Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms

Rodger Loutzenhiser,1 Karen Griffin,2 Geoffrey Williamson, and !nil "idani2 1Smooth Muscle Research Group, University of Calgary, Alberta, Canada; !epartment of "nternal Medicine, #oyola University Medical Center and $d%ard &ines, 'r( )eterans Affairs &ospital, May%ood, "llinois; and *!epartment of $lectrical and Computer $ngineering, "llinois "nstitute of +echnology, Chicago, "llinois

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When the kidney is subjected to acute increases in blood pressure (BP), renal blood flow (RBF) and glomerular filtration rate ( FR) are obser!ed to remain relati!ely constant" #wo mechanisms, tubuloglomerular feedback (# F) and the myogenic response, are thought to act in concert to achie!e a precise moment$by$moment regulation of FR and distal salt deli!ery" #he current !iew is that this mechanism insulates renal e%cretory function from fluctuations in BP" &ndeed, the concept that renal autoregulation is necessary for normal renal function and !olume homeostasis has long been a cornerstone of renal physiology"

#his article presents a !ery different !iew, at least regarding the myogenic component of this response" We suggest that its primary purpose is to protect the kidney against the damaging effects of hypertension" #he arguments ad!anced take into consideration the uni'ue properties of the afferent arteriolar myogenic response that allow it to protect against the oscillating systolic pressure and the accruing e!idence that when this response is impaired, the primary conse'uence is not a disturbed !olume homeostasis but rather an increased susceptibility to hypertensi!e injury" &t is suggested that redundant and compensatory mechanisms achie!e !olume regulation, despite considerable fluctuations in distal deli!ery, and the assumed moment$by$moment regulation of renal hemodynamics is 'uestioned"

(!idence is presented suggesting that additional mechanisms e%ist to maintain ambient le!els of RBF and FR within normal range, despite chronic alterations in BP and se!erely impaired acute responses to pressure" Finally, the implications of this new perspecti!e on the di!ergent roles of the myogenic response to pressure !s" the # F response to changes in distal deli!ery are considered, and it is proposed that in addition to # F$induced !asoconstriction, !asodepressor responses to reduced distal deli!ery may play a critical role in modulating afferent arteriolar reacti!ity to integrate the regulatory and protecti!e functions of the renal micro!asculature, renal microcirculation) afferent arteriole) myogenic) tubuloglomerular feedback"

*+( *F #,( -*.# .#R&/&+ 0,1R10#(R&.#&0. of the renal circulation is the ability of the kidney to maintain a constant renal blood flow (RBF) and glomerular filtration rate ( FR) as renal perfusion pressure is altered" #he dual regulation of both RBF and FR is achie!ed by proportionate changes in the preglomerular resistance and is belie!ed to be mediated by two mechanisms, tubuloglomerular feedback (# F) and the renal myogenic response" # F in!ol!es a flow$ dependent signal that is sensed at the macula densa and alters tone in the adjacent segment of the afferent arteriole !ia a mechanism that remains contro!ersial but likely in!ol!es adenosine and2or 1#P"

#he myogenic response in!ol!es a direct !asoconstriction of the afferent arteriole when this !essel is presented with an increase in transmural pressure" #he current !iew is that these two mechanisms act in concert and that their primary role is to stabili3e renal function by pre!enting pressure$induced fluctuations in RBF, FR, and the deli!ery of filtrate to the distal tubule (distal deli!ery)" *!er the last two decades, e!idence has accrued to indicate that this autoregulatory response plays a concurrent role in protecting the kidney from hypertensi!e injury" #his !iew is based on the strong link between autoregulatory capacity and susceptibility to hypertensi!e injury" &n the presence of intact autoregulation, minimal injury is obser!ed, despite substantial hypertension" ,owe!er, when blood pressure (BP) is ele!ated beyond the upper limit of normal autoregulatory capacity, renal damage de!elops rapidly"

0on!ersely, if autoregulatory capacity is diminished, susceptibility to hypertensi!e renal damage is greatly enhanced and injury is obser!ed with e!en moderate hypertension" +e!ertheless, the primary function of the renal !ascular responses to pressure, and of the myogenic and # F mechanisms, is belie!ed to be regulatory, as reflected in the !ery term autoregulation" #hus renal protection is lost when renal autoregulation fails" ,owe!er, as discussed below, the re'uirements for maintaining a constant FR and for protecting the glomerulus from hypertensi!e injury differ, e!en though both in!ol!e a regulation of glomerular capillary pressure (P 0)" -oreo!er, the myogenic response and # F system clearly sense different signals and, therefore, may play distinct roles in protection and regulation" #his re!iew presents the authors4 perspecti!e on the role of !ascular responses to pressure in regulating renal function and in protecting the kidney against the ad!erse effects of ele!ated systemic BP"

