Stimulation of carnitine palmitoyltransferase 1 improves renal function and attenuates tissue damage after ischemia/reperfusion.
BACKGROUND
Renal injury as a result of ischemia/reperfusion (I/R) is a major clinical problem with a high mortality rate and a lack of therapeutic treatment. During I/R, cellular homeostasis is disrupted owing to energy depletion, leading to cell death. Fatty acid β-oxidation is the major metabolic pathway for generating adenosine triphosphate (ATP) in the kidneys, which is governed by carnitine palmitoyltransferase 1 (CPT1). C75 is a synthetic compound that up-regulates CPT1 activity. Thus, we hypothesized that C75 treatment could increase energy production and alleviate renal I/R injury.


METHODS
We subjected male adult rats to renal I/R by bilateral renal pedicle clamping with microvascular clips for 60 min, followed by administration of 8% dimethyl sulfoxide (vehicle) or C75 (3 mg/kg body weight), with 5 animals/group. We collected blood and renal tissues 24 h after reperfusion and subjected them to various measurements and histological examination.


RESULTS
C75 treatment restored the loss of CPT1 activity and intracellular ATP levels in the kidneys after I/R. Administration of C75 significantly lowered serum creatinine, blood urea nitrogen, aspartate aminotransferase, and lactate dehydrogenase levels elevated by I/R. C75 treatment preserved morphological features of the kidneys with a significant improvement in the damage score. In addition, C75 treatment inhibited the increase of TNF-α levels in serum and kidneys, and lowered myeloperoxidase activity in the kidneys after I/R.


CONCLUSIONS
Stimulation of CPT1 activity by C75 recovered ATP depletion, improved renal function, attenuated tissue injury, and inhibited proinflammatory cytokine production and neutrophil infiltration after renal I/R injury. Therefore, enhancing the metabolism pathways for energy production may provide a novel modality to treat renal I/R injury.
Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York 11030, USA.
Juan-Pablo
JP
Idrovo
Weng-Lang
WL
Yang
Jeffrey
J
Nicastro
Gene F
GF
Coppa
Ping
P
Wang
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058186:Acute Kidney Injury / Q000276:immunology / Q000517:prevention & control*; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D004487:Edema / Q000517:prevention & control; D004734:Energy Metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000276:immunology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D009195:Peroxidase; D002334:Carnitine O-Palmitoyltransferase; D015107:4-Butyrolactone