomechanisms, tubuloglomerular feedback (TGF) and themyogenic response, are thought to act in concert to achieve aprecise moment-by-moment regulation of GFR and distal saltdelivery. The current view is that this mechanism insulatesrenal excretory function from fluctuations in BP. Indeed, the

concept that renal autoregulation is necessary for normal renalfunction and volume homeostasis has long been a cornerstoneof renal physiology.


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This article presents a very different view, at leastregarding the myogenic component of this response. We

suggest that its primary purpose is to protect the kidney againstthe damaging effects of hypertension. The argumentsadvanced take into consideration the unique properties of theafferent arteriolar myogenic response that allow it to protectagainst the oscillating systolic pressure and the accruingevidence that when this response is impaired, the primaryconsequence is not a disturbed volume homeostasis but rather

an increased susceptibility to hypertensive injury. It issuggested that redundant and compensatory mechanismsachieve volume regulation, despite considerable fluctuations indistal delivery, and the assumed moment-by-moment regulationof renal hemodynamics is questioned.


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E vidence is presented suggesting that additionalmechanisms exist to maintain ambient levels of RBF and GFRwithin normal range, despite chronic alterations in BP andseverely impaired acute responses to pressure. Finally, theimplications of this new perspective on the divergent roles of the myogenic response to pressure vs. the TGF response tochanges in distal delivery are considered, and it is proposedthat in addition to TGF-induced vasoconstriction,

vasodepressor responses to reduced distal delivery may play acritical role in modulating afferent arteriolar reactivity tointegrate the regulatory and protective functions of the renalmicrovasculature, renal microcirculation; afferent arteriole;myogenic; tubuloglomerular feedback.


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ONE O F TH E MOS T S TRIKIN G CHARACT E RIS TICS of the renal circulation is the ability of the kidney to maintain aconstant renal blood flow (RBF) and glomerular filtration rate(GFR) as renal perfusion pressure is altered. The dualregulation of both RBF and GFR is achieved by proportionatechanges in the preglomerular resistance and is believed to bemediated by two mechanisms, tubuloglomerular feedback(TGF) and the renal myogenic response. TGF involves a flow-

dependent signal that is sensed at the macula densa and alterstone in the adjacent segment of the afferent arteriole via amechanism that remains controversial but likely involvesadenosine and/or ATP.


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The myogenic response involves a direct vasoconstriction of theafferent arteriole when this vessel is presented with an increase intransmural pressure. The current view is that these two mechanismsact in concert and that their primary role is to stabilize renal function bypreventing pressure-induced fluctuations in RBF, GFR, and thedelivery of filtrate to the distal tubule (distal delivery).

O ver the last two decades, evidence has accrued to indicate thatthis autoregulatory response plays a concurrent role in protecting thekidney from hypertensive injury. This view is based on the strong linkbetween autoregulatory capacity and susceptibility to hypertensiveinjury. In the presence of intact autoregulation, minimal injury isobserved, despite substantial hypertension. However, when bloodpressure (BP) is elevated beyond the upper limit of normalautoregulatory capacity, renal damage develops rapidly.


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Conversely, if autoregulatory capacity is diminished,susceptibility to hypertensive renal damage is greatly enhanced andinjury is observed with even moderate hypertension. N evertheless, theprimary function of the renal vascular responses to pressure, and of the myogenic and TGF mechanisms, is believed to be regulatory, asreflected in the very term autoregulation. Thus renal protection is lostwhen renal autoregulation fails.

However, as discussed below, the requirements for maintaininga constant GFR and for protecting the glomerulus from hypertensiveinjury differ, even though both involve a regulation of glomerular capillary pressure (PGC). M oreover, the myogenic response and TGFsystem clearly sense different signals and, therefore, may play distinctroles in protection and regulation. This review presents the authorsperspective on the role of vascular responses to pressure in regulatingrenal function and in protecting the kidney against the adverse effectsof elevated systemic BP.


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HI STOR ICAL PERSPECT IV ES

Renal autoregulation may have first been described by Rein in 1931Bayliss-in 1902, he observed that the renal vasculature exhibits a profoundvasoconstriction when the kidney was subjected to elevated pressure.

- He viewed the renal response as an example of themyogenic response of vascular beds.

