The role of mitochondria in oxidative and nitrosative stress during ischemia/reperfusion in the rat kidney

Plotnikov, Egor Y.; Kazachenko, A.V.; Vysokikh, Mikhail; Vasileva, A. K.; Tcvirkun, D.V.; Isaev, N. K.; Kirpatovskiy, V.I.; Zorov, Dmitry B.

doi:10.1038/sj.ki.5002568

Cited by 191 publications

(166 citation statements)

References 59 publications

(70 reference statements)

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“…26 Interestingly, differences in PT and DT signal were reported in vivo during an investigation of the excretion of a fluorescent substrate for organic cation transport in the kidney. 27 In addition, a study of ⌬ m in live kidney slices using confocal imaging of tissue loaded with tetramethyl rhodamine ethyl ester (TMRE) showed heterogeneity in signal among different cell types, 3 but the investigators did not comment on the nature of these differences.…”

Section: Discussionmentioning

confidence: 99%

Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments

Hall

Unwin

Parker

et al. 2009

Journal of the American Society of Nephrology

138

115

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Mitochondrial dysfunction may play a role in the pathogenesis of several renal diseases. Although functional roles and metabolic demands differ among tubule segments, relatively little is known about the properties of mitochondria in different parts of the nephron. Clinically, the proximal tubule seems particularly vulnerable to mitochondrial toxicity. In this study, we used multiphoton imaging of live rat kidney slices to investigate differences in mitochondrial function along the nephron. The mitochondrial membrane potential was markedly higher in distal than proximal tubules. Inhibition of respiration rapidly collapsed the membrane potential in proximal tubules, but potential was better maintained in distal tubules. Inhibition of the F 1 F o -ATPase abolished this difference, suggesting that maintenance of potential via ATPase activity is more effective in distal than proximal tubules. Immunostaining revealed that the ratio of the expression of ATPase to IF1, an endogenous inhibitor of the mitochondrial ATPase, was lower in proximal tubules than in distal tubules. Production of reactive oxygen species was higher in proximal than distal cells, but inhibition of NADPH oxidase eliminated this difference. Glutathione levels were higher in proximal tubules. Overall, mitochondria in the proximal tubules were in a more oxidized state than those in the distal tubules. In summary, there are axial differences in mitochondrial function along the nephron, which may contribute to the pattern and pathophysiology of some forms of renal injury.

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Section: Discussionmentioning

confidence: 99%

Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments

Hall

Unwin

Parker

et al. 2009

Journal of the American Society of Nephrology

138

115

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show abstract

“…86 Finally, rats that were injected 30 minutes before ischemia-reperfusion with lithium displayed reduced levels of renal oxidative stress, because they exhibited a diminished mitochondrial membrane depolarization and reactive oxygen species (ROS) production. 13 In addition, a 30-day pretreatment of rats with lithium reduced renal damage induced by ischemia-reperfusion, which was shown by the reduction in BUN and serum creatinine and the improved preservation of the tubular structure. 20 Remarkably, lithium treatment of mice 8 hours after the onset of ischemiareperfusion was also effective in reducing kidney injury, because these mice exhibited less necrosis and a faster recovery of serum creatinine levels.…”

Section: Lithium Reduces Kidney Damage In Various Nephropathy Modelsmentioning

confidence: 99%

“…10,11 In contrast to these adverse effects of lithium treatment, accumulating evidence suggests that the administration of low lithium amounts (,0.6 mM in blood) improves kidney function in different animal nephropathy models. Single-bolus injections or short-term treatment (,1 week) of lithium reduced adriamycin-, LPS-, cisplatin-, gentamicin-, and ischemiainduced AKI, [12][13][14][15][16][17][18] whereas prolonged treatment ($1 month) alleviated kidney damage because of ischemia-reperfusion, hypertension, and the autoimmune disease lupus erythematosus. [19][20][21] To understand these opposing findings, we will first present an overview of renal lithium handling and then, discuss the molecular pathways underlying the toxic and potential therapeutic effects of lithium in the kidney.…”

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confidence: 99%

Lithium in the Kidney: Friend and Foe?

