Redox state of cytochrome aa3 in isolated perfused rat kidney

Epstein, F. H.; Balaban, Robert S.; Ross, Brian D.

doi:10.1152/ajprenal.1982.243.4.f356

Cited by 35 publications

(33 citation statements)

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“…By improving local oxygenation, furosemide reduces HIF-1 expression in the outer and inner medulla (Zou et al, 2001). In the isolated perfused rat kidney, furosemide and bumetanide (the other NKCC inhibitor) reduced the amount of cytochrome c oxidase existing in the reduced state from 40 to 20% (Epstein et al, 1982). Likewise, in the intact anesthetized rat, furosemide increased medullary pO 2 from 16 to 35 mm Hg (Brezis et al, 1994).…”

Section: Hypoxia In the Renal Medulla And Its Role In Local H 2 S Sigmentioning

confidence: 97%

“…In most cells in the body, cytochrome c oxidase is almost completely oxidized under physiological conditions because its K m for oxygen is attained at only 1 to 2 mm Hg in isolated mitochondria and at approximately 10 mm Hg in the whole cells, which is much less than ambient pO 2 in these tissues. However, in medullary tubular cells, 20 to 40% of cytochrome c oxidase exists in the reduced state, indicating that local pO 2 is close to critical at which mitochondrial respiration might be compromised (Epstein et al, 1982). Due to low pO 2 , the expression of a major molecular target of hypoxia, hypoxia-induced factor-1 (HIF-1), and its target genes, such as inducible NO synthase, cyclooxygenase-2 (COX-2), and heme oxygenase-1 (HO-1), is much higher in the medulla than in the cortex.…”

Section: Hypoxia In the Renal Medulla And Its Role In Local H 2 S Sigmentioning

confidence: 99%

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Hypoxia in the Renal Medulla: Implications for Hydrogen Sulfide Signaling

Bełtowski

2010

J Pharmacol Exp Ther

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Hydrogen sulfide (H 2 S) is enzymatically generated in mammalian tissues from either L-cysteine or L-homocysteine. H 2 S possesses multiple biological activities, including regulation of vascular tone and blood pressure. Hydrogen sulfide produced in endothelial cells, vascular smooth muscle cells, and perivascular adipose tissue dilates blood vessels by activating ATP-sensitive potassium channels. In addition, H 2 S produced locally within the kidney stimulates natriuresis and diuresis by increasing glomerular filtration and inhibiting tubular sodium reabsorption. Because H 2 S is oxidized in mitochondria in pO 2 -dependent manner and ambient pO 2 is physiologically low in the renal medulla, it is expected that the activity of H 2 S is higher in the medullary region than the cortical region. H 2 S, accumulating in increased amounts in the renal medulla under hypoxic conditions, may function as an oxygen sensor that restores O 2 balance by increasing medullary blood flow, reducing energy requirements for tubular transport, and directly inhibiting mitochondrial respiration. Hypoxia is an important pathogenic factor in many renal diseases, such as ischemia/reperfusion-or nephrotoxin-induced acute renal failure, progression of chronic nephropathies, diabetic nephropathy, and arterial hypertension. Deficiency of endogenous H 2 S may contribute to the pathogenesis of these pathologies by compromising medullary oxygenation, and administration of H 2 S donors may be of therapeutic value in these disorders.Studies performed during the last decade indicate that, apart from NO and CO, H 2 S is the third "gasotransmitter" involved in the regulation of various physiological functions, including vascular tone and blood pressure, inflammatory reaction, neurotransmission and gastrointestinal system function. H 2 S is enzymatically synthesized in three metabolic pathways (Fig. 1): 1) desulfhydration of L-cysteine or L-homocysteine by cystathionine ␥-lyase (CSE, EC 4.4.1.1), 2) desulfhydration of L-cysteine by cystathionine ␤-synthase (CBS, EC 4.2.1.22), and 3) transamination of L-cysteine by cysteine aminotransferase (identical with aspartate aminotransferase) to 3-mercaptopyruvate, followed by its desulfhydration to pyruvate by 3-mercaptopyruvate sulfurtransferase (3-MST, EC 2.8.1.2). Hydrogen sulfide activates ATP-sensitive potassium channels (K ATP ) in various cells, although many other signaling mechanisms have also been described. H 2 S is inactivated by binding to hemoglobin to form sulfhemoglobin, excretion in exhaled air, and, first and foremost, oxidation in mitochondria. Many studies addressed the role of H 2 S in the regulation of vascular tone and blood pressure. Indeed, it is suggested that H 2 S deficiency may contribute to the pathogenesis of arterial hypertension both in experimental animal models and in humans. Recently, renal synthesis and activity of H 2 S have been characterized (Xia et al., 2009). Because renal sodium handling has a prominent role in the long-term regulation of blood pressure (apart...

