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.

Renal injury in the Dahl salt-sensitive rat mimics human salt-sensitive forms of hypertension that are particularly prevalent in black individuals, but the mechanisms that lead to the development of this injury are incompletely understood. We studied the impact of renal perfusion pressure (RPP) on the development of renal injury in this model. During the development of salt-induced hypertension over 2 wk, the RPP to the left kidney was maintained at control levels (125 Ϯ 2 mmHg) by continuous servocontrol inflation of an aortic balloon implanted between the renal arteries; during the same period, the RPP to the right kidney rose to 164 Ϯ 8 mmHg. After 2 wk of a 4% salt diet, DNA microarray and real-time PCR identified genes related to fibrosis and epithelial-to-mesenchymal transition in the kidneys exposed to hypertension. The increased RPP to the right kidney accounted for differences in renal injury between the two kidneys, measured by percentage of injured cortical and juxtamedullary glomeruli, quantified proteinaceous casts, number of ED-1-positive cells per glomerular tuft area, and interstitial fibrosis. Interlobular arteriolar injury was not increased in the kidney exposed to elevated pressure but was reduced in the control kidney. We conclude that elevations of RPP contribute significantly to the fibrosis and epithelial-to-mesenchymal transition found in the early phases of hypertension in the salt-sensitive rat. Rapid development of renal injury is a prominent feature of salt-induced hypertension in the Dahl salt-sensitive (SS) rat. Within a few weeks of high salt exposure, SS rats develop substantial injuries in preglomerular vessels, glomeruli, and the tubulointerstitial compartment. [1][2][3] This prominence of renal injury in the SS rat mimics human salt-sensitive forms of hypertension that are particularly prevalent in black individuals. 4 The extent of renal injury is known to vary widely in various forms of hypertension. Rapid development of renal injury in SS rats is in sharp contrast with that observed in spontaneously hypertensive rats (SHR), another commonly used rat model of hypertension. Hypertension in the SHR of a magnitude and duration similar to that seen in SS rats results in little or no renal injury. [5][6][7][8] Moreover, although it is recognized that hypertension is a strong independent risk factor for renal failure, the effectiveness of BP control in the reduction of renal injury varies greatly between subpopulations of hypertensive patients. 9 -11 These observations have clouded the question of how much physical factors related to the elevation of renal perfusion pressure (RPP) actually contribute to renal injury in hypertension. This issue has not been easily clarified given the difficulty in sustaining a chronic increase

To understand the role of muscle perfusion in the sex differences of muscle fatigue, we compared the time to task failure, postcontraction (active) hyperemia, and vascular conductance for an isometric fatiguing contraction performed by young men and women with the handgrip muscles at 20% of maximal voluntary contraction (MVC) force. In study 1, the men ( n = 16) were stronger than the women ( n = 18), and study 2, the men ( n = 7) and women ( n = 7) were matched for strength. Isometric contractions were sustained during two sessions: 1) until the target force could no longer be achieved or 2) for 4 min. For both studies, blood flow and vascular conductance were similar for the men and women at rest and after 10 min of occlusion, and at task failure for the fatiguing contraction estimated using forearm venous occlusion plethysmography. In study 1, the time to task failure was longer for the women (11.4 ± 2.8 min) than for the men (8.4 ± 2.4 min; P = 0.003). However, at the end of the 4-min contraction, active hyperemia and vascular conductance were greater for the men than the women (99 vs. 70% peak blood flow; P < 0.001). In study 2, the men and women had similar strength and a similar time to failure (8.4 ± 1.6 vs. 8.6 ± 2.3 min). Active hyperemia was greater for the men than the women (86 vs. 64% peak flow; P = 0.038) after the 4-min contraction, as was vascular conductance (80 vs. 57% peak conductance; P = 0.02). Thus the briefer time to failure of men than women for an isometric fatiguing contraction is a function of the greater strength of men but is not dependent on differences in the active hyperemia and vascular conductance.

