Determinants of intrarenal oxygenation. I. Effects of diuretics

To study renal cortical and medullary oxygen tensions, we used sensitive Clark-type O2 microelectrodes, inserted by micromanipulators into the cortex and medulla of kidneys of anesthetized rats. As previously reported, under basal conditions, medullary PO2 was significantly lower than cortical PO2. Furosemide, which inhibits reabsorptive transport in the medullary thick ascending limb, increased medullary PO2 from 16 +/- 4 to 35 +/- 4 mmHg (P < 0.0005) without altering cortical PO2. This effect, reproduced by ethacrynic acid and bumetanide, was selective for loop diuretics and was directly due to decreased tubular O2 consumption, since medullary blood flow was remarkably reduced by furosemide (-28 +/- 6% from baseline, P < 0.0001, as measured by a laser-Doppler probe). By contrast, acetazolamide, which decreases proximal tubule metabolism, selectively increased cortical PO2. These data are, in general, consistent with tubular metabolism as a major determinant of intrarenal oxygenation and suggest, in particular, that medullary reabsorptive work is at least in part responsible for renal medullary hypoxia.

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Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

AJP Renal Physiology ◽

10.1152/ajprenal.00455.2014 ◽

2015 ◽

Vol 308 (3) ◽

pp. F179-F197 ◽

Cited By ~ 57

Author(s):

Allen W. Cowley ◽

Michiaki Abe ◽

Takefumi Mori ◽

Paul M. O'Connor ◽

Yusuke Ohsaki ◽

...

Keyword(s):

Nitric Oxide ◽

Reactive Oxygen Species ◽

Hydrogen Peroxide ◽

Blood Flow ◽

Reactive Oxygen ◽

Selective Reduction ◽

Renal Medulla ◽

Thick Ascending Limb ◽

Oxygen Species ◽

Medullary Blood Flow

The physiological evidence linking the production of superoxide, hydrogen peroxide, and nitric oxide in the renal medullary thick ascending limb of Henle (mTAL) to regulation of medullary blood flow, sodium homeostasis, and long-term control of blood pressure is summarized in this review. Data obtained largely from rats indicate that experimentally induced elevations of either superoxide or hydrogen peroxide in the renal medulla result in reduction of medullary blood flow, enhanced Na+ reabsorption, and hypertension. A shift in the redox balance between nitric oxide and reactive oxygen species (ROS) is found to occur naturally in the Dahl salt-sensitive (SS) rat model, where selective reduction of ROS production in the renal medulla reduces salt-induced hypertension. Excess medullary production of ROS in SS rats emanates from the medullary thick ascending limbs of Henle [from both the mitochondria and membrane NAD(P)H oxidases] in response to increased delivery and reabsorption of excess sodium and water. There is evidence that ROS and perhaps other mediators such as ATP diffuse from the mTAL to surrounding vasa recta capillaries, resulting in medullary ischemia, which thereby contributes to hypertension.

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Potassium deprivation upregulates expression of renal basolateral Na+-HCO3 −cotransporter (NBC-1)

AJP Renal Physiology ◽

10.1152/ajprenal.2000.279.3.f532 ◽

2000 ◽

Vol 279 (3) ◽

pp. F532-F543 ◽

Cited By ~ 20

Author(s):

Hassane Amlal ◽

Khalid Habo ◽

Manoocher Soleimani

Keyword(s):

Proximal Tubule ◽

Collecting Duct ◽

Thick Ascending Limb ◽

Mrna Levels ◽

Time Intervals ◽

Outer Medulla ◽

Medullary Thick Ascending Limb ◽

Medullary Collecting Duct ◽

Potassium Deprivation ◽

Expression And Activity

The purpose of the present experiments was to examine the effect of potassium deprivation on the expression of the renal basolateral Na+-HCO3 − cotransporter (NBC-1). Rats were placed on a K+-free diet for various time intervals and examined. NBC-1 mRNA levels increased by about threefold in the cortex ( P < 0.04) at 72 h of K+ deprivation and remained elevated at 21 days. NBC activity increased by ∼110% in proximal tubule suspensions, with the activity increasing from 0.091 in control to 0.205 pH/min in the K+-deprived group ( P < 0.005). The inner stripe of outer medulla and cells of medullary thick ascending limb of Henle (mTAL) showed induction of NBC-1 mRNA and activity in K+-deprived rats, with the activity in mTAL increasing from 0.010 in control to 0.133 pH/min in the K+-deprived group ( P < 0.004). K+ deprivation also increased NBC-1 mRNA levels in the renal papilla ( P < 0.02). We conclude that 1) K+ deprivation increases NBC-1 expression and activity in proximal tubule and 2) K+deprivation causes induction of NBC-1 expression and activity in mTAL tubule and inner medulla. We propose that NBC-1 likely mediates enhanced HCO3 − reabsorption in proximal tubule, mTAL, and inner medullary collecting duct in K+ deprivation and contributes to the maintenance of metabolic alkalosis in this condition.