- He suggested that "The peripheral powers of reactionpossessed by the arteries is of such a nature as to provide as far as possiblefor the maintenance of a constant flow of blood through the tissues supplied bythem, whatever may be the height of the general blood-pressure. ..."Forster and M aes- in 1947, observed that not only RBF but also GFR

remained constant with acute elevations in BP; dual regulation of GFR andRBF could only be achieved if pressure-induced vasoconcstriction wasrestricted to preglomerular resistancde vesselsIt was generally accepted that, in the kidney, the need for volume preservationrequired that the capacity of the tubules to reabsorb the filtrate not beoverwhelmed by excessive GFRs.


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The unique anatomical relationship between the early distal nephronand its glomerular vascular pole was recognized by Goormaghtigh toprovide a potential site for such regulation. Thus in the vast majority of mammalian nephrons, the early distal tubule makes direct contact withthe vascular pole of its originating glomerulus.The early observations of Hrsing et al., that inhibition of proximal fluidreabsorption decreased both GFR and RBF, led to his suggestion thatincreased filling of the distal tubule might evoke signaling via themacula densa to regulate vascular resistanceS ubsequent demonstrations that alterations in the composition of thefluid presented to this early distal site caused reductions in theupstream proximal stop-flow pressure and that increased early distaltubular flow reduced the GFR of the affected nephron established thepresence of such a feedback response coupling distal filtrate deliveryto preglomerular vascular responses.


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In addition to a general myogenic response, the differing physiologicand metabolic requirements of tissues needed to be achieved byorgan-specific vascular regulatory mechanisms. S ubsequentapproaches, including mathematical modeling, led to the consensusthat both TGF and myogenic vasoconstriction are essential for normalautoregulation, although their relative contributions remaincontroversialO verwhelming of the myogenic capacity in some vascular segmentsby excessive BP led to focal vasodilatation, increased wall tensionand, ultimately, hypertensive cerebral vascular injury

The importance of local myogenic mechanisms in protecting againsthypertensive injury was formally recognized in the concept proposed in1972 that hypertensive encephalopathy may develop only when BPsexceed the upper limit of cerebral blood flow autoregulation.


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Collectively, such observations suggest that the samemechanisms responsible for renal autoregulation play a critical

role in protecting the kidney from the damaging effects of hypertension.S ince P GC is a primary determinant of GFR and an elevation inP GC is thought to be an initiating event in the sequence leadingto glomerular injury, renal protection might be viewed simply asan ancillary consequence of the regulation of GFR. Indeed,despite the clear linkage of the loss of autoregulatory capacityand glomerular injury, the primary importance of the regulatoryrole of renal autoregulation and its requirement for volumehomeostasis has remained a cornerstone of renal physiology.


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BP V AR IAB ILITY AND T H EREQU IREMENTS FOR PROTECT IONV S. REGULAT ION

A fundamental consideration regarding both the regulatory andthe protective functions of the renal vasculature is the fact that

BP spontaneously fluctuates at multiple frequenciesBP signals that evoke renal autoregulatory responses arealways oscillatory in nature, and the kinetic attributes of TGFand the myogenic mechanism determine the frequency rangeover which both autoregulation and renal protection canmanifest.To elicit a TGF response, a pressure increase must betransmitted and elicit an increase in the flow rate through thethick ascending limb. This, in turn, alters the composition of thefluid presented to the macula densa, stimulating the secretionof a vasoconstrictor near the afferent arteriole to increasepreglomerular resistance.


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In contrast, the myogenic mechanism involves an intrinsic smoothmuscle response to increased transmural pressure. The underlyingmechanisms, though not fully resolved, involve depolarization,activation of voltage-gated L-type Ca2+ channels and Ca2+ entrytriggering a rapid vasoconstriction.major variations in BP occur primarily at frequencies well below 0.3 Hzand the natural frequencies of the myogenic and TGF mechanisms aresufficient to attenuate their effects on renal function.Perturbations in BP that persist for only a fraction of a second wouldhave insignificant effects on mean RBF and GFR.Conversely, to be effective, renal protection must be achieved over thefull range of BP frequencies. Indeed, it is most critical to provideprotection against the rapidly oscillating systolic BP, as this componenthas been shown to correlate most closely with end organ hypertensiveinjury


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RENAL MYOGEN IC RESPONSE TOTH E OSC ILLAT ING SYSTOL ICPRESSURE S IGNAL

