dani. Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms. Am J Physiol Regul Integr Comp Physiol 290: R1153-R1167, 2006. doi:10.1152/ajpregu.00402.2005.-When the kidney is subjected to acute increases in blood pressure (BP), renal blood flow (RBF) and glomerular filtration rate (GFR) are observed to remain relatively constant. Two mechanisms, tubuloglomerular feedback (TGF) and the myogenic response, are thought to act in concert to achieve a precise moment-by-moment regulation of GFR and distal salt delivery. The current view is that this mechanism insulates renal excretory function from fluctuations in BP. Indeed, the concept that renal autoregulation is necessary for normal renal function and volume homeostasis has long been a cornerstone of renal physiology. This article presents a very different view, 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. The arguments advanced take into consideration the unique properties of the afferent arteriolar myogenic response that allow it to protect against the oscillating systolic pressure and the accruing evidence that when this response is impaired, the primary consequence is not a disturbed volume homeostasis but rather an increased susceptibility to hypertensive injury. It is suggested that redundant and compensatory mechanisms achieve volume regulation, despite considerable fluctuations in distal delivery, and the assumed moment-by-moment regulation of renal hemodynamics is questioned. Evidence is presented suggesting that additional mechanisms exist to maintain ambient levels of RBF and GFR within normal range, despite chronic alterations in BP and severely impaired acute responses to pressure. Finally, the implications of this new perspective on the divergent roles of the myogenic response to pressure vs. the TGF response to changes in distal delivery are considered, and it is proposed that in addition to TGF-induced vasoconstriction, vasodepressor responses to reduced distal delivery may play a critical role in modulating afferent arteriolar reactivity to integrate the regulatory and protective functions of the renal microvasculature. renal microcirculation; afferent arteriole; myogenic; tubuloglomerular feedback ONE OF THE MOST STRIKING CHARACTERISTICS of the renal circulation is the ability of the kidney to maintain a constant renal blood flow (RBF) and glomerular filtration rate (GFR) as renal perfusion pressure is altered. The dual regulation of both RBF and GFR is achieved by proportionate changes in the preglomerular resistance and is believed to be mediated 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 alters tone in the adjacent segment of the afferent arteriole via a mechanism that remains controversial but likely involves adenosine and/or ATP (30,80,144). The myo...

P rimary essential hypertension is second only to diabetic nephropathy as a etiology for end-stage renal disease. 1 In addition, coexistent/superimposed hypertension plays a major role in the progression of most forms of chronic kidney disease (CKD), including diabetic nephropathy. [2][3][4][5] Nevertheless, the individual risk is very low, with Ͻ1% of the hypertensive population developing end-stage renal disease. Such data indicate that there must be mechanisms that normally protect the kidneys from hypertensive injury of a severity sufficient to result in end-stage renal disease. The following Brief Review summarizes the evidence that indicates that the renal autoregulatory response, primarily mediated by the myogenic mechanism, is largely responsible for such protection. Moreover, the differing patterns of renal damage that are observed in clinical and experimental hypertension are best explained when considered in the context of alterations in the renal autoregulatory capacity. Recent data also indicate that hypertensive renal damage correlates most strongly with systolic blood pressure (BP). 6 -8 Accordingly, the review further emphasizes the kinetic characteristics of the renal myogenic response to oscillating BP signals that render it particularly capable of providing protection against systolic pressures. Patterns of Hypertensive Renal DamageMost individuals with primary hypertension develop the modest vascular pathology of benign nephrosclerosis. 5 The glomeruli are largely spared, and, therefore, proteinuria is not a prominent feature. Because it progresses fairly slowly with limited ischemic nephron loss, renal function is not seriously compromised, except in some genetically susceptible individuals or groups, such as blacks, in whom a more accelerated course may be seen. 2-5 Thus, the slope of the relationship between renal damage and BP through most of the hypertensive range is fairly flat in individuals with benign nephrosclerosis. [2][3][4] However, if the hypertension becomes very severe and exceeds a critical threshold, severe acute disruptive injury of malignant nephrosclerosis to the renal arteries and arterioles develops that often extends into the glomeruli. 5,9 Many glomeruli show evidence of ischemia from more upstream vascular injury, but lesions of focal and segmental glomerulosclerosis (GS) are uncommon. Proteinuria, hematuria and renal failure develop rapidly. By contrast, patients with pre-existent diabetic and nondiabetic proteinuric CKD exhibit a markedly enhanced susceptibility to renal damage with even moderate BP elevations. [2][3][4] Moreover, in contrast to the predominantly vascular pathology in patients with benign or malignant nephrosclerosis, the dominant lesion associated with the progressive proteinuric CKD is that of GS, suggesting a somewhat different pathogenesis of hypertensive injury in such patients. 2-5 Similar patterns of relationships between BP and renal damage and the accompanying differences in renal pathology have been demonstrated in experimental models of ...