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Renal autoregulation may ha!e first been described by Rein in 5675 Bayliss$in 5689, he obser!ed that the renal !asculature e%hibits a profound !asoconstriction when the kidney was subjected to ele!ated pressure" $ ,e !iewed the renal response as an e%ample of the myogenic response of !ascular beds" $ ,e suggested that :#he peripheral powers of reaction possessed by the arteries is of such a nature as to pro!ide as far as possible for the maintenance of a constant flow of blood through the tissues supplied by them, whate!er may be the height of the general blood$pressure" """: Forster and -aes$ in 56;<, obser!ed that not only RBF but also FR remained constant with acute ele!ations in BP) dual regulation of FR and RBF could only be achie!ed if pressure$induced !asoconcstriction was restricted to preglomerular resistancde !essels &t was generally accepted that, in the kidney, the need for !olume preser!ation re'uired that the capacity of the tubules to reabsorb the filtrate not be o!erwhelmed by e%cessi!e FRs"

#he uni'ue anatomical relationship between the early distal nephron and its glomerular !ascular pole was recogni3ed by oormaghtigh to pro!ide a potential site for such regulation" #hus in the !ast majority of mammalian nephrons, the early distal tubule makes direct contact with the !ascular pole of its originating glomerulus" #he early obser!ations of ,=rsing et al", that inhibition of pro%imal fluid reabsorption decreased both FR and RBF, led to his suggestion that increased filling of the distal tubule might e!oke signaling !ia the macula densa to regulate !ascular resistance .ubse'uent demonstrations that alterations in the composition of the fluid presented to this early distal site caused reductions in the upstream pro%imal stop$flow pressure and that increased early distal tubular flow reduced the FR of the affected nephron established the presence of such a feedback response coupling distal filtrate deli!ery to preglomerular !ascular responses"

&n addition to a general myogenic response, the differing physiologic and metabolic re'uirements of tissues needed to be achie!ed by organ$specific !ascular regulatory mechanisms" .ubse'uent approaches, including mathematical modeling, led to the consensus that both # F and myogenic !asoconstriction are essential for normal autoregulation, although their relati!e contributions remain contro!ersial *!erwhelming of the myogenic capacity in some !ascular segments by e%cessi!e BP led to focal !asodilatation, increased wall tension and, ultimately, hypertensi!e cerebral !ascular injury #he importance of local myogenic mechanisms in protecting against hypertensi!e injury was formally recogni3ed in the concept proposed in 56<9 that hypertensi!e encephalopathy may de!elop only when BPs e%ceed the upper limit of cerebral blood flow autoregulation"

0ollecti!ely, such obser!ations suggest that the same mechanisms responsible for renal autoregulation play a critical role in protecting the kidney from the damaging effects of hypertension" .ince P 0 is a primary determinant of FR and an ele!ation in P 0 is thought to be an initiating e!ent in the se'uence leading to glomerular injury, renal protection might be !iewed simply as an ancillary conse'uence of the regulation of FR" &ndeed, despite the clear linkage of the loss of autoregulatory capacity and glomerular injury, the primary importance of the regulatory role of renal autoregulation and its re'uirement for !olume homeostasis has remained a cornerstone of renal physiology"

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1 fundamental consideration regarding both the regulatory and the protecti!e functions of the renal !asculature is the fact that BP spontaneously fluctuates at multiple fre'uencies BP signals that e!oke renal autoregulatory responses are always oscillatory in nature, and the kinetic attributes of # F and the myogenic mechanism determine the fre'uency range o!er which both autoregulation and renal protection can manifest" #o elicit a # F response, a pressure increase must be transmitted and elicit an increase in the flow rate through the thick ascending limb" #his, in turn, alters the composition of the fluid presented to the macula densa, stimulating the secretion of a !asoconstrictor near the afferent arteriole to increase preglomerular resistance"

&n contrast, the myogenic mechanism in!ol!es an intrinsic smooth muscle response to increased transmural pressure" #he underlying mechanisms, though not fully resol!ed, in!ol!e depolari3ation, acti!ation of !oltage$gated >$type 0a9? channels and 0a9? entry triggering a rapid !asoconstriction" major !ariations in BP occur primarily at fre'uencies well below 8"7 ,3 and the natural fre'uencies of the myogenic and # F mechanisms are sufficient to attenuate their effects on renal function" Perturbations in BP that persist for only a fraction of a second would ha!e insignificant effects on mean RBF and FR" 0on!ersely, to be effecti!e, renal protection must be achie!ed o!er the full range of BP fre'uencies" &ndeed, it is most critical to pro!ide protection against the rapidly oscillating systolic BP, as this component has been shown to correlate most closely with end organ hypertensi!e injury