BP signals present to the afferent arteriole in vivo as complexwaveforms, consisting of a summation of oscillations occurring at eachfrequency. The rapidly oscillating systolic BP is an incessantcomponent of this signal and is always superimposed on the slower oscillationsM agnitude of the responses evoked under such conditions isexclusively determined by the systolic signal. Changes in diastolic andmean pressures had no effect, whereas elevations in systolic pressureevoked responses even if mean pressure was held constant.Thus not only is the afferent arteriole capable of responding tooscillating systolic BP, it is this signal that would provide the primarystimulus for setting myogenic tone under in vivo conditions.Young and M arsh found that, in response to an acute BP increase,renal vascular resistance increased after a delay of


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IMPL ICAT IONS FOR PROTECT IV E ANDREGULATORY ROLES OF RENALAUTOREGULATORY RESPONSE

RBF and GFR are determined by mean, not systolic, BP.a myogenic mechanism that responds exclusively to the systolic BP couldcontribute to autoregulation only to the extent changes in mean BP parallelchanges in systolic BPHowever, regarding renal protection, the dominant influence of the systolicBP is quite logical.The systolic BP signal determines a level of sustained ambient myogenictone. Increases in this signal trigger increases in tone, thereby imposingincreased impedance to limit the transmission of BP transients to thedownstream glomerulus. To the extent that changes in mean BP mirror

changes in the systolic BP signal, such alterations in myogenic tone wouldalso result in autoregulation.The natural frequencies of the myogenic response and TGF woulddetermine the dynamic range over which autoregulation would manifest.However, renal protection would be achieved over the full range of pressure oscillations by the sustained increase in myogenic tone. Thismodified view may explain how a myogenic mechanism operating at 0.3Hz normally protects the kidney from the more rapidly oscillating systolic

BP.


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If the myogenic mechanism protects the

glomerulus by responding exclusively to thesystolic BP, it must be recognized that aninherent corollary to this hypothesis is thatautoregulation of GFR or RBF, at least as it

relates to the myogenic mechanism, wouldbe a secondary consequence.


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CONSEQUENCES OF IMPA IREDRENAL AUTOREGULAT ION V OLUMEH OMEOSTAS IS

The kidney appears to normally be protected from hypertensive injuryas long as the BP remains within the autoregulatory range. However,

when autoregulation is impaired, the vulnerability to such injury ismarkedly augmented.There is little, if any, evidence to suggest that impaired autoregulationis accompanied by disturbed volume homeostasisHypertension, a potential manifestation of impaired volume regulation,is not clearly linked to a loss of autoregulation.Impaired TGF may cause volume disturbances only when the systemis exposed to specific stresses.Precise acute stabilization of renal hemodynamics is not an a priorireqirement for volume control.


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REGULAT ION OF RBF AND GFRINDEPENDENT OFAUTOREGULATORY RESPONSES

Autoregulation concerns the rapidly-acting

mechanisms that prevent imposed perturbations inBP from causing acute changes in RBF and GFRThe lack of influence of chronic BP elevations,despite impaired acute autoregulatory capacity,suggests the presence of other mechanisms capableof regulating basal GFR and RBF over a longer timecourse. Clearly, chronic alterations in GFR and RBFoccur in response to metabolic and excretory needs


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INTERACT IONS BETWEEN MYOGEN ICAND TGF MEC H AN ISMS

Because the myogenic and TGF responses share the same effector site, the afferent arteriole, interactions between these two systems areunavoidable. E ach response is capable of modulating the other. Theprevailing view is that these two mechanisms act in concert toaccomplish the same end, a stabilization of renal function when BP isaltered. This has led to a focus on synergistic interactions.If TGF and myogenic mechanisms play distinct roles in regulating

function and protection, their interactions might be more complex.M acula densa-triggered responses, because of their slower timecourse, could modulate the more rapid operation of a protective

myogenic mechanism.M oreover, both synergistic and antagonistic interactions could occur,based on physiologic needs. Thus in addition to TGF-mediatedvasoconstriction, macula densa-mediated vasodepressor responsescould limit myogenic reactivity, when protective responses disruptrenal function.


