Nitric oxide kinetics during hypoxia in proximal tubules: Effects of acidosis and glycine

Yaqoob, Muhammad; Edelstein, Charles L.; Wieder, Eric; Alkhunaizi, Ahmed M.; Gengaro, Patricia E.; Nemenoff, Raphael A.; Schrier, Robert W.

doi:10.1038/ki.1996.187

Cited by 86 publications

(40 citation statements)

References 20 publications

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“…The partial pressure of oxygen at the tissue surface was 50-100 mmHg, which represented oxygen consumption by the slice cells. As was previously reported by Yaqoob et al [20] using suspensions of kidney cortical tubules, reduction of oxygen availability was associated with a large increase in [NO]. To evaluate if sufficient oxygen was available, we determined if elevation or reduction of the bath flow influenced the [NO] during 600 mOsm NaCl, which caused a very large increase in [NO].…”

Section: In Vitro Tissue Supportmentioning

confidence: 89%

Nitric oxide production by mouse renal tubules can be increased by a sodium-dependent mechanism

et al. 2007

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Renal tubules process large amounts of NaCl that other investigators indicate increases tubular generation of nitric oxide. We questioned whether medullary or superficial cortical tubules would have the greater increase in nitric oxide concentration, [NO], when stressed by sodium and if the sodium/calcium exchanger was involved. Sodium stress in proximal tubules is due to the large amount of sodium absorbed and medullary tubules exist in a hypertonic sodium environment. To sodium stress the tissue, mouse kidney slices were exposed to monensin to allow passive entry of sodium ions from isotonic media and in separate studies, 400 and 600 mOsm NaCl was used. [NO] was measured with microelectrodes. Monensin (10 μM) caused a sustained increase in medullary and cortical [NO] to ∼180% of control and 400 mOsm NaCl caused a similar initial increase in [NO] that then subsided. 600 mOsm NaCl caused a more sustained increase in [NO] of >250% of control. L-NAME strongly attenuated the increased [NO] during sodium stress. The increase in [NO] during NaCl elevation was due to sodium ions because mannitol hyperosmolarity caused ∼20% of the increase in [NO]. Entry of sodium during NaCl hyperosmolarity was through bumetanide sensitive channels because the drug suppressed increased [NO]. Blockade of the sodium/calcium ion exchanger strongly suppressed the increased [NO] during monensin, to increase sodium entry into cells, and the elevated NaCl concentration. The data support a sodium -NO linkage that increased NO signaling in proportion to sodium stress by cortical tubules and was highly dependent upon sodium-calcium exchange.

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Section: In Vitro Tissue Supportmentioning

confidence: 89%

Nitric oxide production by mouse renal tubules can be increased by a sodium-dependent mechanism

et al. 2007

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“…Therefore, it is likely that increased NO generation (as a result of iNOS induction) in the setting of a pro-oxidant, hypoxic microenvironment caused by decreased perfusion, exacerbates renal injury (31). In models of AKI associated with iNOS induction, the contribution of RNS has drawn recent attention, particularly in ischemia/reperfusion injury and LPS-induced injury (32)(33)(34)(35). These studies are the first to examine the potential therapeutic benefits of pharmacologic inhibition of iNOS in CLP-induced AKI.…”

Section: Discussionmentioning

confidence: 99%

Evidence for the Role of Reactive Nitrogen Species in Polymicrobial Sepsis-Induced Renal Peritubular Capillary Dysfunction and Tubular Injury

