Abstract 36: Deficiency in the Production of 20-HETE Contributes to Impaired Myogenic and TGF Responses in the Afferent Arteriole of Dahl S Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ying Ge ◽  
Fan Fan ◽  
Sydney R Murphy ◽  
Jan Michael Williams ◽  
Ruisheng Liu ◽  
...  
Keyword(s):  
Renal Injury ◽  
Tubuloglomerular Feedback ◽  
Brown Norway ◽  
Sodium Reabsorption ◽  
Thick Ascending Limb ◽  
Afferent Arteriole ◽  
Synthesis Inhibitor ◽  
Renal Vasculature ◽  
Luminal Diameter ◽  
Consomic Strain

Previous studies have indicated that a deficiency in the formation of 20-HETE in the proximal tubule and thick ascending limb of Henle in Dahl S rats increases sodium reabsorption and contributes to the development of hypertension. The present study examined whether the lack of 20-HETE production in the renal vasculature contributes to the progression of renal injury by altering the myogenic or tubuloglomerular feedback (TGF) response of the afferent arteriole (Af-Art). The production of 20-HETE was significantly lower by 54% in renal microvessels isolated from the kidneys of Dahl S rats versus that seen than in SS.5BN consomic strain in which chromosome 5 from the Brown Norway (BN) rat containing the CYP4A genes responsible for the formation of 20-HETE was transferred into the Dahl S genetic background. The luminal diameter of the Af-Art decreased by 14.7± 1.5% (from 20.5 ± 0.7 to 17.5 ± 0.8 μm, n=6) in SS.5BN rats whereas the diameter of the Af-Art remained unaltered in Dahl S rats (from 20.1 ± 0.6 to 21.7 ± 0.6 μm, n=7) when the perfusion pressure was increased from 60 mmHg to 120 mmHg. In other experiments, adenosine (1 μM) reduced the diameter of the Af-Art in the SS.5BN rats by 15±0.7% (from 20.1 ±0.4 to 17.1 ± 0.9 μm, n=3) whereas the Af-Art of Dahl S rats was unaltered. However, administration of a 20-HETE synthesis inhibitor, HET0016 (1 μM, n=6), or a selective 20-HETE antagonist, 6, 15-20-HEDE (10 μM, n=6) completely blocked the myogenic and adenosine responses in the Af-Art of SS.5BN rats but it had no effect in Dahl S rats. Administration of a 20-HETE agonist, 5, 14-20-HEDE (1 μM) restored the myogenic response (from 20.7 ± 0.7 to 17.6 ± 0.6 μm, n=7) and vasoconstrictor response to adenosine in the Af-Art of Dahl S rats. These studies confirm the key role of 20-HETE in modulating the responsiveness of the Af-Art and indicate that a deficiency in the formation of 20-HETE in renal microvessels contributes to the marked susceptibility of Dahl S rats to develop hypertension induced renal injury.

scholarly journals Role of 20-HETE in the impaired myogenic and TGF responses of the Af-Art of Dahl salt-sensitive rats

2014 ◽  
Vol 307 (5) ◽  
pp. F509-F515 ◽  
Author(s):  
Ying Ge ◽  
Sydney R. Murphy ◽  
Fan Fan ◽  
Jan Michael Williams ◽  
John R. Falck ◽  
...  
Keyword(s):  
Genetic Background ◽  
Receptor Agonist ◽  
Perfusion Pressure ◽  
Tubuloglomerular Feedback ◽  
Brown Norway ◽  
Synthesis Inhibitor ◽  
Renal Vasculature ◽  
Luminal Diameter