Alsady

Baumgarten²,

Deen

et al. 2015

JASN

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Trace amounts of lithium are essential for our physical and mental health, and administration of lithium has improved the quality of life of millions of patients with bipolar disorder for .60 years. However, in a substantial number of patients with bipolar disorder, long-term lithium therapy comes at the cost of severe renal side effects, including nephrogenic diabetes insipidus and rarely, ESRD. Although the mechanisms underlying the lithium-induced renal pathologies are becoming clearer, several recent animal studies revealed that short-term administration of lower amounts of lithium prevents different forms of experimental AKI. In this review, we discuss the knowledge of the pathologic and therapeutic effects of lithium in the kidney. Furthermore, we discuss the underlying mechanisms of these seemingly paradoxical effects of lithium, in which fine-tuned regulation of glycogen synthase kinase type 3, a prime target for lithium, seems to be key. The new discoveries regarding the protective effect of lithium against AKI in rodents call for follow-up studies in humans and suggest that long-term therapy with low lithium concentrations could be beneficial in CKD.

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“…Although it is precisely not known how mPT contributes to PTN formation, mitochondria have been shown to produce reactive oxygen species (ROS), as well as NO, 57 and induction of mPT has been suggested as one mechanism for such mitochondrial ROS and NO generation. 58,59 Moreover, as peroxynitrite, largely generated in mitochondria, is the major free radical responsible for PTN, 53 it is likely that superoxide and NO produced by mPT might lead to PTN. Consistent with this view, Burke et al 60 have shown blockade of PTN by CsA in mouse hepatocytes exposed to chloroform.…”

Section: This Study Demonstrates That Exposure Of Primary Cultures Ofmentioning

confidence: 99%

The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes

Reddy

Rao

Norenberg

2008

Laboratory Investigation

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Copper is an essential element and an integral component of various enzymes. However, excess copper is neurotoxic and has been implicated in the pathogenesis of Wilson's disease, Alzheimer's disease, prion conditions, and other disorders. Although mechanisms of copper neurotoxicity are not fully understood, copper is known to cause oxidative stress and mitochondrial dysfunction. As oxidative stress is an important factor in the induction of the mitochondrial permeability transition (mPT), we determined whether mPT plays a role in copper-induced neural cell injury. Cultured astrocytes and neurons were treated with 20 mM copper and mPT was measured by changes in the cyclosporin A (CsA)-sensitive inner mitochondrial membrane potential (DCm), employing the potentiometric dye TMRE. In astrocytes, copper caused a 36% decrease in the DCm at 12 h, which decreased further to 48% by 24 h and remained at that level for at least 72 h. Cobalt quenching of calcein fluorescence as a measure of mPT similarly displayed a 45% decrease at 24 h. Pretreatment with antioxidants significantly blocked the copper-induced mPT by 48-75%. Copper (24 h) also caused a 30% reduction in ATP in astrocytes, which was completely blocked by CsA. Copper caused death (42%) in astrocytes by 48 h, which was reduced by antioxidants (35-60%) and CsA (41%). In contrast to astrocytes, copper did not induce mPT in neurons. Instead, it caused early and extensive death with a concomitant reduction (63%) in ATP by 14 h. Neuronal death was prevented by antioxidants and nitric oxide synthase inhibitors but not by CsA. Copper increased protein tyrosine nitration in both astrocytes and neurons. These studies indicate that mPT, and oxidative and nitrosative stress represent major factors in copper-induced toxicity in astrocytes, whereas oxidative and nitrosative stress appears to play a major role in neuronal injury.

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The role of mitochondria in oxidative and nitrosative stress during ischemia/reperfusion in the rat kidney

Cited by 191 publications

References 59 publications

Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments

Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments

Lithium in the Kidney: Friend and Foe?

The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes

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