We investigated the signaling basis for tubule pathology during fibrosis after renal injury. Numerous signaling pathways are activated physiologically to direct tubule regeneration after acute kidney injury (AKI) but several persist pathologically after repair. Among these, transforming growth factor (TGF)-β is particularly important because it controls epithelial differentiation and profibrotic cytokine production. We found that increased TGF-β signaling after AKI is accompanied by PTEN loss from proximal tubules (PT). With time, subpopulations of regenerating PT with persistent loss of PTEN (phosphate and tension homolog) failed to differentiate, became growth arrested, expressed vimentin, displayed profibrotic JNK activation, and produced PDGF-B. These tubules were surrounded by fibrosis. In contrast, PTEN recovery was associated with epithelial differentiation, normal tubule repair, and less fibrosis. This beneficial outcome was promoted by TGF-β antagonism. Tubule-specific induction of TGF-β led to PTEN loss, JNK activation, and fibrosis even without prior AKI. In PT culture, high TGF-β depleted PTEN, inhibited differentiation, and activated JNK. Conversely, TGF-β antagonism increased PTEN, promoted differentiation, and decreased JNK activity. Cre-Lox PTEN deletion suppressed differentiation, induced growth arrest, and activated JNK. The low-PTEN state with JNK signaling and fibrosis was ameliorated by contralateral nephrectomy done 2 wk after unilateral ischemia, suggesting reversibility of the low-PTEN dysfunctional tubule phenotype. Vimentin-expressing tubules with low-PTEN and JNK activation were associated with fibrosis also after tubule-selective AKI, and with human chronic kidney diseases of diverse etiology. By preventing tubule differentiation, the low-PTEN state may provide a platform for signals initiated physiologically to persist pathologically and cause fibrosis after injury.

Preexisting CKD may affect the severity of and/or recovery from AKI. We assessed the impact of prior graded normotensive renal mass reduction on ischemia-reperfusion-induced AKI. Rats underwent 40 minutes of ischemia 2 weeks after right uninephrectomy and surgical excision of both poles of the left kidney (75% reduction of renal mass), right uninephrectomy (50% reduction of renal mass), or sham reduction of renal mass. The severity of AKI was comparable among groups, which was reflected by similarly increased serum creatinine (S Cr ; approximately 4.5 mg/dl) at 2 days, tubule necrosis at 3 days, and vimentinexpressing regenerating tubules at 7 days postischemia-reperfusion. However, S Cr remained elevated compared with preischemia-reperfusion values, and more tubules failed to differentiate during late recovery 4 weeks after ischemia-reperfusion in rats with 75% renal mass reduction relative to other groups. Tubules that failed to differentiate continued to produce vimentin, exhibited vicarious proliferative signaling, and expressed less vascular endothelial growth factor but more profibrotic peptides. The disproportionate failure of regenerating tubules to redifferentiate in rats with 75% renal mass reduction associated with more severe capillary rarefaction and greater tubulointerstitial fibrosis. Furthermore, initially normotensive rats with 75% renal mass reduction developed hypertension and proteinuria, 2-4 weeks postischemia-reperfusion. In summary, severe (.50%) renal mass reduction disproportionately compromised tubule repair, diminished capillary density, and promoted fibrosis with hypertension after ischemia-reperfusion-induced AKI in rats, suggesting that accelerated declines of renal function may occur after AKI in patients with preexisting CKD. 25: 149625: -150725: , 201425: . doi: 10.1681 Clinical studies suggest that AKI worsens preexisting CKD and accelerates progression to end stage because of residual structural and functional deficits. 1-7 CKD, per se, may increase the risk and severity of AKI and the likelihood of incomplete recovery from AKI. 8 Thus, AKI and CKD reinforce each other to increase nephron loss and tubulointerstitial fibrosis (TIF). 9 Nevertheless, causal relationships for both aspects of the AKI-CKD nexus 10 (AKI resulting in CKD/ESRD and CKD, per se, predisposing to AKI) have been questioned. 11,12 These concerns were recently reviewed. 13 AKI-CKD relationships have also been questioned on the grounds that mechanisms for AKI-CKD interactions are ill-defined and controversial. [14][15][16] We addressed these uncertainties by investigating the impact of normotensive renal mass reduction (RMR; 0%, 50%, and 75%) of 2-weeks duration on AKI induced by ischemia-reperfusion (I/R) in rats. We addressed three questions. (1) Does prior RMR increase AKI severity? (2) Does prior RMR impair recovery from AKI? (3) Does prior RMR predispose to the development of more severe TIF during J Am Soc Nephrol