The present study examined whether 20-HETE production is reduced in the renal vasculature and whether this impairs myogenic or tubuloglomerular feedback (TGF) responses of the afferent arteriole (Af-Art). The production of 20-HETE was 73% lower in renal microvessels of Dahl salt-sensitive rats (SS) rats than in SS.5BN rats, in which chromosome 5 from the Brown Norway (BN) rat containing the CYP4A genes was transferred into the SS genetic background. The luminal diameter of the Af-Art decreased by 14.7 ± 1.5% in SS.5BN rats when the perfusion pressure was increased from 60 to 120 mmHg, but it remained unaltered in SS rats. Administration of an adenosine type 1 receptor agonist (CCPA, 1 μM) reduced the diameter of the Af-Art in the SS.5BN rats by 44 ± 2%, whereas the diameter of the Af-Art of SS rats was unaltered. Autoregulation of renal blood flow (RBF) and glomerular capillary pressure (PGC) was significantly impaired in SS rats but was intact in SS.5BN rats. Administration of a 20-HETE synthesis inhibitor, HET0016 (1 μM), completely blocked the myogenic and adenosine responses in the Af-Art and autoregulation of RBF and PGC in SS.5BN rats, but it had no effect in SS rats. These data indicate that a deficiency in the formation of 20-HETE in renal microvessels impairs the reactivity of the Af-Art of SS rats and likely contributes to the development of hypertension induced renal injury.

Does endoplasmic reticulum stress mediate endothelin-1-induced renal inflammation?

2013 ◽  
Vol 305 (2) ◽  
pp. R107-R109 ◽  
Author(s):  
Carmen De Miguel ◽  
Jennifer S. Pollock
Keyword(s):  
Endoplasmic Reticulum ◽  
Thick Ascending Limb ◽  
Afferent Arteriole ◽  
Renal Vasculature ◽  
Renal Inflammation ◽  
Endothelin 1 ◽  
Collecting Ducts ◽  
Potent Vasoconstrictor ◽  
Eventual Death ◽  
Vasoconstrictor Peptide

Endothelin-1 (ET-1) is the most potent vasoconstrictor peptide known. It exerts its actions through two pharmacologically different receptors: ETA and ETB receptors. In the renal vasculature, there is a majority of ETB receptors in the efferent arteriole, whereas a greater amount of ETA receptors are located in the afferent arteriole. The nephron is rich in ETB receptors, especially in the thick ascending limb and collecting ducts, while containing a smaller amount of ETA receptors. High levels of circulating or renal ET-1 have been described in cardiovascular diseases such as hypertension or diabetes, diseases also associated to renal inflammation. Despite extensive evidence associating high levels of ET-1 to increased renal inflammation, the molecular mechanism(s) by which ET-1 leads to renal immune infiltration and/or immune activation remains unknown. In this minireview, we propose that the ET-1/ETA pathway mediates an increase in renal endoplasmic reticulum (ER) stress, initially a survival mechanism that if prolonged, leads to the eventual death of the cell via apoptosis.

scholarly journals Genetic basis of the impaired renal myogenic response in FHH rats

2013 ◽  
Vol 304 (5) ◽  
pp. F565-F577 ◽  
Author(s):  
Marilyn Burke ◽  
Malikarjuna Pabbidi ◽  
Fan Fan ◽  
Ying Ge ◽  
Ruisheng Liu ◽  
...  
Keyword(s):  
Renal Injury ◽  
Chromosome 1 ◽  
Brown Norway ◽  
Myogenic Response ◽  
Renal Vasculature ◽  
Congenic Strains ◽  
Channel Current ◽  
Protein Excretion ◽  
Afferent Arterioles ◽  
Renal Vascular

This study examined the effect of substitution of a 2.4-megabase pair (Mbp) region of Brown Norway (BN) rat chromosome 1 (RNO1) between 258.8 and 261.2 Mbp onto the genetic background of fawn-hooded hypertensive (FHH) rats on autoregulation of renal blood flow (RBF), myogenic response of renal afferent arterioles (AF-art), K+ channel activity in renal vascular smooth muscle cells (VSMCs), and development of proteinuria and renal injury. FHH rats exhibited poor autoregulation of RBF, while FHH.1BN congenic strains with the 2.4-Mbp BN region exhibited nearly perfect autoregulation of RBF. The diameter of AF-art from FHH rats increased in response to pressure but decreased in congenic strains containing the 2.4-Mbp BN region. Protein excretion and glomerular and interstitial damage were significantly higher in FHH rats than in congenic strains containing the 2.4-Mbp BN region. K+ channel current was fivefold greater in VSMCs from renal arterioles of FHH rats than cells obtained from congenic strains containing the 2.4-Mbp region. Sequence analysis of the known and predicted genes in the 2.4-Mbp region of FHH rats revealed amino acid-altering variants in the exons of three genes: Add3, Rbm20, and Soc-2. Quantitative PCR studies indicated that Mxi1 and Rbm20 were differentially expressed in the renal vasculature of FHH and FHH.1BN congenic strain F. These data indicate that transfer of this 2.4-Mbp region from BN to FHH rats restores the myogenic response of AF-art and autoregulation of RBF, decreases K+ current, and slows the progression of proteinuria and renal injury.

