Stimulation of carnitine palmitoyltransferase 1 improves renal function and attenuates tissue damage after ischemia/reperfusion.

Abstract

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.

• Authors: Juan-Pablo Idrovo, Weng-Lang Yang, Jeffrey Nicastro, Gene F Coppa, Ping Wang
• Journal: The Journal of surgical research (J Surg Res) Vol. 177 Issue 1 Pg. 157-64 (Sep 2012) ISSN: 1095-8673 [Electronic] United States
• PMID: 22698429 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Tumor Necrosis Factor-alpha
• Adenosine Triphosphate
• Peroxidase
• Carnitine O-Palmitoyltransferase
• 4-Butyrolactone

Topics

• 4-Butyrolactone (analogs & derivatives, pharmacology, therapeutic use)
• Acute Kidney Injury (immunology, prevention & control)
• Adenosine Triphosphate (biosynthesis)
• Animals
• Carnitine O-Palmitoyltransferase (metabolism)
• Edema (prevention & control)
• Energy Metabolism
• Kidney (drug effects, metabolism)
• Leukocytes (physiology)
• Male
• Peroxidase (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (immunology, prevention & control)
• Tumor Necrosis Factor-alpha (metabolism)