Trimetazidine reduces early and long-term effects of experimental renal warm ischemia

A dose effect study

Jerome Cau, Frederic Favreau, Jean Paul Tillement, Lilach O Lerman, Thierry Hauet, Jean Michel Goujon

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Objective: Renal ischemia reperfusion (IR) injury (IRI) is an important mechanism of acute renal failure (ARF) and a crucial factor of tissue damage during vascular surgery. IR may lead to tissue destruction and influence the early and long-term outcome of organs. The anti-anginal medication trimetazidine (TMZ) is a drug, the protective effects of which have been already assessed during cold preservation and warm ischemia (WI). The objective of this dose-effect study was to assess the role of TMZ in severe renal WI model. Materials and Methods: We have used an established WI pig kidney model associated with a uninephrectomy condition and studied the dose-dependent role of TMZ (1, 5, and 10 mg/Kg, i.v. for 24 hours before WI) against deleterious effects of WI (60 minutes of WI followed by reperfusion) compared with sham-operated (control) and uninephrectomized animals (unif). Direct effect of TMZ was determined using different variables: renal function (creatinine clearance; Ccr) and indirectly, the consequences on inflammation (cells infiltration), rate of apoptosis, fibrosis development, and renal epithelial cells change into myofibroblast, which defined epithelial to mesenchymal transition (α-smooth muscle actin [α-SMA] and vimentin expression). Results: TMZ (5 or 10 mg/Kg) significantly increased Ccr and reduced the inflammatory response prevalent in ischemic kidney injury and rate of apoptosis expression. In addition, the limitation of initial IRI was correlated with an earlier and greater expression of hypoxia-inducible transcription factor-1α (HIF-1α), which is a hypoxia marker during kidney regeneration. A reduction of the tubulointerstitial development of fibrosis and a limitation of the α-smooth muscle actin expression (α-SMA) was observed with TMZ treatment. At 3 months, vimentin expression was increased in WI groups without TMZ or low TMZ dose treatment compared with 5 or 10 mg/Kg treated groups. Conclusion: Collectively, these data suggest that TMZ made the warm ischemic kidneys more resistant to the deleterious impact of a single episode of IR and could have a role in preserving the ischemic kidney from long-term damage.

Original languageEnglish (US)
JournalJournal of Vascular Surgery
Volume47
Issue number4
DOIs
StatePublished - Apr 2008

Fingerprint

Trimetazidine
Warm Ischemia
Kidney
Reperfusion
Vimentin
Smooth Muscle
Actins
Fibrosis
Ischemia
Apoptosis
Cold Ischemia
Protective Agents
Hypoxia-Inducible Factor 1
Epithelial-Mesenchymal Transition
Myofibroblasts
Wounds and Injuries
Thromboplastin
Reperfusion Injury
Acute Kidney Injury
Blood Vessels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Trimetazidine reduces early and long-term effects of experimental renal warm ischemia : A dose effect study. / Cau, Jerome; Favreau, Frederic; Tillement, Jean Paul; Lerman, Lilach O; Hauet, Thierry; Goujon, Jean Michel.

In: Journal of Vascular Surgery, Vol. 47, No. 4, 04.2008.

Research output: Contribution to journalArticle

Cau, Jerome ; Favreau, Frederic ; Tillement, Jean Paul ; Lerman, Lilach O ; Hauet, Thierry ; Goujon, Jean Michel. / Trimetazidine reduces early and long-term effects of experimental renal warm ischemia : A dose effect study. In: Journal of Vascular Surgery. 2008 ; Vol. 47, No. 4.
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T1 - Trimetazidine reduces early and long-term effects of experimental renal warm ischemia