Impaired myogenic autoregulation in kidneys of Brown Norway rats

2000 ◽  
Vol 278 (6) ◽  
pp. F962-F969 ◽  
Author(s):  
Xuemei Wang ◽  
David O. Ajikobi ◽  
Fred C. Salevsky ◽  
William A. Cupples
Keyword(s):  
Renal Failure ◽  
Renal Injury ◽  
Wistar Rats ◽  
Functional Limitation ◽  
Renal Perfusion ◽  
Tubuloglomerular Feedback ◽  
Brown Norway ◽  
Spontaneously Hypertensive ◽  
Renal Autoregulation ◽  
Extended Lifespan

The Brown Norway (BN) rat is normotensive and has an extended lifespan but is extremely sensitive to hypertension-induced renal injury. Relative impairment of autoregulation has been implicated in the progression of renal failure whereas absence of myogenic autoregulation is associated with early renal failure. Therefore, we tested the hypothesis that there is conditional failure of renal autoregulation in BN rats. In isoflurane-anesthetized BN rats, the pressure-flow transfer function was normal when pressure fluctuated spontaneously. External forcing increased pressure fluctuation and exposed weakness of the myogenic component of autoregulation; the component mediated by tubuloglomerular feedback was less affected. In the presence of vasopressin to raise renal perfusion pressure, myogenic autoregulation was further impaired during forcing in BN rats but not in Wistar rats. Compensation by the myogenic system was rapidly restored on cessation of forcing, suggesting a functional limitation rather than a structural failure. Graded forcing in Wistar rats and in spontaneously hypertensive rats revealed that compensation due to the myogenic system was strong and independent of forcing amplitude. In contrast, graded forcing in BN rats showed that compensation was reduced when fluctuation of blood pressure was increased but that the reduction was independent of forcing amplitude. The results demonstrate conditional failure of myogenic autoregulation in BN rats. These acute studies provide a possible explanation for the observed sensitivity to hypertension-induced renal injury in BN rats.

Effects of inhibition of the Na+/K+/2Cl− cotransporter on myogenic and angiotensin II responses of the rat afferent arteriole

2007 ◽  
Vol 292 (3) ◽  
pp. F999-F1006 ◽  
Author(s):  
Xuemei Wang ◽  
Jennifer Breaks ◽  
Kathy Loutzenhiser ◽  
Rodger Loutzenhiser
Keyword(s):  
Smooth Muscle ◽  
Time Course ◽  
Rat Kidney ◽  
Tubuloglomerular Feedback ◽  
Sodium Reabsorption ◽  
Dependent Manner ◽  
Afferent Arteriole ◽  
Concentration Dependent Manner ◽  
Vasomotor Function ◽  
Myogenic Responses

The Na+/K+/2Cl− cotransporter (NKCC) plays diverse roles in the kidney, contributing sodium reabsorption and tubuloglomerular feedback (TGF). However, NKCC is also expressed in smooth muscle and inhibitors of this transporter affect contractility in both vascular and nonvascular smooth muscle. In the present study, we investigated the effects of NKCC inhibitors on vasoconstrictor responses of the renal afferent arteriole using the in vitro perfused hydronephrotic rat kidney. This preparation has no tubules and no TGF, eliminating this potential complication. Furosemide and bumetanide inhibited myogenic responses in a concentration-dependent manner. Bumetanide was ∼20-fold more potent (IC50 1.0 vs. 20 μmol/l). At 100 and 10 μmol/l, furosemide and bumetanide inhibited myogenic responses by 72 ± 4 and 68 ± 5%, respectively. The maximal level of inhibition by bumetanide was not affected by nitric oxide synthase inhibition (100 μmol/l NG-nitro-l-arginine methyl ester). However, the time course for the dilation was slowed (from t1/2 = 4.0 ± 0.5 to 8.3 ± 1.7 min, P = 0.04), suggesting either a partial involvement of NO or a permissive effect of NO on relaxation kinetics. Bumetanide also inhibited ANG II-induced afferent arteriolar vasconstriction at similar concentrations. Finally, NKCC1, but not NKCC2, expression was demonstrated in the afferent arteriole by RT-PCR and the presence of NKCC1 in afferent arteriolar myocytes was confirmed by immunohistochemistry. In concert, these results indicate that NKCC modulation is capable of altering myogenic responses by a mechanism that does not involve TGF and suggest a potential role of NKCC1 in the regulation of vasomotor function in the renal microvasculature.