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BP signals present to the afferent arteriole in !i!o as comple% wa!eforms, consisting of a summation of oscillations occurring at each fre'uency" #he rapidly oscillating systolic BP is an incessant component of this signal and is always superimposed on the slower oscillations -agnitude of the responses e!oked under such conditions is e%clusi!ely determined by the systolic signal" 0hanges in diastolic and mean pressures had no effect, whereas ele!ations in systolic pressure e!oked responses e!en if mean pressure was held constant" #hus not only is the afferent arteriole capable of responding to oscillating systolic BP, it is this signal that would pro!ide the primary stimulus for setting myogenic tone under in !i!o conditions" @oung and -arsh found that, in response to an acute BP increase, renal !ascular resistance increased after a delay of A5 s, it achie!ed B8C of the response within 7D; s and the response reached completion by 5BD98 s"

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RBF and FR are determined by mean, not systolic, BP" a myogenic mechanism that responds e%clusi!ely to the systolic BP could contribute to autoregulation only to the e%tent changes in mean BP parallel changes in systolic BP ,owe!er, regarding renal protection, the dominant influence of the systolic BP is 'uite logical" #he systolic BP signal determines a le!el of sustained ambient myogenic tone" &ncreases in this signal trigger increases in tone, thereby imposing increased impedance to limit the transmission of BP transients to the downstream glomerulus" #o the e%tent that changes in mean BP mirror changes in the systolic BP signal, such alterations in myogenic tone would also result in autoregulation" #he natural fre'uencies of the myogenic response and # F would determine the dynamic range o!er which autoregulation would manifest" ,owe!er, renal protection would be achie!ed o!er the full range of pressure oscillations by the sustained increase in myogenic tone" #his modified !iew may e%plain how a myogenic mechanism operating at 8"7 ,3 normally protects the kidney from the more rapidly oscillating systolic BP"

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the myogenic mechanism protects the glomerulus by responding e%clusi!ely to the systolic BP, it must be recogni3ed that an inherent corollary to this hypothesis is that autoregulation of FR or RBF, at least as it relates to the myogenic mechanism, would be a secondary conse'uence"

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#he kidney appears to normally be protected from hypertensi!e injury as long as the BP remains within the autoregulatory range" ,owe!er, when autoregulation is impaired, the !ulnerability to such injury is markedly augmented" #here is little, if any, e!idence to suggest that impaired autoregulation is accompanied by disturbed !olume homeostasis ,ypertension, a potential manifestation of impaired !olume regulation, is not clearly linked to a loss of autoregulation" &mpaired # F may cause !olume disturbances only when the system is e%posed to specific stresses" Precise acute stabili3ation of renal hemodynamics is not an a priori re'irement for !olume control"

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1utoregulation concerns the rapidly$acting mechanisms that pre!ent imposed perturbations in BP from causing acute changes in RBF and FR #he lack of influence of chronic BP ele!ations, despite impaired acute autoregulatory capacity, suggests the presence of other mechanisms capable of regulating basal FR and RBF o!er a longer time course" 0learly, chronic alterations in FR and RBF occur in response to metabolic and e%cretory needs

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Because the myogenic and # F responses share the same effector site, the afferent arteriole, interactions between these two systems are una!oidable" (ach response is capable of modulating the other" #he pre!ailing !iew is that these two mechanisms act in concert to accomplish the same end, a stabili3ation of renal function when BP is altered" #his has led to a focus on synergistic interactions" &f # F and myogenic mechanisms play distinct roles in regulating function and protection, their interactions might be more comple%" -acula densa$triggered responses, because of their slower time course, could modulate the more rapid operation of a protecti!e myogenic mechanism" -oreo!er, both synergistic and antagonistic interactions could occur, based on physiologic needs" #hus in addition to # F$mediated !asoconstriction, macula densa$mediated !asodepressor responses could limit myogenic reacti!ity, when protecti!e responses disrupt renal function"

#he maintenance of an ade'uate FR and2or distal deli!ery is clearly important for normal !olume homeostasis 0ompensatory mechanisms may accommodate increases in distal deli!ery, but se!ere reductions are generally associated with !olume retention Reductions in BP e!oke !asodilation by a reduced acti!ation of # F and myogenic mechanisms" ,owe!er, additional mechanisms contribute to preser!ing FR when renal perfusion is impaired