Wu¹,

Gökden²,

Mayeux³

2007

Journal of the American Society of Nephrology

119

132

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Acute kidney injury (AKI) remains a frequent and serious complication of human sepsis that contributes significantly to mortality. For better understanding of the development of AKI during sepsis, the cecal ligation and puncture (CLP) murine model of sepsis was studied using intravital video microscopy (IVVM) of the kidney. IVVM with FITC-dextran was used to determine the percentage of capillaries with continuous, intermittent or no flow at 0 (sham), 10, 16, and 22 h after CLP. There was a dramatic fall in capillary perfusion as early as 10 h after CLP that persisted through 22 h. The percentage of vessels with continuous flow at 16 h decreased from 73 ؎ 2% in shams to 16 ؎ 2% (P < 0.05), whereas the percentage of vessels with no flow increased from 4 ؎ 1% in shams to 42 ؎ 2% (P < 0.05). The capillary perfusion defect preceded the rise in serum creatinine. IVVM with dihydrorhodamine-123 was used to quantify in real time reactive nitrogen species (RNS) generation by renal tubules, and the inducible nitric oxide synthase inhibitor L-iminoethyl-lysine (mg/kg) was used to examine the role of inducible nitric oxide synthase inhibitor on capillary dysfunction and RNS generation. Tubular generation of RNS was significantly elevated at 10 h after CLP and was associated with tubules that were bordered by capillaries with reduced perfusion. L-Iminoethyl-lysine significantly reversed the capillary perfusion defect, blocked RNS generation, and reduced AKI. These data show that capillary dysfunction and RNS generation contribute to tubular injury and suggest that RNS should be considered a potential therapeutic target in the treatment of sepsis-induced AKI.

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“…The few islet enzymes that utilize NADP ϩ /NADPH as a cofactor (as opposed to NAD ϩ /NADH) include glutamate dehydrogenase, isocitrate dehydorgenase, and neuronal nitric oxide (NO) synthase (nNOS). Although all of these enzymes are pH sensitive, nNOS is the most likely candidate due to its strongly alkaline pH optimum, which ranges from 7.5 to 9.5 (23)(24)(25).…”

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confidence: 99%

Mechanisms of Time-Dependent Potentiation of Insulin Release

et al. 2006

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Time-dependent potentiation (TDP) of insulin release is normally absent in mice. However, we recently demonstrated that TDP occurs in mouse islets under conditions of forced decrease of intracellular pH (pH i ) associated with elevated NADPH؉H ؉ (NADPH) levels. Hence, TDP in mouse islets may be kept suppressed by neuronal nitric oxide (NO) synthase (nNOS), an NADPH-utilizing enzyme with alkaline pH optimum. To determine the role of nNOS in the suppression of TDP in mouse islets, glucose-induced TDP was monitored in mouse islets in which nNOS activity had been genetically removed or chemically inhibited and compared with the TDP response in wild-type mouse islets with and without forced intracellular acidification. Genetic deletion of nNOS was provided by an nNOS knockout (NOS-KO) mouse model, B6 -129S4-Nos1tm1Plh /J. To explore how nNOS inhibits TDP, we compared pH i and NADPH levels in wild-type and NOS-KO islets and monitored TDP with various components of the nNOS reaction added. Glucose normally does not produce TDP in wildtype mouse islets except under forced intracellular acidification. Remarkably, glucose produced strong TDP in NOS-KO islets and in wild-type islets treated with nNOS inhibitors. TDP in NOS-KO islets was not inhibited by the addition of NO, and NOS-KO islets exhibited a lower pH i than wild-type islets. The addition of arginine to wild-type islets also enabled glucose to induce TDP. Our results show that nNOS activity contributes to the absence of TDP in mouse islets putatively through depletion of intracellular arginine.

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Nitric oxide kinetics during hypoxia in proximal tubules: Effects of acidosis and glycine

Cited by 86 publications

References 20 publications

Nitric oxide production by mouse renal tubules can be increased by a sodium-dependent mechanism

Nitric oxide production by mouse renal tubules can be increased by a sodium-dependent mechanism

Evidence for the Role of Reactive Nitrogen Species in Polymicrobial Sepsis-Induced Renal Peritubular Capillary Dysfunction and Tubular Injury

Mechanisms of Time-Dependent Potentiation of Insulin Release

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