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Section: Hypoxia In the Renal Medulla And Its Role In Local H 2 S Sigmentioning

confidence: 97%

Section: Hypoxia In the Renal Medulla And Its Role In Local H 2 S Sigmentioning

confidence: 99%

Hypoxia in the Renal Medulla: Implications for Hydrogen Sulfide Signaling

Bełtowski

2010

J Pharmacol Exp Ther

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“…The mTAL are nourished only through the descending VR that are capable of providing an amount of oxygen barely exceeding basal needs. With the outer medulla operating on the brink of hypoxia (18,50), either a reduction of blood supply or an increased metabolic load can generate greater amounts of ROS production in the mTAL. The metabolic work of the mTAL is increased as more Na ϩ is delivered to the loop of Henle, an event that occurs with a rise in renal perfusion pressure or a greater filtration of NaCl as seen with high-salt feeding, hypertension, and the early stages of diabetes (134,154,196,202).…”

Section: ·ϫmentioning

confidence: 99%

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

Cowley

Abe

Mori

et al. 2015

American Journal of Physiology-Renal Physiology

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logical 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 ϩ 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.superoxide (O 2 ·Ϫ ); hydrogen peroxide (H2O2); nitric oxide (NO); NAD(P)H oxidase; mTAL; medullary blood flow; kidney; Dahl SS rats REACTIVE OXYGEN SPECIES (ROS) are chemically reactive molecules derived from oxygen, whose role as mediators of intracellular signaling cascades is well recognized. The following is a brief review of physiological data linking superoxide (O 2 ·Ϫ ), hydrogen peroxide (H 2 O 2 ), and nitric oxide (NO) production in the medullary thick ascending limbs of Henle (mTAL) to sodium (Na ϩ ) homeostasis, the regulation of medullary blood flow (MBF), and the long-term regulation of arterial blood pressure. MBF to the renal medulla can be importantly controlled by the constriction and dilation of the descending vasa recta (VR) capillaries, which branch from the efferent arterioles of the juxtamedullary glomeruli (49, 147, 149) and whose tone is controlled by the smooth muscle-like pericytes (49, 90, 146 -149). The role of NO cross talk from mTAL to surrounding VR in the renal medulla has been reviewed in detail elsewhere (19, 33) and will be discussed here largely with regard to its ROS-related counterregulatory functions. The present review will first summarize data showing that either the excess endogenous production or reduced scavenging of O 2 ·Ϫ or H 2 O 2 within the renal medulla results in a decrease in MBF and Na ϩ excretion, leading to hypertension and renal injury. Second, evidence will be summarized supporting the hypothesis that a high dietary salt intake results in increased luminal flow and delivery of NaCl to the mTAL, thereby signaling via both mechanical forces (stretch and shear) and increased Na ϩ transport, an increased mitochondrial and membrane NA-D(P)H oxidase production of O 2 ·Ϫ and H 2 O 2 . Third, studies will be reviewed showing that reduction of MBF leads to hypertension a...