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31P nuclear magnetic resonance study of steady-state adenosine 5′-triphosphate levels during graded hypoxia in the isolated perfused rat kidney

Clinical Science ◽

10.1042/cs0740437 ◽

1988 ◽

Vol 74 (4) ◽

pp. 437-448 ◽

Cited By ~ 23

Author(s):

P. J. Ratcliffe ◽

Z. H. Endre ◽

S. J. Scheinman ◽

J. D. Tange ◽

J. G. G. Ledingham ◽

...

Keyword(s):

Steady State ◽

Proximal Tubule ◽

Oxygen Delivery ◽

Rat Kidney ◽

Thick Ascending Limb ◽

Cellular Injury ◽

Isolated Perfused Rat Kidney ◽

Medullary Thick Ascending Limb ◽

Henle's Loop ◽

Perfused Rat Kidney

1. A model of controlled hypoxia in the isolated perfused rat kidney has been used to compare the extent of reduction in the steady-state level of adenosine 5′-triphosphate (ATP) from that initially observed with alterations in renal function and with the development of tubular cell injury. 2. ATP depletion was observed in response to decreased total oxygen delivery even when delivery greatly exceeded consumption and the venous oxygen tension remained in excess of 150 mmHg. 3. Increases in the fractional excretion of sodium occurred progressively below an apparent threshold value of whole kidney ATP of approximately 80% of the baseline. 4. With modestly decreased oxygen delivery, cellular injury was confined to deep proximal tubule and medullary thick ascending limb of Henle's loop. Severely decreased oxygen delivery rates were associated with cellular damage spreading throughout the cortex. 5. Even the smallest reductions in whole kidney ATP were associated with morphological damage to tubular cells. The extent of reduction in whole kidney ATP was closely correlated and approximately equivalent to the calculated volume of injured cells. 6. Our results indicate that reduction in whole kidney ATP during decreased oxygen delivery is a valid marker of the extent of injurious cellular hypoxia and are consistent with the view that cellular ATP concentrations in hypoxia are markedly inhomogeneous. They support the hypothesis that specific regions of the perfused kidney become critically hypoxic and develop cellular injury while overall oxygen delivery remains high. Areas at risk include deep proximal tubule as well as the medullary thick ascending limb of Henle's loop.

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Changes in adrenal oxygen consumption during catecholamine secretion in anesthetized dogs

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1990.259.3.h681 ◽

1990 ◽

Vol 259 (3) ◽

pp. H681-H688 ◽

Cited By ~ 1

Author(s):

M. J. Breslow ◽

J. R. Tobin ◽

T. D. Mandrell ◽

L. C. Racusen ◽

H. Raff ◽

...

Keyword(s):

