EUK-134 reduces renal dysfunction and injury caused by oxidative and nitrosative stress of the kidney

P K Chatterjee, N S A Patel, E O Kvale, P A J Brown, K N Stewart, H Mota-Filipe, M A Sharpe, R Di Paola, S Cuzzocrea, C Thiemermann

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Abstract

Background/Aims: Oxidative and nitrosative stress plays important roles in the pathogenesis of renal ischemia/ reperfusion (I/R) injury. Here we investigate the effect of EUK-134, a synthetic superoxide dismutase and catalase mimetic, (i) on renal dysfunction and injury caused by I/R in vivo and (ii) on proximal tubular cell (PTC) injury and death caused by oxidative and nitrosative stress. Methods: Rats, subjected to bilateral renal ischemia ( 45 min) followed by reperfusion ( 6 h), were administered EUK-134 (0.3 and 3 mg/kg, i. v.) prior to and during reperfusion, after which biochemical and histological indicators of renal dysfunction and injury were measured. The expression of poly( ADP-ribose) ( PAR) and inducible nitric oxide ( NO) synthase ( iNOS) and nitrotyrosine formation were determined immunohistochemically and used as indicators of oxidative and nitrosative stress. Primary cultures of rat PTCs, isolated and cultured from the kidney cortex, were incubated with hydrogen peroxide (H2O2; 1 mM for 2 h) in the presence of increasing concentrations of EUK-134 (1 - 100 muM) after which PTC injury and death were measured. The effects of EUK-134 on serum levels of NO in rats subjected to renal I/R or on NO production by PTCs incubated with interferon-gamma ( IFN-gamma, 100 IU/ml) and bacterial lipopolysaccharide (LPS, 10 mug/ ml) in combination for 24 h were also measured. Results: EUK-134 produced a significant reduction in renal dysfunction and injury caused by I/R. Specifically, serum creatinine levels, an indicator of renal dysfunction, were reduced from 227 +/- 11 (n = 12, I/R only) to 146 +/- 9 muM (n = 12, I/R + 3 mg/ kg EUK- 134). Urinary N-acetyl-beta-D-glucosaminidase activity, an indicator of tubular damage, was reduced from 42 +/- 5 (n = 12, I/R only) to 22 +/- 3 IU/l (n = 12, I/R + 3 mg/kg EUK-134). EUK-134 significantly reduced renal injury caused by oxidative stress in vivo ( reduction in PAR formation), and in vitro EUK- 134 reduced PTC injury and death caused by H2O2. However, EUK- 134 also reduced nitrosative stress caused by I/R in vivo ( reduction of iNOS expression and nitrotyrosine formation), which was reflected by a significant reduction in serum NO levels in rats subjected to renal I/R. Specifically, serum NO levels were reduced from 57 +/- 12 ( n = 12, I/R only) to 23 +/- 3 mM (n = 12, I/ R + 3 mg/kg EUK- 134). In vitro, EUK- 134 significantly reduced NO production by PTCs incubated with IFN-gamma/LPS. Conclusion: We propose that EUK- 134 reduces renal I/ R injury not only via reduction of oxidative stress, but also by reducing nitrosative stress caused by renal I/R. Copyright (C) 2004 S. Karger AG, Basel.

Original languageEnglish
Pages (from-to)165-177
Number of pages13
JournalAmerican Journal of Nephrology
Volume24
DOIs
Publication statusPublished - 2004

Keywords

  • kidney
  • proximal tubule
  • ischemia
  • reperfusion injury
  • oxidative stress
  • nitrosative stress
  • superoxide dismutase
  • catalase
  • EUK-134
  • ISCHEMIA-REPERFUSION INJURY
  • SYNTHETIC SUPEROXIDE-DISMUTASE
  • NITRIC-OXIDE
  • ISCHEMIA/REPERFUSION INJURY
  • RAT-KIDNEY
  • IN-VIVO
  • CATALYTIC SCAVENGER
  • RADICAL SCAVENGER
  • INDUCED DAMAGE
  • CELL BIOLOGY

Cite this

Chatterjee, P. K., Patel, N. S. A., Kvale, E. O., Brown, P. A. J., Stewart, K. N., Mota-Filipe, H., ... Thiemermann, C. (2004). EUK-134 reduces renal dysfunction and injury caused by oxidative and nitrosative stress of the kidney. American Journal of Nephrology, 24, 165-177. https://doi.org/10.1159/000076547

EUK-134 reduces renal dysfunction and injury caused by oxidative and nitrosative stress of the kidney. / Chatterjee, P K ; Patel, N S A ; Kvale, E O ; Brown, P A J ; Stewart, K N ; Mota-Filipe, H ; Sharpe, M A ; Di Paola, R ; Cuzzocrea, S ; Thiemermann, C .