T2 - A dose effect study

AU - Cau, Jerome

AU - Favreau, Frederic

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AU - Lerman, Lilach O

AU - Hauet, Thierry

AU - Goujon, Jean Michel

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N2 - Objective: Renal ischemia reperfusion (IR) injury (IRI) is an important mechanism of acute renal failure (ARF) and a crucial factor of tissue damage during vascular surgery. IR may lead to tissue destruction and influence the early and long-term outcome of organs. The anti-anginal medication trimetazidine (TMZ) is a drug, the protective effects of which have been already assessed during cold preservation and warm ischemia (WI). The objective of this dose-effect study was to assess the role of TMZ in severe renal WI model. Materials and Methods: We have used an established WI pig kidney model associated with a uninephrectomy condition and studied the dose-dependent role of TMZ (1, 5, and 10 mg/Kg, i.v. for 24 hours before WI) against deleterious effects of WI (60 minutes of WI followed by reperfusion) compared with sham-operated (control) and uninephrectomized animals (unif). Direct effect of TMZ was determined using different variables: renal function (creatinine clearance; Ccr) and indirectly, the consequences on inflammation (cells infiltration), rate of apoptosis, fibrosis development, and renal epithelial cells change into myofibroblast, which defined epithelial to mesenchymal transition (α-smooth muscle actin [α-SMA] and vimentin expression). Results: TMZ (5 or 10 mg/Kg) significantly increased Ccr and reduced the inflammatory response prevalent in ischemic kidney injury and rate of apoptosis expression. In addition, the limitation of initial IRI was correlated with an earlier and greater expression of hypoxia-inducible transcription factor-1α (HIF-1α), which is a hypoxia marker during kidney regeneration. A reduction of the tubulointerstitial development of fibrosis and a limitation of the α-smooth muscle actin expression (α-SMA) was observed with TMZ treatment. At 3 months, vimentin expression was increased in WI groups without TMZ or low TMZ dose treatment compared with 5 or 10 mg/Kg treated groups. Conclusion: Collectively, these data suggest that TMZ made the warm ischemic kidneys more resistant to the deleterious impact of a single episode of IR and could have a role in preserving the ischemic kidney from long-term damage.

AB - Objective: Renal ischemia reperfusion (IR) injury (IRI) is an important mechanism of acute renal failure (ARF) and a crucial factor of tissue damage during vascular surgery. IR may lead to tissue destruction and influence the early and long-term outcome of organs. The anti-anginal medication trimetazidine (TMZ) is a drug, the protective effects of which have been already assessed during cold preservation and warm ischemia (WI). The objective of this dose-effect study was to assess the role of TMZ in severe renal WI model. Materials and Methods: We have used an established WI pig kidney model associated with a uninephrectomy condition and studied the dose-dependent role of TMZ (1, 5, and 10 mg/Kg, i.v. for 24 hours before WI) against deleterious effects of WI (60 minutes of WI followed by reperfusion) compared with sham-operated (control) and uninephrectomized animals (unif). Direct effect of TMZ was determined using different variables: renal function (creatinine clearance; Ccr) and indirectly, the consequences on inflammation (cells infiltration), rate of apoptosis, fibrosis development, and renal epithelial cells change into myofibroblast, which defined epithelial to mesenchymal transition (α-smooth muscle actin [α-SMA] and vimentin expression). Results: TMZ (5 or 10 mg/Kg) significantly increased Ccr and reduced the inflammatory response prevalent in ischemic kidney injury and rate of apoptosis expression. In addition, the limitation of initial IRI was correlated with an earlier and greater expression of hypoxia-inducible transcription factor-1α (HIF-1α), which is a hypoxia marker during kidney regeneration. A reduction of the tubulointerstitial development of fibrosis and a limitation of the α-smooth muscle actin expression (α-SMA) was observed with TMZ treatment. At 3 months, vimentin expression was increased in WI groups without TMZ or low TMZ dose treatment compared with 5 or 10 mg/Kg treated groups. Conclusion: Collectively, these data suggest that TMZ made the warm ischemic kidneys more resistant to the deleterious impact of a single episode of IR and could have a role in preserving the ischemic kidney from long-term damage.

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