Comparison of protective effects of trimetazidine against experimental warm ischemia of different durations: early and long-term effects in a pig kidney model

Abstract

Acute renal failure (ARF) is often the consequence of an ischemia-reperfusion injury (IRI) and associated with high mortality. Warm ischemia (WI) is a crucial factor of tissue damage, and tissue destruction led by ischemia-reperfusion (I/R) can impact the early and long-term functional outcome. Trimetazidine (TMZ) is an anti-ischemic drug. Previously, we already verified its protective effect on a cold-ischemic pig kidney model by directly adding TMZ into the preservation solution (Faure JP, Baumert H, Han Z, Goujon JM, Favreau F, Dutheil D, Petit I, Barriere M, Tallineau C, Tillement JP, Carretier M, Mauco G, Papadopoulos V, Hauet T. Biochem Pharmacol 66: 2241–2250, 2003; Faure JP, Petit I, Zhang K, Dutheil D, Doucet C, Favreau F, Eugene M, Goujon JM, Tillement JP, Mauco G, Vandewalle A, Hauet T. Am J Transplant 4: 495–504, 2004). In this study, we aimed to study the potential effect of TMZ pretreatment (5 mg/kg iv 24 h before WI) on the injury caused by WI for 45, 60, and 90 min and reperfusion in a WI pig kidney model. Compared with sham-operated (control) and uninephrectomized animals (UNX), TMZ pretreatment significantly reduced deleterious effects after 45 min, and particularly 60 and 90 min, of WI by improving the recovery of renal function and minimizing the inflammatory response commonly prevalent in ischemic kidney injury. Compared with controls (control group and UNX group), it was observed that 1) hypoxia-inducible factor-1 (HIF-1α) expression occurred earlier and with a higher intensity in the TMZ-treated groups; 2) the reduction of IRI during the first week following reperfusion was correlated with an earlier and greater expression of stathmin, which is involved in the process of tubular repair; and 3) the tubulointerstitial fibrosis was reduced, particularly after 60 and 90 min of WI. In conclusion, TMZ made the warm-ischemic kidneys more resistant to the deleterious impact of a single episode of I/R and reduced early and long-term subsequent damage.

Comparative study between trimetazidine and ice slush hypothermia in protection against renal ischemia/reperfusion injury in a porcine model

“…Several papers have shown the protective effect of trimetazidine on kidney grafts from cold preservation and reperfusion (27,28) and against warm ischemia (12,15,16). Hauet et al (27) evaluated the renal function of isolated perfused pig kidneys after 48 hours of cold storage with Euro-Collins (EC) solution plus trimetazidine (EC+TMZ), standard EC solution, or University of Wisconsin (UW) solution.…”

“…Renal function was significantly improved and lipid peroxidation reduced after preservation in Euro-Collins solution plus TMZ. Jayle et al (12) evaluated the effect of TMZ pretreatment on the injury caused by warm ischemia for 45, 60, and 90 minutes, and reperfusion in a pig kidney model. TMZ pretreatment reduced deleterious effects after 45 minutes and particularly 60 and 90 minutes of WI However, the exact mechanism of action of TMZ on renal tubular cells is not clear.…”

“…Several drugs have been studied in the protection of the kidney from I/R injury (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). The anti-anginal medication trimetazidine (TMZ) has been shown to protect the myocardium cells through inhibition of fatty acid oxidation and reciprocal activation of pyruvate oxidation, resulting in less production and accumulation of lactate and hydrogen cation, H+, during ischaemia (14).…”

Collared Pecary (tayassu tajacu) as a new model of renal ischemic injury induced by clamping the renal artery

“…Thus, one cannot state the degree of nephritis found in this experiment, since all histological analyzes were performed only at 20 days. The chronicity of the lesions is marked by the recruitment and proliferation of immune cells, increased extracellular matrix, collagen proliferation and fibrosis 51 . Thus, the continued presence of glomerular and interstitial fibrotic lesions could determine progressive loss of nephrons and glomerular filtration 4 , it is likely that tubulointerstitial fibrosis and inflammation contribute to the progressive failure of nephrons 35 .…”

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

“…HEPES, 4-(2-Hydroxyethyl)-1-piperazine ethanesulfonic acid; HES, hydroxyethyl starch; PEG, polyethylene glycol; UW, University of Wisconsin a Adapted from Bon et al [30], with permission found that inhibition of the pro-inflammatory P38 MAPK [35] or the addition of trimetazidine, a molecule mainly used in patients with angina pectoris, which has pleiotropic effects, including the inhibition of β-oxidation of fatty acids-during the preservation period improved renal function after transplantation [47]. The addition of Vectisol®, a molecular complex in which a washable vector composed of a cyclic polysaccharide is associated with the strong antioxidant resveratrol (a polyphenol present in red wine)-to the preservation solution has also been shown to be beneficial for renal function recovery [48].…”