Inorganic iron effects on in vitro hypoxic proximal renal tubular cell injury.

Zager, Richard A.; Schimpf, Brian A.; Bredl, Charles R.; Gmur, Dennis J.

doi:10.1172/jci116251

Cited by 45 publications

(43 citation statements)

References 27 publications

(29 reference statements)

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“…Alternatively, decrements in DHBA indicate decreased OH production or OH scavenging. Supporting the utility of this technique are that (a) increased DHBA production occurs with OH generating systems (11)(12)(13)(14)(15)(16); and (b) selected antioxidants (oxypurinol, dimethylthiourea, DFO) decrease DHBA production both in vivo and in vitro ( 1 1, 16, and unpublished observations by this laboratory). Eight rats were anesthetized, they were injected with Na salicylate, 100 mg/kg i.p., and then half were injected with glycerol, the remaining half serving as controls.…”

Section: Methodsmentioning

confidence: 91%

“…To assess whether plasma/urinary catalytic Fe increments cause excess intrarenal 'OH generation, the salicylate trap method was used (11)(12)(13)(14)(15)(16). In brief, Na salicylate serves as a stable 'OH trap, 2,3-and 2,5-dihydroxybenzoic acids (DHBA) being byproducts ofthis reaction.…”

Section: Methodsmentioning

confidence: 99%

“…The 2,3-, 2,5-DHBA, and salicylate concentrations were quantified by electrochemical detection ( 15, 16) (sensitivity, 0.1 nmol / ml). The DHBA results were expressed in two ways: (a) as absolute concentrations per gram tissue dry wt; and (b) as absolute concentrations divided by the salicylate concentration (thereby factoring for differences in DHBA precursor accumulation within each kidney) ( 16).…”

Section: Methodsmentioning

confidence: 99%

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Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications.

Zager¹

1992

J. Clin. Invest.

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128

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Section: Methodsmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications.

Zager¹

1992

J. Clin. Invest.

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128

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“…They were then used for either glomerular isolation by a previously reported sieving technique (n ϭ 6 PHN and 6 control rats), 30 or for isolated PTS collection (n ϭ 4 PHN and 4 controls), as previously described in detail. 35,36 The isolated tubules and glomeruli were subjected to lipid extraction, followed by FC and CE analysis, as noted above.…”

Section: Isolated Glomeruli and Isolated Proximal Tubule Segment (Ptsmentioning

confidence: 99%

Experimental Glomerulopathy Alters Renal Cortical Cholesterol, SR-B1, ABCA1, and HMG CoA Reductase Expression

Johnson

Yabu

Hanson

et al. 2003

The American Journal of Pathology

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Previous studies indicate that acute tubular injury causes free cholesterol (FC) and cholesteryl ester (CE) accumulation within renal cortex/proximal tubules. This study assessed whether similar changes occur with glomerulopathy/nephrotic syndrome, in which highcirculating/filtered lipoprotein levels increase renal cholesterol supply. Potential adaptive changes in cholesterol synthetic/transport proteins were also assessed. Nephrotoxic serum (NTS) or passive Heymann nephritis (PHN) was induced in Sprague-Dawley rats. Renal injury (blood urea nitrogen, proteinuria) was assessed 2 and 7 days (NTS), or 10 and 30 days (PHN) later. FC and CE levels in renal cortex, isolated glomeruli, and proximal tubule segments were determined. SR-B1 (a CE influx protein), ABCA1 (a FC exporter), and HMG CoA reductase protein/mRNA levels were also assessed. FC was minimally elevated in renal cortex (0 to 15%), the majority apparently localizing to proximal tubules. More dramatic CE elevations were found (ϳ5 to 15؋), correlating with the severity of proteinuria at any single time point (r > 0.85). Cholesterol increments were associated with decreased SR-B1, increased ABCA1, and increased HMG CoA reductase (HMGCR) protein and its mRNA. Tubule (HK-2) cell culture data indicated that SR-B1 and ABCA1 levels are responsive to cholesterol supply. Experimental nephropathy can increase renal FC, and particularly CE, levels, most notably in proximal tubules. These changes are associated with adaptations in SR-B1 and ABCA1 expression, which are physiologically appropriate changes for a cholesterol overload state. However, HMGCR protein/mRNA increments can also result. These seem to reflect a maladaptive response, potentially contributing to a cell cholesterol overload state. Previous work from this laboratory has indicated that diverse forms of renal tubular injury (eg, ischemia/reperfusion, myohemoglobinuria, sepsis syndrome, heat shock, urinary tract obstruction), can each trigger accumulation of free cholesterol (FC) and cholesteryl esters (CE) within renal cortex.

