Plasma membrane phospholipid integrity and orientation during hypoxic and toxic proximal tubular attack

Zager, Richard A.; Sacks, Benjamin; Burkhart, Kristin M.; Williams, Ali C.

doi:10.1046/j.1523-1755.1999.00533.x

Cited by 34 publications

(30 citation statements)

References 28 publications

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“…This created five experimental groups: 1) control incubation for 25 min at 37°C; 2) control incubation with LS vehicle for 25 min; 3) incubation with LS (500 ng/ml) for 25 min; 4) hypoxia-reoxygenation (H/R) injury (12.5 min at 95% N 2-5% CO2, followed by 12.5 min reoxygenation with 95% O2-5% CO2) in the presence of LS vehicle; and 5) H/R in the presence of 500 ng/ml LS. After these incubations were completed, cell injury was assessed as percent lactate dehydrogenase (LDH) release (56).…”

Section: Isolated Tubule Experiments: Effects Of K Atp Channel Agonismentioning

confidence: 99%

“…Four sets of tubules were incubated for 25 min under control conditions (GCM vehicle) or with 500 M GCM. After the incubations were completed, tubule lipids were extracted in chloroform-methanol and the recovered lipid was assayed for NEFA as previously described (56). Results were expressed as nanomoles of fatty acid per milligram of tubule protein.…”

Section: Isolated Tubule Experiments: Effects Of K Atp Channel Agonismentioning

confidence: 99%

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Levosimendan protects against experimental endotoxemic acute renal failure

Zager¹,

Johnson²,

Lund³

et al. 2006

American Journal of Physiology-Renal Physiology

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126

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Endotoxemia induces a hemodynamic form of acute renal failure (ARF; renal vasoconstriction +/- reduced glomerular ultrafiltration coefficient, K(f); minimal/no histological damage). We tested whether levosimendan (LS), an ATP-sensitive K+ (K(ATP)) channel opener with cardiac ionotropic and possible anti-inflammatory properties, might have utility in combating this form of ARF. CD-1 mice were injected with LPS +/- LS. LS effects on LPS-induced systemic inflammation (plasma TNF-alpha/MCP-1; cardiorenal mRNAs), plasma NO levels, and azotemia were assessed. Because K(ATP) channel opening has been reported to mediate hypoxic tubular injury, possible adverse LS effects on ischemic ARF and ATP depletion injury were sought. Effects of diazoxide (another K(ATP) channel agonist) and glibenclamide (a channel antagonist) on hypoxic tubular injury also were assessed. Finally, the ability of LS to alter rat mesangial cell (MC) contraction in response to ANG II (elevated in sepsis) was tested. LS conferred almost complete protection against LPS-induced ARF, without any apparent reduction in the LPS-induced inflammatory response. Neither LS nor diazoxide altered ATP depletion-mediated tubule injury (in vivo or in vitro). Conversely, glibenclamide induced a marked and direct cytotoxic effect. LS completely blocked ANG II-induced MC contraction, an action likely to increase K(f). We concluded that 1) LS can confer marked protection against LPS-induced ARF; 2) this likely stems from vasoactive properties, rather than reductions in LPS-induced inflammation; and 3) K(ATP) channel agonists (but not antagonists) appear to be devoid of toxic proximal tubular cell effects. This suggests that LS, and other K(ATP) channel agonists, have a margin of safety if employed in situations (sepsis syndrome, heart failure) in which severe renal vasoconstriction might lead to ischemic ARF.

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Section: Isolated Tubule Experiments: Effects Of K Atp Channel Agonismentioning

confidence: 99%

Section: Isolated Tubule Experiments: Effects Of K Atp Channel Agonismentioning

confidence: 99%

Levosimendan protects against experimental endotoxemic acute renal failure

Zager¹,

Johnson²,

Lund³

et al. 2006

American Journal of Physiology-Renal Physiology

Self Cite

126

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“…Phospholipid degradation contributes to tissue injury in many organs, particularly during ischemic kidney injury. In hypoxemic kidney injury, increased accumulation of intracellular FA secondary to decreased mitochondrial metabolism has been reported [27]. Phospholipase A2 (PLA2) acts on membrane phospholipids at the sn-2 position to generate lysophospholipids and free fatty acids (FFA).…”