The susceptibility to renal perfusion pressure (RPP)-induced renal injury was investigated in angiotensin II (AngII) versus norepinephrine (NE)-infused hypertensive rats. To determine the magnitude of RPP-induced injury, Sprague-Dawley rats fed a 4% salt diet were instrumented with a servocontrolled aortic balloon occluder positioned between the renal arteries to maintain RPP to the left kidney at baseline levels while the right kidney was exposed to elevated RPP during a 2 week infusion of: 1) AngII i.v. (25 ng/kg/min), 2) NE i.v. (0.5, 1, and 2 ug/kg/min on Days 1, 2, and 3-14, respectively), or saline i.v. (sham rats). Over the 14 days of AngII infusion, RPP averaged 161.5 ± 8 mmHg to uncontrolled kidneys and 121.9 ± 2 mmHg to servocontrolled kidneys. In NE-infused rats, RPP averaged 156.3 ± 3 mmHg to uncontrolled kidneys and 116.9 ± 2 mmHg to servocontrolled kidneys. RPP averaged 111.1 ± 1 mmHg to kidneys of sham rats. Interlobular arterial injury and juxtamedullary glomerulosclerosis were largely RPP-dependent in both models of hypertension. Superficial cortical glomerulosclerosis was greater and RPP-dependent in NE versus AngII-infused rats, which was primarily independent of RPP. Outer medullary tubular necrosis and interstitial fibrosis was also primarily RPP-dependent in both models of hypertension; however, the magnitude of injury was exacerbated in AngII-infused rats. We conclude that elevated RPP is the dominant cause of renal injury in both NE and AngII-induced hypertensive rats and that underlying neurohumoral factors in these models of hypertension alter the pattern and magnitude of RPP-induced renal injury.

Abstract-Studies were designed to determine the effects of increases of renal perfusion pressure on the production of hydrogen peroxide (H 2 O 2 ) and NO 2 Ϫ ϩNO 3 Ϫ within the renal outer medulla. Sprague-Dawley rats were studied with either the renal capsule intact or removed to ascertain the contribution of changes of medullary blood flow and renal interstitial hydrostatic pressure on H 2 O 2 and NO 2 Ϫ ϩNO 3 Ϫ production. Responses to three 30-minute step changes of renal perfusion pressure (from Ϸ85 to Ϸ115 to Ϸ145 mm Hg) were studied using adjustable aortic occluders proximal and distal to the left renal artery. Medullary interstitial H 2 O 2 determined by microdialysis increased at each level of renal perfusion pressure from 640 to 874 to 1593 nmol/L, as did H 2 O 2 urinary excretion rates, and these responses were significantly attenuated by decapsulation. Medullary interstitial NO 2 Ϫ ϩNO 3 Ϫ increased from 9.2 to 13.8 to 16.1 mol/L, with parallel changes in urine NO 2 Ϫ ϩNO 3 Ϫ , but decapsulation did not significantly blunt these responses. Over the range of renal perfusion pressure, medullary blood flow (laser-Doppler flowmetry) rose Ϸ30% and renal interstitial hydrostatic pressure rose from 7.8 to 19.7 cm H 2 O. Renal interstitial hydrostatic pressure and the natriuretic and diuretic responses were significantly attenuated with decapsulation, but medullary blood flow was not affected. The data indicate that pressure-induced increases of H 2 O 2 emanated largely from increased tubular flow rates to the medullary thick-ascending limbs of Henle and NO largely from increased medullary blood flow to the vasa recta. The parallel pressure-induced increases of H 2 O 2 and NO indicate a participation in shaping the "normal" pressure-natriuresis relationship and explain why an imbalance in either would affect the blood pressure salt sensitivity. Key Words: renal medullary oxidative stress Ⅲ hydrogen peroxide Ⅲ nitrate and nitrite Ⅲ nitric oxide Ⅲ pressure natriuresis Ⅲ renal medullary blood flow R enal oxidative stress is enhanced in many animal models of hypertension and renal disease and is associated with renal fibrosis, vasoconstriction, apoptosis, and a reduction of urinary excretion of sodium (UNaV). 1 It has been demonstrated that either a reduction of NO production or an increase in renal oxidative stress within the renal medulla can produce hypertension and renal injury. [1][2][3][4][5][6][7] The mechanisms leading to excess production of reactive oxygen species within the kidney are beginning to be understood. It is evident, eg, that both elevations of hormones such as angiotensin II and increased tubular or extracellular sodium concentrations can stimulate the production of superoxide (O 2 Ϫ ) within the medullary thick ascending limbs of Henle (mTALs) and contribute to hypertension and renal injury. 8 -10 The elevation of renal perfusion pressure (RPP) with hypertension can contribute importantly to the progressive renal injury generally observed in hypertension, 11 as demonstrated in 2 rat mode...