In: American Journal of Nephrology, Vol. 24, 2004, p. 165-177.

Research output: Contribution to journalArticle

Chatterjee, PK, Patel, NSA, Kvale, EO, Brown, PAJ, Stewart, KN, Mota-Filipe, H, Sharpe, MA, Di Paola, R, Cuzzocrea, S & Thiemermann, C 2004, 'EUK-134 reduces renal dysfunction and injury caused by oxidative and nitrosative stress of the kidney', American Journal of Nephrology, vol. 24, pp. 165-177. https://doi.org/10.1159/000076547
Chatterjee, P K ; Patel, N S A ; Kvale, E O ; Brown, P A J ; Stewart, K N ; Mota-Filipe, H ; Sharpe, M A ; Di Paola, R ; Cuzzocrea, S ; Thiemermann, C . / EUK-134 reduces renal dysfunction and injury caused by oxidative and nitrosative stress of the kidney. In: American Journal of Nephrology. 2004 ; Vol. 24. pp. 165-177.
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T1 - EUK-134 reduces renal dysfunction and injury caused by oxidative and nitrosative stress of the kidney

AU - Chatterjee, P K

AU - Patel, N S A

AU - Kvale, E O

AU - Brown, P A J

AU - Stewart, K N

AU - Mota-Filipe, H

AU - Sharpe, M A

AU - Di Paola, R

AU - Cuzzocrea, S

AU - Thiemermann, C

PY - 2004

Y1 - 2004

N2 - Background/Aims: Oxidative and nitrosative stress plays important roles in the pathogenesis of renal ischemia/ reperfusion (I/R) injury. Here we investigate the effect of EUK-134, a synthetic superoxide dismutase and catalase mimetic, (i) on renal dysfunction and injury caused by I/R in vivo and (ii) on proximal tubular cell (PTC) injury and death caused by oxidative and nitrosative stress. Methods: Rats, subjected to bilateral renal ischemia ( 45 min) followed by reperfusion ( 6 h), were administered EUK-134 (0.3 and 3 mg/kg, i. v.) prior to and during reperfusion, after which biochemical and histological indicators of renal dysfunction and injury were measured. The expression of poly( ADP-ribose) ( PAR) and inducible nitric oxide ( NO) synthase ( iNOS) and nitrotyrosine formation were determined immunohistochemically and used as indicators of oxidative and nitrosative stress. Primary cultures of rat PTCs, isolated and cultured from the kidney cortex, were incubated with hydrogen peroxide (H2O2; 1 mM for 2 h) in the presence of increasing concentrations of EUK-134 (1 - 100 muM) after which PTC injury and death were measured. The effects of EUK-134 on serum levels of NO in rats subjected to renal I/R or on NO production by PTCs incubated with interferon-gamma ( IFN-gamma, 100 IU/ml) and bacterial lipopolysaccharide (LPS, 10 mug/ ml) in combination for 24 h were also measured. Results: EUK-134 produced a significant reduction in renal dysfunction and injury caused by I/R. Specifically, serum creatinine levels, an indicator of renal dysfunction, were reduced from 227 +/- 11 (n = 12, I/R only) to 146 +/- 9 muM (n = 12, I/R + 3 mg/ kg EUK- 134). Urinary N-acetyl-beta-D-glucosaminidase activity, an indicator of tubular damage, was reduced from 42 +/- 5 (n = 12, I/R only) to 22 +/- 3 IU/l (n = 12, I/R + 3 mg/kg EUK-134). EUK-134 significantly reduced renal injury caused by oxidative stress in vivo ( reduction in PAR formation), and in vitro EUK- 134 reduced PTC injury and death caused by H2O2. However, EUK- 134 also reduced nitrosative stress caused by I/R in vivo ( reduction of iNOS expression and nitrotyrosine formation), which was reflected by a significant reduction in serum NO levels in rats subjected to renal I/R. Specifically, serum NO levels were reduced from 57 +/- 12 ( n = 12, I/R only) to 23 +/- 3 mM (n = 12, I/ R + 3 mg/kg EUK- 134). In vitro, EUK- 134 significantly reduced NO production by PTCs incubated with IFN-gamma/LPS. Conclusion: We propose that EUK- 134 reduces renal I/ R injury not only via reduction of oxidative stress, but also by reducing nitrosative stress caused by renal I/R. Copyright (C) 2004 S. Karger AG, Basel.