Section: Discussionmentioning

confidence: 99%

Distinct urinary lipid profile in children with focal segmental glomerulosclerosis

et al. 2015

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Background Focal segmental glomerulosclerosis (FSGS) accounts for the majority of new-onset end-stage renal disease (ESRD) during adolescence. FSGS treatment is a great challenge for pediatric nephrologists due to intertwined molecular pathways underlining its complex pathophysiology. There is emerging evidence showing that perturbed lipid metabolism plays a role in the pathophysiology of FSGS. Methods We postulate that the nephrotic milieu in FSGS differs from minimal change disease (MCD) and that urinary lipidomics can be used as a tool for early diagnosis of FSGS. We explored the urinary lipid profile of patients with FSGS and MCD using an unbiased metabolomics approach. Results We discovered a unique lipid signature characterized by increased concentration of fatty acid (FA) and lysophosphatidylcholines (LPC) and a decrease in urinary concentration of phosphatidylcholine (PC) in patients with FSGS. These findings indicate increased metabolism of membrane phospholipid PC by phospholipase A2 (PLA2), resulting in higher urinary concentrations of LPC and FA. Conclusions We propose that increased PC by-products can be used as a biomarker to diagnose FSGS and shed light on the mechanism of tubular and podocyte damage. Validation of identified urinary lipids as a biomarker in predicting the diagnosis and progression of FSGS in a larger patient population is warranted.

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“…They were subjected to lipid extraction as previously described in detail. 16 The lipid samples were dried under N 2 and saved for cholesterol analysis (vide infra). The values for FC and CE were expressed as nmol/mol recovered phospholipid phosphate, the latter being determined by the method of Van Veldhoven and Mannaerts.…”

Section: Impact Of Hypoxia On Pts-fc and Ce Expressionmentioning

confidence: 99%

“…[13][14][15][16] Based on these studies, it is accepted that with the onset of acute cell injury, phospholipases (most notably PLA 2 ) are activated, resulting in phospholipid degradation and reciprocal lysophospholipid/free fatty acid increments. These changes have been widely implicated in the evolution of acute membrane injury, and hence, necrotic cell death.…”

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confidence: 99%

Changes in Free and Esterified Cholesterol

Zager

Kalhorn

2000

The American Journal of Pathology

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Acute tubular cell injury is accompanied by plasma membrane phospholipid breakdown. Although cholesterol is a dominant membrane lipid which interdigitates with, and impacts, phospholipid homeostasis, its fate during the induction and recovery phases of acute renal failure (ARF) has remained ill defined. The present study was performed to ascertain whether altered cholesterol expression is a hallmark of evolving tubular damage. Using gas chromatographic analysis, free cholesterol (FC) and esterified cholesterol (CE) were quantified in: 1) isolated mouse proximal tubule segments (PTS) after 30 minutes of hypoxic or oxidant (ferrous ammonium sulfate) injury; 2) cultured proximal tubule (HK-2) cells after 4 or 18 hours of either ATP depletion/Ca 2؉ ionophoreor ferrous ammonium sulfate-mediated injury; and 3) in renal cortex 18 hours after induction of glycerolinduced myoglobinuric ARF, a time corresponding to the so-called "acquired cytoresistance" state (ie, resistance to further renal damage). Hypoxic and oxidant injury each induced ϳ33% decrements in CE (but not FC) levels in PTS, corresponding with lethal cell injury (ϳ50 to 60% LDH release). When comparable CE declines were induced in normal PTS by exogenous cholesterol esterase treatment, proportionate lethal cell injury resulted. During models of slowly evolving HK-2 cell injury, progressive CE increments occurred: these were first noted at 4 hours, and reached ϳ600% by 18 hours. In vivo myoglobinuric ARF produced comparable renal cortical CE (and to a lesser extent FC) increments. Renal CE accumulation strikingly correlated with the severity of ARF (eg, blood urea nitrogen versus CE; r, 0. Cholesterol is a critical constituent of plasma membranes.

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Plasma membrane phospholipid integrity and orientation during hypoxic and toxic proximal tubular attack

Cited by 34 publications

References 28 publications

Levosimendan protects against experimental endotoxemic acute renal failure

Levosimendan protects against experimental endotoxemic acute renal failure

Distinct urinary lipid profile in children with focal segmental glomerulosclerosis

Changes in Free and Esterified Cholesterol

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