Blood Flow ◽

Venous Blood ◽

Splanchnic Nerve ◽

Catecholamine Secretion ◽

O2 Consumption ◽

Medullary Blood Flow ◽

O2 Extraction ◽

Anesthetized Dogs ◽

Glomerulosa Cells ◽

Splanchnic Nerve Stimulation

Prior attempts to study adrenal medullary O2 metabolism during catecholamine secretion have been unsuccessful because venous blood from medulla mixes with venous blood from the much larger cortex. To circumvent this problem, eight adult mongrel dogs were pretreated for 5-6 wk with the adrenocorticolytic agent 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane (o,p'-DDD). Prednisolone (5 mg/day) and fludrocortisone (0.1 mg.10 kg-1.day-1) were administered orally to prevent adrenocortical insufficiency. Animals were then anesthetized with pentobarbital sodium and subjected to splanchnic nerve stimulation (NS) at 20 and 4 Hz to elicit catecholamine secretion. NS at 20 Hz increased epinephrine secretion from 1.6 +/- 0.7 to 1,780 +/- 762 ng.min-1.g medulla-1 but had no effect on medullary O2 consumption. Medullary blood flow (MQ) increased from 216 +/- 63 to 1,522 +/- 182 ml.min-1.100 g-1, and O2 extraction decreased from 2.7 +/- 0.7 to 0.8 +/- 0.2%. NS at 4 Hz increased epinephrine secretion from 3.1 +/- 1.4 to 76 +/- 17 ng.min-1.g medulla-1 and MQ from 226 +/- 66 to 649 +/- 122 ml.min-1.100 g-1 but had no effect on adrenal O2 consumption or extraction. Cortical blood flow was 342 +/- 98 ml.min-1.100 g-1 at baseline and was unaffected by NS. Gross weight of cortex was reduced by 80% in o,p'-DDD-treated animals, and histological examination of glands from three animals showed only rare islands of glomerulosa cells remaining. These data suggest that increases in MQ during NS do not occur in response to changes in O2 consumption.

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A Mathematical Model of Mitochondria in Proximal Tubule and Thick Ascending Limb Cells

10.1101/2021.12.16.473049 ◽

2021 ◽

Author(s):

William Bell ◽

Anita Layton

Keyword(s):

Oxidative Phosphorylation ◽

Proximal Tubule ◽

Tissue Injury ◽

Ischemia Reperfusion ◽

Complex Iii ◽

Thick Ascending Limb ◽

Metabolic Demand ◽

Medullary Thick Ascending Limb ◽

Baseline Activity ◽

Lower Baseline

Mitochondria are a key player in several kinds of tissue injury, and are even the ultimate cause of certain diseases. In this work we introduce new models of mitochondrial ATP generation in multiple tissues, including liver hepatocytes and the medullary thick ascending limb in the kidney. Using this model, we predict these tissues' responses to hypoxia, uncoupling, ischemia-reperfusion, and oxidative phosphorylation dysfunction. Our results suggest mechanisms explaining differences in robustness of mitochondrial function across tissues. The medullary thick ascending limb and proximal tubule in the kidney both experience a high metabolic demand, while having lower baseline activity of oxidative phosphorylation relative to the liver. These factors make these tissues susceptible to dysfunction of Complex III. A lower baseline oxygen tension observed in the thick ascending limb makes it susceptible to Complex IV. On the other hand, since the liver lacks these risk factors, and has higher baseline rates of glycolysis, it is less susceptible to all kinds of oxidative phosphorylation dysfunction.

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Clinical use of diuretics

10.1093/med/9780199592548.003.0033 ◽

2015 ◽

Author(s):

David H. Ellison ◽

Arohan R. Subramanya

Keyword(s):

Proximal Tubule ◽

Collecting Duct ◽

Extracellular Fluid ◽

Chronic Administration ◽

Distal Convoluted Tubule ◽

Loop Diuretics ◽

Sodium Reabsorption ◽

Thick Ascending Limb ◽

Response Curves ◽

Collecting Tubules

Diuretics are widely employed to treat extracellular fluid volume expansion caused by heart failure, cirrhosis of the liver, nephrotic syndrome, and chronic kidney disease. Major classes of diuretic inhibit sodium reabsorption along the proximal tubule, the loop of Henle, the distal convoluted tubule, and the connecting and collecting tubules. Loop diuretics have the highest ceiling of action and often form the cornerstones of diuretic treatment of oedema. Members of this class are short-acting drugs, with different bioavailabilities, the specifics of which contribute importantly to a rational and effective approach to their use. They are not filtered substantially because they are all protein bound. They enter tubules by secretion along the proximal tubule, thereby gaining access to the Na-K-2Cl cotransporter of the thick ascending limb. Their dose–response curves are sigmoidal and altered by several disease processes. Chronic administration can elicit adaptive processes along the nephron that limit their efficacy. Distal convoluted tubule diuretics, such as the thiazides, inhibit NaCl absorption along the distal convoluted tubule. While used predominantly to treat hypertension, they are also useful to treat oedema, especially when combined with loop diuretics. Drugs acting along the connecting tubule and collecting duct either inhibit Na+ channels directly or block mineralocorticoid receptors. These drugs are effective in states of very high aldosterone secretion, and can also be used to reduce the hypokalaemia caused by other classes of diuretics. An evidence-based approach to treating the oedematous patient is described.