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“…Those free iron ions catalyze the Haber-Weiss reaction under the acidic milieu caused by tissue hypoxia to generate hydroxyl radicals that injure renal cells. It has been known that a high concentration of ferrous (Fe 2+ ) iron exerts a cytotoxic effect, especially in the proximal tubule [35][36][37][38] . It stands to reason that decreasing urinary iron excretion could decrease the rate of kidney function deterioration [39,40] .…”

Section: Discussionmentioning

confidence: 99%

Urine Catalytic Iron and Neutrophil Gelatinase Associated Lipocalin as Companion Early Markers of Acute Kidney Injury After Cardiac Surgery: A Prospective Pilot Study

2013

American Journal of Kidney Diseases

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Background: Open heart surgery with cardiopulmonary bypass is recognized as a common cause of acute kidney injury (AKI). The conventional biomarker creatinine is not sensitive enough to detect AKI until a significant decline in renal filtration has occurred. Urine neutrophil gelatinase-associated lipocalin (NGAL), part of an acute response to the release of tissue iron from cells, is an early biomarker and a predictor of AKI in a variety of clinical settings. We sought to evaluate the relationship between urine catalytic iron (unbound iron) and NGAL over the course of AKI due to cardiac surgery. Methods: Fourteen patients who underwent open heart surgery had the following measured: serum creatinine (0, 12, 24, 48 and 72 h postoperatively), urine NGAL and urine catalytic iron (0, 8, 24 and 48 h postoperatively). Urine NGAL and urine catalytic iron were quantified by immunoassay and bleomycin-detectable iron assay, respectively. AKI was defined by the Acute Kidney Injury Network (AKIN) criteria. Results: Urine catalytic iron increased significantly (p < 0.05) within 8 h and peaked at 24 h postoperatively in patients who developed AKI (n = 8, baseline 101.96 ± 177.48, peak 226.35 ± 238.23 nmol/l, p = 0.006), but not in non-AKI patients (n = 6, baseline 131.08 ± 116.21, peak 163.99 ± 109.62 nmol/l, p = 0.380). Urine NGAL levels also peaked at 24 h with significant increase observed only in AKI patients: AKI -baseline 34.88 ± 26.47, peak 65.50 ± 27.03 ng/ml, p = 0.043; non-AKI -baseline 59.33 ± 31.72, peak 71.00 ± 31.76 ng/ml, p = 0.100. The correlation between baseline levels of urine catalytic iron and NGAL and peak levels of urine catalytic iron and NGAL was r = 0.86, p < 0.0001. Conclusion: Urine catalytic iron appears to rise and fall in concert with NGAL in patients undergoing cardiac surgery and may be indicative of early AKI. Future research into the role that catalytic iron plays in acute organ injury syndromes and its potential diagnostic and therapeutic implications is warranted.

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Inorganic iron effects on in vitro hypoxic proximal renal tubular cell injury.

Cited by 45 publications

References 27 publications

Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications.

Combined mannitol and deferoxamine therapy for myohemoglobinuric renal injury and oxidant tubular stress. Mechanistic and therapeutic implications.

Experimental Glomerulopathy Alters Renal Cortical Cholesterol, SR-B1, ABCA1, and HMG CoA Reductase Expression

Urine Catalytic Iron and Neutrophil Gelatinase Associated Lipocalin as Companion Early Markers of Acute Kidney Injury After Cardiac Surgery: A Prospective Pilot Study

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