Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat

P. K. Chatterjee, Paul Anthony James Brown, K. Zacharowski, S. Cuzzocrea, Keith Nicol Stewart, H. Mota-Filipe, M. C. McDonald, C. Thiemermann

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Background. Activation of the cysteine protease calpain has been implicated in renal ischemia/reperfusion (I/R) injury. The aim of this study was to investigate the effects of calpain inhibitor-1 (Cal I-1) in an in vivo model of renal I/R injury.

Methods. Male Wistar rats were administered (Cal I-1 (10 mg/kg, IP) 30 minutes before undergoing bilateral renal ischemia (45 minutes) followed by reperfusion (6 hours). Plasma concentrations of urea, creatinine, Na+, gamma -glutamyl transferase (gamma GT), aspartate aminotransferase (AST) and urinary Na+ glutathione S-transferase (GST), and N-acetyl-beta -D-glucosaminidase (NAG) were measured for the assessment of renal dysfunction and I/R injury. Creatinine clearance (C-Cr) and fractional excretion of Na+ (FENa) were used as indicators of glomerular and tubular function, respectively. Kidney myeloperoxidase (MPO) activity and malondialdehyde (MI)A) levels were measured for assessment of neutrophil infiltration and lipid peroxidation, respectively. Renal sections were used for histologic grading of renal injury and for immunohistochemical localization of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2).

Results. Cal I-1 significantly reduced I/R-mediated increases in urea, creatinine, gamma GT, AST, NAG, and FENa and significantly improved C-Cr. Cal I-1 also significantly reduced kidney MPO activity and MDA levels. Cal I-1 also reduced histologic evidence of I/R-mediated renal damage and caused a substantial reduction in the expression of iNOS and COX-2, both of which involve activation of nuclear factor-kappaB (NF-kappaB).

Conclusions. These results suggest that Cal I-1 reduces the renal dysfunction and injury associated with I/R of the kidney. We suggest that the mechanism could involve the inhibition of I/R-mediated activation of NF-kappaB.

Original languageEnglish
Pages (from-to)2073-2083
Number of pages10
JournalKidney International
Volume59
Issue number6
Publication statusPublished - 2001

Keywords

  • kidney injury
  • inducible nitric oxide synthase
  • COX-2
  • nuclear factor-kappa B
  • acute renal failure
  • NITRIC-OXIDE SYNTHASE
  • NF-KAPPA-B
  • ISCHEMIA-REPERFUSION INJURY
  • PROXIMAL TUBULAR INJURY
  • CYSTEINE PROTEASES
  • KIDNEY
  • PROTEOLYSIS
  • FAILURE
  • DAMAGE
  • INFILTRATION

Cite this

Chatterjee, P. K., Brown, P. A. J., Zacharowski, K., Cuzzocrea, S., Stewart, K. N., Mota-Filipe, H., ... Thiemermann, C. (2001). Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat. Kidney International, 59(6), 2073-2083.

Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat. / Chatterjee, P. K.; Brown, Paul Anthony James; Zacharowski, K.; Cuzzocrea, S.; Stewart, Keith Nicol; Mota-Filipe, H.; McDonald, M. C.; Thiemermann, C.

In: Kidney International, Vol. 59, No. 6, 2001, p. 2073-2083.

Research output: Contribution to journalArticle

Chatterjee, PK, Brown, PAJ, Zacharowski, K, Cuzzocrea, S, Stewart, KN, Mota-Filipe, H, McDonald, MC & Thiemermann, C 2001, 'Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat', Kidney International, vol. 59, no. 6, pp. 2073-2083.
Chatterjee PK, Brown PAJ, Zacharowski K, Cuzzocrea S, Stewart KN, Mota-Filipe H et al. Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat. Kidney International. 2001;59(6):2073-2083.
Chatterjee, P. K. ; Brown, Paul Anthony James ; Zacharowski, K. ; Cuzzocrea, S. ; Stewart, Keith Nicol ; Mota-Filipe, H. ; McDonald, M. C. ; Thiemermann, C. / Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat. In: Kidney International. 2001 ; Vol. 59, No. 6. pp. 2073-2083.
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abstract = "Background. Activation of the cysteine protease calpain has been implicated in renal ischemia/reperfusion (I/R) injury. The aim of this study was to investigate the effects of calpain inhibitor-1 (Cal I-1) in an in vivo model of renal I/R injury.Methods. Male Wistar rats were administered (Cal I-1 (10 mg/kg, IP) 30 minutes before undergoing bilateral renal ischemia (45 minutes) followed by reperfusion (6 hours). Plasma concentrations of urea, creatinine, Na+, gamma -glutamyl transferase (gamma GT), aspartate aminotransferase (AST) and urinary Na+ glutathione S-transferase (GST), and N-acetyl-beta -D-glucosaminidase (NAG) were measured for the assessment of renal dysfunction and I/R injury. Creatinine clearance (C-Cr) and fractional excretion of Na+ (FENa) were used as indicators of glomerular and tubular function, respectively. Kidney myeloperoxidase (MPO) activity and malondialdehyde (MI)A) levels were measured for assessment of neutrophil infiltration and lipid peroxidation, respectively. Renal sections were used for histologic grading of renal injury and for immunohistochemical localization of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2).Results. Cal I-1 significantly reduced I/R-mediated increases in urea, creatinine, gamma GT, AST, NAG, and FENa and significantly improved C-Cr. Cal I-1 also significantly reduced kidney MPO activity and MDA levels. Cal I-1 also reduced histologic evidence of I/R-mediated renal damage and caused a substantial reduction in the expression of iNOS and COX-2, both of which involve activation of nuclear factor-kappaB (NF-kappaB).Conclusions. These results suggest that Cal I-1 reduces the renal dysfunction and injury associated with I/R of the kidney. We suggest that the mechanism could involve the inhibition of I/R-mediated activation of NF-kappaB.",
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author = "Chatterjee, {P. K.} and Brown, {Paul Anthony James} and K. Zacharowski and S. Cuzzocrea and Stewart, {Keith Nicol} and H. Mota-Filipe and McDonald, {M. C.} and C. Thiemermann",
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T1 - Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat

AU - Chatterjee, P. K.

AU - Brown, Paul Anthony James

AU - Zacharowski, K.

AU - Cuzzocrea, S.

AU - Stewart, Keith Nicol

AU - Mota-Filipe, H.

AU - McDonald, M. C.

AU - Thiemermann, C.

PY - 2001

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N2 - Background. Activation of the cysteine protease calpain has been implicated in renal ischemia/reperfusion (I/R) injury. The aim of this study was to investigate the effects of calpain inhibitor-1 (Cal I-1) in an in vivo model of renal I/R injury.Methods. Male Wistar rats were administered (Cal I-1 (10 mg/kg, IP) 30 minutes before undergoing bilateral renal ischemia (45 minutes) followed by reperfusion (6 hours). Plasma concentrations of urea, creatinine, Na+, gamma -glutamyl transferase (gamma GT), aspartate aminotransferase (AST) and urinary Na+ glutathione S-transferase (GST), and N-acetyl-beta -D-glucosaminidase (NAG) were measured for the assessment of renal dysfunction and I/R injury. Creatinine clearance (C-Cr) and fractional excretion of Na+ (FENa) were used as indicators of glomerular and tubular function, respectively. Kidney myeloperoxidase (MPO) activity and malondialdehyde (MI)A) levels were measured for assessment of neutrophil infiltration and lipid peroxidation, respectively. Renal sections were used for histologic grading of renal injury and for immunohistochemical localization of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2).Results. Cal I-1 significantly reduced I/R-mediated increases in urea, creatinine, gamma GT, AST, NAG, and FENa and significantly improved C-Cr. Cal I-1 also significantly reduced kidney MPO activity and MDA levels. Cal I-1 also reduced histologic evidence of I/R-mediated renal damage and caused a substantial reduction in the expression of iNOS and COX-2, both of which involve activation of nuclear factor-kappaB (NF-kappaB).Conclusions. These results suggest that Cal I-1 reduces the renal dysfunction and injury associated with I/R of the kidney. We suggest that the mechanism could involve the inhibition of I/R-mediated activation of NF-kappaB.

AB - Background. Activation of the cysteine protease calpain has been implicated in renal ischemia/reperfusion (I/R) injury. The aim of this study was to investigate the effects of calpain inhibitor-1 (Cal I-1) in an in vivo model of renal I/R injury.Methods. Male Wistar rats were administered (Cal I-1 (10 mg/kg, IP) 30 minutes before undergoing bilateral renal ischemia (45 minutes) followed by reperfusion (6 hours). Plasma concentrations of urea, creatinine, Na+, gamma -glutamyl transferase (gamma GT), aspartate aminotransferase (AST) and urinary Na+ glutathione S-transferase (GST), and N-acetyl-beta -D-glucosaminidase (NAG) were measured for the assessment of renal dysfunction and I/R injury. Creatinine clearance (C-Cr) and fractional excretion of Na+ (FENa) were used as indicators of glomerular and tubular function, respectively. Kidney myeloperoxidase (MPO) activity and malondialdehyde (MI)A) levels were measured for assessment of neutrophil infiltration and lipid peroxidation, respectively. Renal sections were used for histologic grading of renal injury and for immunohistochemical localization of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2).Results. Cal I-1 significantly reduced I/R-mediated increases in urea, creatinine, gamma GT, AST, NAG, and FENa and significantly improved C-Cr. Cal I-1 also significantly reduced kidney MPO activity and MDA levels. Cal I-1 also reduced histologic evidence of I/R-mediated renal damage and caused a substantial reduction in the expression of iNOS and COX-2, both of which involve activation of nuclear factor-kappaB (NF-kappaB).Conclusions. These results suggest that Cal I-1 reduces the renal dysfunction and injury associated with I/R of the kidney. We suggest that the mechanism could involve the inhibition of I/R-mediated activation of NF-kappaB.

KW - kidney injury

KW - inducible nitric oxide synthase

KW - COX-2

KW - nuclear factor-kappa B

KW - acute renal failure

KW - NITRIC-OXIDE SYNTHASE

KW - NF-KAPPA-B

KW - ISCHEMIA-REPERFUSION INJURY

KW - PROXIMAL TUBULAR INJURY

KW - CYSTEINE PROTEASES

KW - KIDNEY

KW - PROTEOLYSIS

KW - FAILURE

KW - DAMAGE

KW - INFILTRATION

M3 - Article

VL - 59

SP - 2073

EP - 2083

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 6

ER -