scholarly journals Abundance of the Na-K-2Cl cotransporter NKCC2 is increased by high-fat feeding in Fischer 344 X Brown Norway (F1) rats

2009 ◽  
Vol 296 (4) ◽  
pp. F762-F770 ◽  
Author(s):  
Shahla Riazi ◽  
Swasti Tiwari ◽  
Nikhil Sharma ◽  
Arjun Rash ◽  
C. M. Ecelbarger
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Blood Pressure ◽  
Brown Norway ◽  
Sodium Reabsorption ◽  
Thick Ascending Limb ◽  
High Fat ◽  
Fischer 344 ◽  
Arterial Blood ◽  
Fat Feeding

Insulin resistance is associated with hypertension by mechanisms likely involving the kidney. To determine how the major apical sodium transporter of the thick ascending limb, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) is regulated by high-fat feeding, we treated young male, Fischer 344 X Brown Norway (F344BN) rats for 8 wk with diets containing either normal (NF, 4%) or high (HF, 36%) fat, by weight, primarily as lard. HF-fed rats had impaired glucose tolerance, increased urine excretion of 8-isoprostane (a marker of oxidative stress), increased protein levels for NKCC2 (50–125%) and the renal outer medullary potassium channel (106%), as well as increased natriuretic response to furosemide (20–40%). To test the role of oxidative stress in this response, in study 2, rats were fed the NF or HF diet plus plain drinking water, or water containing N G-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor (100 mg/l), or tempol, a superoxide dismutase mimetic (1 mmol/l). The combination of tempol with HF nullified the increase in medullary NKCC2, while l-NAME with HF led to the highest expression of medullary NKCC2 (to 498% of NF mean). However, neither of these drugs dramatically affected the elevated natriuretic response to furosemide with HF. Finally, l-NAME led to a marked increase in blood pressure (measured by radiotelemetry), which was significantly enhanced with HF. Mean arterial blood pressure at 7 wk was as follows (mmHg): NF, 100 ± 2; NF plus l-NAME, 122 ± 3; and HF plus l-NAME, 131 ± 2. Overall, HF feeding increased the abundance of NKCC2. Inappropriately high sodium reabsorption in the thick ascending limb via NKCC2 may contribute to hypertension with insulin resistance.

Abstract 39: Cyp4a1 Transgenic Rats Generated Using Sleeping Beauty Transposon System Restores the Impaired Myogenic Responses in the Afferent Arteriole of Dahl S Rats

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Fan Fan ◽  
Ying Ge ◽  
Sydney Murphy ◽  
Aron M Geurts ◽  
Howard Jacob ◽  
...  
Keyword(s):  
Renal Injury ◽  
Vascular Reactivity ◽  
Transgenic Animals ◽  
Sleeping Beauty ◽  
Transgenic Rat ◽  
Transgenic Rats ◽  
Renal Vasculature ◽  
Luminal Diameter ◽  
Sleeping Beauty Transposon ◽  
Transgenic Lines