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Luminal angiotensin II stimulates rat medullary thick ascending limb chloride transport in the presence of basolateral norepinephrine

AJP Renal Physiology ◽

10.1152/ajprenal.00447.2015 ◽

2016 ◽

Vol 310 (4) ◽

pp. F294-F299 ◽

Cited By ~ 4

Author(s):

Michel Baum

Keyword(s):

Angiotensin Ii ◽

Proximal Tubule ◽

Chloride Transport ◽

Bathing Solution ◽

Thick Ascending Limb ◽

Ang Ii ◽

Adrenergic Stimulation ◽

Nacl Transport ◽

Medullary Thick Ascending Limb ◽

Stimulation Of

Angiotensin II (ANG II) is secreted by the proximal tubule resulting in a luminal concentration that is 100- to 1,000-fold greater than that in the blood. Luminal ANG II has been shown to stimulate sodium transport in the proximal tubule and distal nephron. Surprisingly, luminal ANG II inhibits NaCl transport in the medullary thick ascending limb (mTAL), a nephron segment responsible for a significant amount of NaCl absorption from the glomerular ultrafiltrate. We confirmed that addition of 10−8 M ANG II to the lumen inhibited mTAL chloride transport (220 ± 19 to 165 ± 25 pmol·mm−1·min−1, P < 0.01) and examined whether an interaction with basolateral norepinephrine existed to simulate the in vivo condition of an innervated tubule. We found that in the presence of a 10−6 M norepinephrine bath, luminal ANG II stimulated mTAL chloride transport from 298 ± 18 to 364 ± 42 pmol·mm−1·min−1 ( P < 0.05). Stimulation of chloride transport by luminal ANG II was also observed with 10−3 M bath dibutyryl cAMP in the bathing solution and bath isoproterenol. A bath of 10−5 H-89 blocked the stimulation of chloride transport by norepinephrine and prevented the effect of luminal ANG II to either stimulate or inhibit chloride transport. Bath phentolamine, an α-adrenergic agonist, also prevented the decrease in mTAL chloride transport by luminal ANG II. Thus luminal ANG II increases chloride transport with basolateral norepinephrine; an effect likely mediated by stimulation of cAMP. Alpha-1 adrenergic stimulation prevents the inhibition of chloride transport by luminal ANG II.

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Myoglobinuric acute renal failure in the rat: a role for medullary hypoperfusion, hypoxia, and tubular obstruction.

Journal of the American Society of Nephrology ◽

10.1681/asn.v771066 ◽

1996 ◽

Vol 7 (7) ◽

pp. 1066-1074 ◽

Cited By ~ 1

Author(s):

S N Heyman ◽

S Rosen ◽

S Fuchs ◽

F H Epstein ◽

M Brezis

Keyword(s):

Renal Failure ◽

Blood Flow ◽

Kidney Function ◽

Collecting Duct ◽

Tubular Damage ◽

Thick Ascending Limb ◽

Hypoxic Injury ◽

Medullary Blood Flow ◽

O2 Supply ◽

And Function

Myoglobin induces renal injury by mechanisms that remain incompletely defined. In this study, the effects of myoglobin upon renal microcirculation, oxygenation, morphology, and function were investigated in anesthetized rats, and the contribution of coexisting perturbations to myoglobin nephrotoxicity were evaluated. Myoglobin infusion (3.3 mg/min) reduced outer medullary blood flow and Po2, whereas renal blood flow and cortical Po2 were unaffected. Myoglobin infusion (38 mg/100 g weight over 45 min) induced renal failure associated with collecting duct and medullary thick ascending limb dilation and casts, with focal tubular damage, confined mainly to the superficial cortex. Preconditioning with indomethacin, I-N-monomethyl arginine, and theophylline reduced cortical superficial damage but enhanced injury within the inner stripe of the outer medulla and in medullary rays, the zones of lowest O2 supply. In preconditioned animals, tubulorrhexis was primarily observed in collecting ducts transversing the inner stripe, and was remarkably reminiscent of human descriptions (J. Oliver et al., J Clin Invest 1951; 30: 1307-1440). Deterioration in kidney function closely correlated with morphologic features of both tubular obstruction and necrosis. In conclusion, medullary vasoconstriction and intrarenal hypoxia may play a role in myoglobin-induced renal failure. The deterioration in kidney function appears to reflect the combined effects of cortical damage, medullary hypoxic injury, and tubular obstruction.

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