Abstract
IntroductionOperation on the infrarenal aorta and large arteries of the lower extremities may cause rhabdomyolysis of the skeletal muscle, which in turn may induce remote kidney injury. NIM-811 (N-metyl-4-isoleucine-cyclosporine) is a mitochondria specific drug, which can prevent ischemic-reperfusion (IR) injury, by inhibiting mitochondrial permeability transition pores (mPTP).ObjectivesOur aim was to reduce damages in the skeletal muscle and the kidney after IR of the lower limb with NIM-811.Materials and methodsWistar rats underwent 180 minutes of bilateral lower limb ischemia and 240 minutes of reperfusion. Four animal groups were formed called Sham (receiving vehicle and sham surgery), NIM-Sham (receiving NIM-811 and sham surgery), IR (receiving vehicle and surgery), and NIM-IR (receiving NIM-811 and surgery). Serum, urine and histological samples were taken at the end of reperfusion. NADH-tetrazolium staining, muscle Wet/Dry (W/D) ratio calculations, laser Doppler-flowmetry (LDF) and mean arterial pressure (MAP) monitoring were performed. Renal peroxynitrite concentration, serum TNF-α and IL-6 levels were measured.ResultsLess significant histopathological changes were observable in the NIM-IR group as compared with the IR group. Serum K+ and necroenzyme levels were significantly lower in the NIM-IR group than in the IR group (LDH: p<0.001; CK: p<0.001; K+: p = 0.017). Muscle mitochondrial viability proved to be significantly higher (p = 0.001) and renal function parameters were significantly better (creatinine: p = 0.016; FENa: p<0.001) in the NIM-IR group in comparison to the IR group. Serum TNF-α and IL-6 levels were significantly lower (TNF-α: p = 0.003, IL-6: p = 0.040) as well as W/D ratio and peroxynitrite concentration were significantly lower (p = 0.014; p<0.001) in the NIM-IR group than in the IR group.ConclusionNIM-811 could have the potential of reducing rhabdomyolysis and impairment of the kidney after lower limb IR injury.
Highlights
Operation on the infrarenal aorta and large arteries of the lower extremities may cause rhabdomyolysis of the skeletal muscle, which in turn may induce remote kidney injury
Serum K+ and necroenzyme levels were significantly lower in the NIM-IR group than in the IR group (LDH: p,0.001; creatine kinase (CK): p, 0.001; K+: p = 0.017)
NIM-811 could have the potential of reducing rhabdomyolysis and impairment of the kidney after lower limb IR injury
Summary
Operation on the infrarenal aorta and large arteries of the lower extremities may cause rhabdomyolysis of the skeletal muscle, which in turn may induce remote kidney injury. Arterial occlusive diseases are the most frequent causes of acute limb ischemia (ALI) Operative treatments for these diseases, as well as other reconstructive surgeries on abdominal aorta or other major arteries of the lower limb may induce sudden onset ischemia, in which event lower limb tissues suffer ischemicreperfusion (IR) injuries. Damage caused by mitochondrial membrane depolarization can significantly jeopardize energy production, which can lead to cell damage, further to cell death. Decline of the mitochondrial membrane potential causes further opening of the mPTPs, release of different molecules from the dysfunctional mitochondria may provoke cell death [6]
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