We have reported that the production of 20-HETE is reduced in the renal vasculature of Dahl S rats and that myogenic and TGF responses of afferent arteries (Af-Art) are impaired in Dahl S rats. In this study we generated CYP4A1 transgenic rats in the Dahl S inbred strain background utilizing the enhanced Sleeping Beauty (SB100X) transposon system to determine if upregulation of 20-HETE production can restore vascular reactivity and oppose the development of renal injury. Fertilized eggs collected from female Dahl S rats were microinjected with a transposon vector harboring the rat CYP4A1 cDNA under the control of the ubiquitous CAG promoter along with SB100X transposase mRNA to produce transgenic founders. Heterozygous founders were backcrossed to Dahl S rats, transgene insertion sites were identified by Ligation Mediated PCR and sequencing, and the progeny were brother-sister mated to derive homozygous transgenic lines. The expression of CYP4A protein was significantly elevated and the production of 20-HETE was 3-fold higher in the renal outer medullary tissue of CYP4A1 transgenic (n=17) compared to Dahl S rats (n=17). 20-HETE production was 10-fold higher in renal microvessels of CYP4A1 transgenic animals than Dahl S rats. (0.2±0.3, n=22 versus 1.9±0.1 pmol/mg/min, n=14). The luminal diameter of the Af-Art decreased significantly from 15.9 ± 0.6 to 14.1 ± 0.5 μm in CYP4A1 transgenic rats (n=5) when the perfusion pressure was increased from 60 to 120 mmHg, whereas it remained unaltered in Dahl S rats (from 19.4 ± 2.3 to 20.6 ± 5.6 μm, n=22). These studies further support the view that a deficiency in the formation of 20-HETE in the renal microcirculation contributes to the marked susceptibility of Dahl S rats to develop of hypertension and diabetic induced renal injury, and the new CYP4A1 transposon transgenic rat model may be useful for determining the mechanisms involved.

Abstract 490: Constrictor Mechanism of the Afferent Arteriole Initiated by Na/H Exchanger in the Nephron

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Hong Wang ◽  
Martin A D'Ambrosio ◽  
YiLin Ren ◽  
Jeffrey L Garvin ◽  
Oscar A Carretero
Keyword(s):  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Na Channel ◽  
Afferent Arteriole ◽  
Renal Vasculature ◽  
Connecting Tubule ◽  
Flow Pressure ◽  
Stop Flow ◽  
Epithelial Na Channel

The afferent arteriole (Af-Art) accounts for most of renal vasculature resistance, thus controlling glomerular filtration rate and renal function. Two mechanisms have been described in which the nephron helps control Af-Art resistance, namely tubuloglomerular feedback (TGF), and connecting tubule glomerular feedback (CTGF). TGF is a constrictor mechanism initiated at the macula densa by the Na/K/2Cl cotransporter (NKCC2), while CTGF is a dilator mechanism initiated at the connecting tubule by the epithelial Na channel (ENaC). However, when NKCC2 is blocked by furosemide, CTGF-induced Af-Art dilation is not evident, thus we hypothesize that there is a constrictor mechanism that is furosemide-insensitive and counters CTGF. To test this, we used in vivo micropuncture of single nephrons. Stop-flow pressure (P SF ) was measured as an index of glomerular capillary pressure (which decreases when the Af-Art constricts). Two consecutive P SF curves were generated by raising nephron perfusion from 0 to 40 nL/min while adding drugs to the tubular perfusate. The decrease in P SF induced by increasing nephron perfusion was blocked by furosemide 10 -4 M (control: 7.9±0.2 mmHg, furosemide: 0.4±0.2 mmHg, P <0.001, n=6), but was partially restored when blocking CTGF with the ENaC inhibitor benzamil 10 -6 M (furosemide: 0.2±0.1 mmHg, furosemide+benzamil: 4.3±0.3 mmHg, P <0.001, n=6). A possible explanation for these observations is that TGF may be activated to some degree by Na/H exchanger (NHE)-mediated Na entry at the macula densa when NKCC2 is blocked. When we added the NHE blocker dimethylamiloride (DMA, 10 -4 M) in the presence of furosemide and benzamil, the decrease in PSF was significantly prevented (furosemide+benzamil: 4.6±0.3 mmHg, furosemide+benzamil+DMA: 1.1±0.2 mmHg, P <0.001, n=6). Therefore, we conclude that a constrictor mechanism of the Af-Art is initiated by NHE in the nephron and is observable when NKCC2-mediated TGF and ENaC-mediated CTGF have been blocked.