Abstract-The kinetic attributes of the afferent arteriole myogenic response were investigated using the in vitro perfused hydronephrotic rat kidney. Equations describing the time course for pressure-dependent vasoconstriction and vasodilation, and steady-state changes in diameter were combined to develop a mathematical model of autoregulation. Transfer functions were constructed by passing sinusoidal pressure waves through the model. These findings were compared with results derived using data from instrumented conscious rats. In each case, a reduction in gain and increase in phase were observed at frequencies of 0.2 to 0.3 Hz. We then examined the impact of oscillating pressure signals.The model predicted that pressure signals oscillating at frequencies above the myogenic operating range would elicit a sustained vasoconstriction the magnitude of which was dependent on peak pressure. These predictions were directly confirmed in the hydronephrotic kidney. Pressure oscillations presented at frequencies of 1 to 6 Hz elicited sustained afferent vasoconstrictions and the magnitude of the response depended exclusively on the peak pressure. Elevated systolic pressure elicited vasoconstriction even if mean pressure was reduced. These findings challenge the view that the renal myogenic response exists to maintain glomerular capillary pressure constant, but rather imply a primary role in protecting against elevated systolic pressures. Thus, the kinetic features of the afferent arteriole allow this vessel to adjust tone in response to changes in systolic pressures presented at the pulse rate. We suggest that the primary function of this mechanism is to protect the glomerulus from the blood pressure power that is normally present at the pulse frequency.

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. "Step" vs. "dynamic" autoregulation: implications for susceptibility to hypertensive injury. Am J Physiol Renal Physiol 285: F113-F120, 2003. First published March 11, 2003 10.1152/ajprenal.00012.2003.-Renal autoregulatory (AR) mechanisms provide the primary protection against transmission of systemic pressures, and their impairment is believed to be responsible for the enhanced susceptibility to hypertensive renal damage in renal mass reduction (RMR) models. Assessment of AR capacity by the "step" change methodology under anesthesia was compared with that by "dynamic" methods in separate conscious control Sprague-Dawley rats and after uninephrectomy (UNX) and 3 ⁄4 RMR (RK-NX) (n ϭ 7-10/group). Substantially less AR capacity was seen by the dynamic vs. the step methodology in control rats. Moreover, dynamic AR capacity did not differ among controls, UNX, and RK-NX rats (fractional gain in admittance ϳ0.4-0.5 in all groups at frequencies in the range of 0.0025-0.025 Hz). By contrast, significant impairment of step AR was seen in RK-NX vs. control or UNX rats (AR indexes 0.7 Ϯ 0.1 vs. 0.1 Ϯ 0.02 and 0.2 Ϯ 0.04, respectively, P Ͻ 0.01). We propose that the step and dynamic methods evaluate the renal AR responses to different components of blood pressure (BP) power with the step AR assessing the ability to buffer large changes in average BP (DC power), whereas the present "dynamic" methods assess the AR ability to buffer slow BP fluctuations (Ͻ0.25 Hz) superimposed on the average BP (AC power), a substantially smaller component of total BP power. We further suggest that step but not dynamic AR methods as presently performed provide a valid index of the underlying susceptibility to hypertensive glomerular damage after RMR. renal hemodynamics; hypertension; nephrosclerosis; myogenic response; tubuloglomerular feedback CHRONIC RENAL DISEASE regardless of etiology tends to follow a progressively downhill course (8, 36). Experimental animal models of renal mass reduction (RMR) exhibit a similar course of progressive glomerulosclerosis (GS) and nephron loss. On the basis of investigations in such models, it has been proposed that the loss of a critical degree of functional renal mass results in the initiation and perpetuation of pathogenetic mechanisms that are intrinsic to the reduced functional renal mass state (8,19,35,36,39,40). Several lines of evidence have indicated that an exaggerated transmission of systemic blood pressure (BP) to the glomerular capillaries is one such major pathogenetic mechanism (3-7, 23-26, 39-41). The pathophysiological basis for this enhanced glomerular BP transmission after RMR has been postulated to be due to an impairment of the renal autoregulatory (AR) mechanisms that normally provide the primary protection against BP increases, episodic or sustained, from being transmitted to the renal microvasculature (3,5,7,(23)(24)(25)(26)(27)(37)(38)(39)(40)(41).To date, such renal AR impairment in RMR models has only been demonstrated using the conventional "step" AR methodology in which grade...