Polichnowski AJ, Griffin KA, Long J, Williamson GA, Bidani AK. Blood pressure-renal blood flow relationships in conscious angiotensin II-and phenylephrine-infused rats. Am J Physiol Renal Physiol 305: F1074 -F1084, 2013. First published July 3, 2013 doi:10.1152/ajprenal.00111.2013.-Chronic ANG II infusion in rodents is widely used as an experimental model of hypertension, yet very limited data are available describing the resulting blood pressurerenal blood flow (BP-RBF) relationships in conscious rats. Accordingly, male Sprague-Dawley rats (n ϭ 19) were instrumented for chronic measurements of BP (radiotelemetry) and RBF (Transonic Systems, Ithaca, NY). One week later, two or three separate 2-h recordings of BP and RBF were obtained in conscious rats at 24-h intervals, in addition to separate 24-h BP recordings. Rats were then administered either ANG II (n ϭ 11, 125 ng·kg Ϫ1 ·min Ϫ1 ) or phenylephrine (PE; n ϭ 8, 50 mg·kg Ϫ1 ·day Ϫ1 ) as a control, ANG IIindependent, pressor agent. Three days later the BP-RBF and 24-h BP recordings were repeated over several days. Despite similar increases in BP, PE led to significantly greater BP lability at the heart beat and very low frequency bandwidths. Conversely, ANG II, but not PE, caused significant renal vasoconstriction (a 62% increase in renal vascular resistance and a 21% decrease in RBF) and increased variability in BP-RBF relationships. Transfer function analysis of BP (input) and RBF (output) were consistent with a significant potentiation of the renal myogenic mechanism during ANG II administration, likely contributing, in part, to the exaggerated reductions in RBF during periods of BP elevations. We conclude that relatively equipressor doses of ANG II and PE lead to greatly different ambient BP profiles and effects on the renal vasculature when assessed in conscious rats. These data may have important implications regarding the pathogenesis of hypertension-induced injury in these models of hypertension.hypertension; hemodynamics; blood pressure variability INCREASED ACTIVITY OF THE renin-angiotensin-aldosterone system (RAAS) (40,56,73) is postulated to be a major contributor to chronic kidney disease progression through both blood pressure (BP)-dependent and -independent mechanisms (7,28,39,73). Accordingly, chronic ANG II infusion is extensively used to investigate mechanisms that mediate renal damage in hypertensive states characterized by enhanced RAAS activation (3,20,42,65,71). Renal parenchymal injury with significant tubulointerstitial fibrosis and a propensity to develop salt-sensitive hypertension has been observed after ANG II infusions (44, 57). Both barotrauma and renal vasoconstrictionmediated tissue ischemia have been postulated to initiate the pathogenic cascades that lead to renal injury after chronic ANG II infusions. However, despite its wide use, there is a paucity of experimental data describing the BP-renal blood flow (RBF) relationships in conscious ANG II-infused animals, and the relative contribution of these two initiating mechanisms ...