Autoregulation and tubuloglomerular feedback in juxtamedullary glomerular arterioles

1990 ◽  
Vol 258 (3) ◽  
pp. F660-F669 ◽  
Author(s):  
D. Casellas ◽  
L. C. Moore
Keyword(s):  
Blood Perfusion ◽  
Ringer Solution ◽  
Tubuloglomerular Feedback ◽  
Thick Ascending Limb ◽  
Luminal Diameter ◽  
Renal Autoregulation ◽  
Afferent Arterioles ◽  
Shadow Cast ◽  
Working Distance

Videometric measurements of changes in vessel lumen diameters were made to investigate autoregulatory and tubuloglomerular feedback (TGF) responses of early efferent arterioles (EA), mid-to-late afferent arterioles (MAA), and terminal, juxtaglomerular afferent arterioles (JAA) in rat juxtamedullary nephrons in vitro. High-contrast shadow-cast images of blood-perfused arterioles at the glomerular vascular pole were obtained with incident illumination and long-working-distance objectives fitted to a compound microscope. In response to an increase in blood perfusion pressure from 60 to 140 mmHg, strong autoregulatory vasoconstriction was observed in the MAA and JAA, with respective reductions in mean luminal diameter of 23 +/- 4 and 40 +/- 4% (mean +/- SE); EA diameter was unchanged. In response to TGF excitation by direct microinjection of Ringer solution into the cortical thick ascending limb segment near the macula densa, JAA luminal diameter decreased by 34 +/- 5%. The TGF responses were completely inhibited by the addition of 0.1 mM furosemide to the tubular injectate. Calcium channel blockade achieved by adding 1 microM nimodipine to the superfusate had no effect on early EA diameter but produced a blood pressure-dependent JAA and MAA vasodilation and complete inhibition of autoregulatory responses. These results provide direct evidence that the distal afferent arteriole in juxtamedullary nephrons is a major effector site for both renal autoregulation and tubuloglomerular feedback.

scholarly journals Is the process of urinary urea concentration responsible for a high glomerular filtration rate?

1993 ◽  
Vol 4 (5) ◽  
pp. 1091-1103
Author(s):  
L Bankir ◽  
M Ahloulay ◽  
N Bouby ◽  
M M Trinh-Trang-Tan ◽  
F Machet ◽  
...  
Keyword(s):  
Tubuloglomerular Feedback ◽  
Sodium Reabsorption ◽  
Urinary Concentration ◽  
Urinary Flow ◽  
Moderate Increase ◽  
Thick Ascending Limb ◽  
High Concentration ◽  
Plasma Urea ◽  
Urea Excretion ◽  
Urea Reabsorption

For subjects on a normal diet, urea is the major urinary solute and is markedly concentrated in the urine compared with in the plasma. Because urea is not known to undergo active secretion, its excretion rests on filtration lessened to a variable extent by tubular reabsorption. It is well established that the efficiency of urea excretion drops with increasing urinary concentration and decreasing urinary flow rate (from approximately 60% of filtered load, above 2 mL/min, to approximately 20% below 0.5 mL/min) because the prolonged transit time in the distal nephron favors passive urea reabsorption. Thus, a higher urinary concentration is achieved at the expense of a reduced efficiency of urea excretion. Recent experimental observations suggest that GFR could actually increase in parallel with the urinary concentrating activity, thus ensuring a normal urea excretion in the face of a high, concentration-dependent urea reabsorption, with only a moderate increase in plasma urea. A possible mechanism is proposed that could explain how the vasopressin-induced intrarenal recycling of urea (which contributes to improvement in urinary concentration), but not an exogenous urea administration, could indirectly depress the tubuloglomerular feedback and hence increase GFR. An increased concentration of an osmotically active solute in the thick ascending limb of Henle's loop (such as urea and, in some cases, glucose) could enable a lower NaCl concentration to be achieved at the macula densa by reducing the osmotically driven water leakage in this nephron segment. This mechanism could explain the hyperfiltration seen in various pathophysiologic situations such as chronic vasopressin infusion, high protein intake, severe burns, and diabetes mellitus. Whatever the mechanism, if the need to excrete relatively high amounts of urea in a concentrated urine leads to a sustained elevation of GFR, the price to pay for this water economy is higher than generally assumed. It is not limited to the energy spent in the sodium reabsorption providing the "single effect" for the urinary concentrating process. It also includes the consequences on the glomerular filter of sustained high pressure and flow and the energy spent in reabsorbing the extra load of solutes filtered. In chronic renal failure, the ability to form hypertonic urine declines but is nevertheless well preserved with respect to declining GFR, thus imposing on remnant nephrons an additional permanent stimulus for hyperfiltration.(ABSTRACT TRUNCATED AT 400 WORDS)

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