AB - Background/Aims: Oxidative and nitrosative stress plays important roles in the pathogenesis of renal ischemia/ reperfusion (I/R) injury. Here we investigate the effect of EUK-134, a synthetic superoxide dismutase and catalase mimetic, (i) on renal dysfunction and injury caused by I/R in vivo and (ii) on proximal tubular cell (PTC) injury and death caused by oxidative and nitrosative stress. Methods: Rats, subjected to bilateral renal ischemia ( 45 min) followed by reperfusion ( 6 h), were administered EUK-134 (0.3 and 3 mg/kg, i. v.) prior to and during reperfusion, after which biochemical and histological indicators of renal dysfunction and injury were measured. The expression of poly( ADP-ribose) ( PAR) and inducible nitric oxide ( NO) synthase ( iNOS) and nitrotyrosine formation were determined immunohistochemically and used as indicators of oxidative and nitrosative stress. Primary cultures of rat PTCs, isolated and cultured from the kidney cortex, were incubated with hydrogen peroxide (H2O2; 1 mM for 2 h) in the presence of increasing concentrations of EUK-134 (1 - 100 muM) after which PTC injury and death were measured. The effects of EUK-134 on serum levels of NO in rats subjected to renal I/R or on NO production by PTCs incubated with interferon-gamma ( IFN-gamma, 100 IU/ml) and bacterial lipopolysaccharide (LPS, 10 mug/ ml) in combination for 24 h were also measured. Results: EUK-134 produced a significant reduction in renal dysfunction and injury caused by I/R. Specifically, serum creatinine levels, an indicator of renal dysfunction, were reduced from 227 +/- 11 (n = 12, I/R only) to 146 +/- 9 muM (n = 12, I/R + 3 mg/ kg EUK- 134). Urinary N-acetyl-beta-D-glucosaminidase activity, an indicator of tubular damage, was reduced from 42 +/- 5 (n = 12, I/R only) to 22 +/- 3 IU/l (n = 12, I/R + 3 mg/kg EUK-134). EUK-134 significantly reduced renal injury caused by oxidative stress in vivo ( reduction in PAR formation), and in vitro EUK- 134 reduced PTC injury and death caused by H2O2. However, EUK- 134 also reduced nitrosative stress caused by I/R in vivo ( reduction of iNOS expression and nitrotyrosine formation), which was reflected by a significant reduction in serum NO levels in rats subjected to renal I/R. Specifically, serum NO levels were reduced from 57 +/- 12 ( n = 12, I/R only) to 23 +/- 3 mM (n = 12, I/ R + 3 mg/kg EUK- 134). In vitro, EUK- 134 significantly reduced NO production by PTCs incubated with IFN-gamma/LPS. Conclusion: We propose that EUK- 134 reduces renal I/ R injury not only via reduction of oxidative stress, but also by reducing nitrosative stress caused by renal I/R. Copyright (C) 2004 S. Karger AG, Basel.

KW - kidney

KW - proximal tubule

KW - ischemia

KW - reperfusion injury

KW - oxidative stress

KW - nitrosative stress

KW - superoxide dismutase

KW - catalase

KW - EUK-134

KW - ISCHEMIA-REPERFUSION INJURY

KW - SYNTHETIC SUPEROXIDE-DISMUTASE

KW - NITRIC-OXIDE

KW - ISCHEMIA/REPERFUSION INJURY

KW - RAT-KIDNEY

KW - IN-VIVO

KW - CATALYTIC SCAVENGER

KW - RADICAL SCAVENGER

KW - INDUCED DAMAGE

KW - CELL BIOLOGY

U2 - 10.1159/000076547

DO - 10.1159/000076547

M3 - Article

VL - 24

SP - 165

EP - 177

JO - American Journal of Nephrology

JF - American Journal of Nephrology

SN - 0250-8095

ER -