Purpose of review Despite apparent blood pressure (BP) control and renin–angiotensin system (RAS) blockade, the chronic kidney disease (CKD) outcomes have been suboptimal. Accordingly, this review is addressed to renal microvascular and autoregulatory impairments that underlie the enhanced dynamic glomerular BP transmission in CKD progression. Recent findings Clinical data suggest that failure to achieve adequate 24-h BP control is likely contributing to the suboptimal outcomes in CKD. Whereas evidence continues to accumulate regarding the importance of preglomerular autoregulatory impairment to the dynamic glomerular BP transmission, emerging data indicate that nitric oxide-mediated efferent vasodilation may play an important role in mitigating the consequences of glomerular hypertension. By contrast, the vasoconstrictor effects of angiotensin II are expected to potentially reduce glomerular barotrauma and possibly enhance ischemic injury. When adequate BP measurement methods are used, the evidence for BP-independent injury initiating mechanisms is considerably weaker and the renoprotection by RAS blockade largely parallels its antihypertensive effectiveness. Summary Adequate 24-h BP control presently offers the most feasible intervention for reducing glomerular BP transmission and improving suboptimal outcomes in CKD. Investigations addressed to improving myogenic autoregulation and/or enhancing nitric oxide-mediated efferent dilation in addition to the more downstream mediators may provide additional future therapeutic targets.

Phosphorylation of the 20-kDa myosin regulatory light chains (LC(20)) plays a key role in the regulation of smooth muscle contraction. The level of LC(20) phosphorylation is governed by the relative activities of myosin light chain kinase and phosphatase pathways. The regulation of these two pathways differs in different smooth muscle types and in the actions of different vasoactive stimuli. Little is known concerning the regulation of LC(20) phosphorylation in the renal microcirculation. The available pharmacological probes are often nonspecific, and current techniques to directly measure LC(20) phosphorylation are not sensitive enough for quantification in small arterioles. We describe here a novel approach to address this important issue. Using SDS-PAGE with polyacrylamide-bound Mn(2+)-phosphate-binding tag and enhanced Western blot analysis, we were able to detect LC(20) phosphorylation using as little as 5 pg (250 amol) of isolated LC(20). Phosphorylated and unphosphorylated LC(20) were detected in single isolated afferent arterioles, and LC(20) phosphorylation levels could be accurately quantified in pooled samples of three arterioles (<300 cells). The phosphorylation level of LC(20) in the afferent arteriole was 6.8 +/- 1.7% under basal conditions and increased to 34.7 +/- 5.1% and 44.6 +/- 6.6% in response to 30 mM KCl and 10(-8) M angiotensin II, respectively. The application of this technique will enable investigations of the different determinants of LC(20) phosphorylation in afferent and efferent arterioles and provide insights into the signaling pathways that regulate LC(20) phosphorylation in the renal microvasculature under physiological and pathophysiological conditions.

The renal hemodynamic effects of Ca2+ antagonists are considered in the context of their actions on Ca2+ movements during activation of vascular smooth muscle. Observations in intact animals reveal that the renal hemodynamic response to Ca2+ antagonists is highly variable, depending on the neural and hormonal determinants of renal vascular tone. Studies in the isolated perfused kidney and in isolated renal vessels indicate that diverse agonists use different activating mechanisms with differing sensitivities to Ca2+ antagonists. In comparison with other direct-acting vasodilators, Ca2+ antagonists are unique in their ability to maintain or increase glomerular filtration rate. This effect is due, in part, to their selective reduction of afferent arteriolar resistance. This implies that activating mechanisms of the afferent and efferent arterioles differ. The ability of Ca2+ antagonists to augment glomerular filtration rate by concomitant actions on nonvascular sites remains to be elucidated.