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“…Recent observations by Epstein et al (3) using organ spectrophotometry in whole isolated perfused kidneys, have indicated that a significant fraction (20-40%) of cytochrome a,a3 (cytochrome c oxidase) as sensed by this technique is reduced but becomes more oxidized when mTAL transport is decreased by furosemide (3). Cytochrome a,a3 is normally 95-98% oxidized in the presence of oxygen at partial pressures that fulfill the needs of oxidative phosphorylation (4).…”

Section: Introductionmentioning

confidence: 99%

Selective vulnerability of the medullary thick ascending limb to anoxia in the isolated perfused rat kidney.

Brezis¹,

Rosen²,

Silva³

et al. 1984

J. Clin. Invest.

230

106

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As bstract. A specific anatomical lesion sharply localized to the cells of the medullary thick ascending limbs (mTAL) and characterized by mitochondrial swelling progressing to nuclear pyknosis and cell death is elicited reproducibly in isolated rat kidneys perfused for 15 or 90 min with cell-free albumin-Ringer's medium gassed with 5% Co2, 95% 02 (02 content, 1.5 vol/100 ml). The lesion, involving about half of mTALs, appears first in mTALs removed from vascular bundles and near the inner medulla, areas most likely to be anoxic. Hypoxic perfusion (02 content 0.12 vol/100 ml) exaggerates the lesion, wiping out gradations of damage and extending it to all mTALs. 02-enriched perfusions using rat erythrocytes (02 content 7.1 vol/100 ml) completely eliminates the lesion (unless gassed with carbon monoxide). Simi Oxypherol, Alpha-Therapeutic, Los Angeles, CA) was used as a blood substitute instead of the regular perfusion medium. Monitoring of oxygenationIn all experimental groups, the Po2 ofthe perfusate was monitored using a blood gas monitor (PHM 73, Radiometer, Copenhagen). In groups A Po2 (mmHg) Figure 1. Expected oxygen dissociation curves for blood (hematocrit 45 and 14%), hemoglobin, FC-43 emulsion, and albumin. The points represent actual measurements during perfusions with erythrocytes (0), hemoglobin 3-4 g/100 ml (X) or 4-5 g/100 ml (0), FC-43 emulsion (A), and albumin (-).and B, the 02 content was calculated using the constant of solubility of 02 in plasma, and confirmed by direct measurement in 10 randomly selected samples. In group C the 02 content was measured directly by volumetry using a Lex 02 con (Lexington Instrument Corp., Waltham, MA). As shown in Fig. 1 The histological evaluation was completed by one of us in a "blinded" fashion; that is, without knowledge of experimental conditions. Three zones of the inner stripe were analyzed: upper third: all mTALs intersecting a line immediately adjacent to outer stripe (within -0.2 mm); middle third: all mTALs intersecting a line drawn midway between the borders of the inner stripe; and lower third: all mTALs intersecting a line immediately adjacent to the inner medulla (within -0.2 mm).These points were chosen for analysis because they provided areas in which topographical landmarks were easily ascertained. A percentage score was used to indicate the fraction oftubules involved with minimal to mild (chromatin margination, minor degrees of mitochondrial swelling), moderate (blatant mitochondrial swelling with limited nuclear pyknosis), or severe (blatant mitochondrial swelling with extensive nuclear pyknosis and cell fragmentation) changes. Between 68 and 272 tubules (mean 137) were evaluated per kidney in a total of 61 kidneys.The data are presented as mean±SEM. Statistical analysis was by the t test, unless specified otherwise.

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Redox state of cytochrome aa3 in isolated perfused rat kidney

Cited by 35 publications

References 0 publications

Hypoxia in the Renal Medulla: Implications for Hydrogen Sulfide Signaling

Hypoxia in the Renal Medulla: Implications for Hydrogen Sulfide Signaling

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

Selective vulnerability of the medullary thick ascending limb to anoxia in the isolated perfused rat kidney.

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