1 clinical e%ample is renal arterial stenosis in which increased renin release e!okes 1+ &&$dependent efferent arteriolar tone to maintain FR" #he local formation of P (9 is essential in such settings, as illustrated by the critical role of cycloo%ygenase (0*E) in congesti!e heart failure and cirrhosis" #he renin and 0*E pathways interact in a comple% manner" 1+ && stimulates 0*E acti!ity, and P (9 is critical in macula densa signaling of renin release" 1t the micro!ascular le!el, P (9 attenuates afferent arteriolar responses to 1+ &&, while preser!ing the efferent !asoconstriction" #he resultant increase in glomerular outflow resistance maintains P 0 and preser!es FR when renal perfusion is compromised" #he macula densa constituti!ely e%presses high le!els of both neuronal nitric o%ide (+*) synthase and 0*E9" #he roles of these two !asodilator pathways in classic # F signaling are not fully resol!ed, but both are implicated in # F resetting" P (9 and +* ha!e also been shown to modulate the strength and kinetics of the myogenic component of autoregulation

&t is generally accepted that an acti!e # F system (normal or increased distal deli!ery) is necessary for the full e%pression of the myogenic response, and se!ere reductions in distal deli!ery ha!e been shown to impair myogenic responses" Foes # F$induced !asoconstriction actually play an obligate role in myogenic signalingG #he robust myogenic responses seen in the hydronephrotic kidney, which has no # F mechanism, suggests this is perhaps not the case" .tudies e!aluating the possibility that myogenic reacti!ity is modulated by a macula densa !asodepressor mechanism when distal deli!ery is impaired would be of great interest" Finally, the uni'ue anatomy suggests a primary importance of macula densa signaling in settings associated with internephron heterogeneity"

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&& and endothelin$5 potently enhance myogenic reacti!ity and a stimulation of either of these pathways could promote locali3ed preglomerular !asospasm" 1 macula densa$mediated !asodilatory response could play an important regulatory role in affected nephrons"

Conclusions and Perspectives

#he obser!ed autoregulation of RBF and FR has long been interpreted as reflecting a mechanism that is re'uired for normal renal e%cretory function and !olume homeostasis" +e!ertheless, obser!ations in di!erse animal models indicate that when renal autoregulation is impaired, there is no e!idence of disturbed !olume regulation" While it may be argued that redundant compensatory mechanisms mask the impact of impaired autoregulation, these obser!ations clearly demonstrate that intact renal autoregulatory mechanisms are not an obligate re'uirement for ade'uate !olume control

&ntact autoregulation does appear to be absolutely essential for normal renal protection, because impaired renal autoregulatory capacity is in!ariably associated with an increase in the susceptibility to hypertensi!e injury" *f the two underlying mechanisms, the myogenic response is uni'uely suited to this protecti!e role" &ts unusual kinetic attributes allow the afferent arteriole to sense ele!ations in the rapidly oscillating systolic BP and adjust tone to this signal" While it is important to emphasi3e that this postulate awaits critical e!aluations using in !i!o preparations and other e%perimental models, an important 'uestion concerns the determinants of this adaptation" #he rapid onset in !asoconstriction, which is also obser!ed in !i!o, is critical regarding the response to oscillating signals" What no!el smooth muscle mechanisms are in!ol!edG (le!ations in the systolic BP correlate most closely with end organ damage"

+ormal autoregulation re'uires both myogenic and # F mechanisms, and a myogenic constriction triggered by the systolic BP would contribute to autoregulation when this signal changes in concert with mean BP" .imilarly, any mechanism ele!ating preglomerular tone, including # F, could be !iewed as contributing to renal protection" ,owe!er, it is also possible that the myogenic and # F responses play distinct roles regarding protection and regulation of function and considerations of their potential interactions should be e%panded"

-acula densa$mediated !asodepressor mechanisms, triggered by reduced distal deli!ery, could protect FR by attenuating inappropriate preglomerular !asoconstriction" 1n interesting possibility is that such a response may modulate myogenic reacti!ity when a protecti!e !asoconstriction to ele!ated systolic BP disrupts the regulation of distal deli!ery" .uch interactions would ser!e to integrate the protecti!e and regulatory functions of the renal !asculature" .tudies e!aluating this possibility would be of interest" Finally, obser!ations that ambient FR and RBF remain normal, despite hypertension, in animal models with impaired acute autoregulatory responses suggest the e%istence of pre!iously unappreciated long$term adaptations" #he nature of the underlying mechanisms deser!es in!estigation"