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The maintenance of an adequate GFR and/or distaldelivery is clearly important for normal volumehomeostasisCompensatory mechanisms may accommodateincreases in distal delivery, but severe reductionsare generally associated with volume retention

Reductions in BP evoke vasodilation by a reducedactivation of TGF and myogenic mechanisms.However, additional mechanisms contribute topreserving GFR when renal perfusion is impaired


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A clinical example is renal arterial stenosis in which increased reninrelease evokes A N G II-dependent efferent arteriolar tone to maintainGFR. The local formation of PG E 2 is essential in such settings, asillustrated by the critical role of cyclooxygenase (C OX ) in congestiveheart failure and cirrhosis. The renin and C OX pathways interact in acomplex manner. A N G II stimulates C OX activity, and PG E 2 is criticalin macula densa signaling of renin release. At the microvascular level,PG E 2 attenuates afferent arteriolar responses to A N G II, whilepreserving the efferent vasoconstriction. The resultant increase inglomerular outflow resistance maintains PGC and preserves GFR

when renal perfusion is compromised.The macula densa constitutively expresses high levels of bothneuronal nitric oxide ( NO ) synthase and C OX 2. The roles of these twovasodilator pathways in classic TGF signaling are not fully resolved,but both are implicated in TGF resetting. PG E 2 and NO have alsobeen shown to modulate the strength and kinetics of the myogeniccomponent of autoregulation


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It is generally accepted that an active TGF system (normal or increased distal delivery) is necessary for the full expression of

the myogenic response, and severe reductions in distal deliveryhave been shown to impair myogenic responses.Does TGF-induced vasoconstriction actually play an obligaterole in myogenic signaling? The robust myogenic responsesseen in the hydronephrotic kidney, which has no TGFmechanism, suggests this is perhaps not the case. S tudiesevaluating the possibility that myogenic reactivity is modulated

by a macula densa vasodepressor mechanism when distaldelivery is impaired would be of great interest.Finally, the unique anatomy suggests a primary importance of macula densa signaling in settings associated withinternephron heterogeneity.


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AN G II and endothelin-1 potently enhance

myogenic reactivity and a stimulation of either of these pathways could promotelocalized preglomerular vasospasm. Amacula densa-mediated vasodilatory

response could play an important regulatoryrole in affected nephrons.


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Conclusions and Perspectives

The observed autoregulation of RBF and GFR haslong been interpreted as reflecting a mechanism thatis required for normal renal excretory function andvolume homeostasis. N evertheless, observations indiverse animal models indicate that when renalautoregulation is impaired, there is no evidence of disturbed volume regulation. While it may be arguedthat redundant compensatory mechanisms mask theimpact of impaired autoregulation, theseobservations clearly demonstrate that intact renalautoregulatory mechanisms are not an obligaterequirement for adequate volume control


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Intact autoregulation does appear to be absolutely essential for normal renal protection, because impaired renal autoregulatorycapacity is invariably associated with an increase in thesusceptibility to hypertensive injury.O f the two underlying mechanisms, the myogenic response isuniquely suited to this protective role. Its unusual kineticattributes allow the afferent arteriole to sense elevations in therapidly oscillating systolic BP and adjust tone to this signal.While it is important to emphasize that this postulate awaits

critical evaluations using in vivo preparations and other experimental models, an important question concerns thedeterminants of this adaptation. The rapid onset invasoconstriction, which is also observed in vivo, is criticalregarding the response to oscillating signals. What novelsmooth muscle mechanisms are involved? E levations in thesystolic BP correlate most closely with end organ damage.


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N ormal autoregulation requires both myogenic andTGF mechanisms, and a myogenic constrictiontriggered by the systolic BP would contribute toautoregulation when this signal changes in concertwith mean BP. S imilarly, any mechanism elevatingpreglomerular tone, including TGF, could be viewedas contributing to renal protection. However, it is alsopossible that the myogenic and TGF responses playdistinct roles regarding protection and regulation of function and considerations of their potentialinteractions should be expanded.


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M acula densa-mediated vasodepressor mechanisms, triggeredby reduced distal delivery, could protect GFR by attenuatinginappropriate preglomerular vasoconstriction. An interestingpossibility is that such a response may modulate myogenicreactivity when a protective vasoconstriction to elevated systolicBP disrupts the regulation of distal delivery. S uch interactionswould serve to integrate the protective and regulatory functionsof the renal vasculature. S tudies evaluating this possibilitywould be of interest.

Finally, observations that ambient GFR and RBF remainnormal, despite hypertension, in animal models with impairedacute autoregulatory responses suggest the existence of previously unappreciated long-term adaptations. The nature of the underlying mechanisms deserves investigation.

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