Fatty acid-bearing albumin induces VCAM-1 expression through c-Src kinase-AP-1/NF-kB pathways: effect of L-carnitine.
BACKGROUND
Fatty acid-bearing albumin [FA(+) albumin] exerts more deleterious effects in tubular cells than albumin alone. We investigated the effect of FA(+) albumin on the vascular cell adhesion molecule-1 (VCAM-1) expression and elucidated the underlying signaling pathways. We further examined the effect of L-carnitine, since it was known to modulate intracellular fatty acid concentration.


METHODS
Activation of AP-1 and NF-kappaB was assessed by electrophoretic mobility shift assay. Phosphorylation of protein kinase was examined by Western blot analysis. VCAM-1 mRNA and protein expression were measured by Northern blot analysis and cell ELISA.


RESULTS
FA(+) albumin induced VCAM-1 expression via activation of AP-1 and NF-kappaB, which was mediated through activation of c-Src kinase, followed by MAP kinases (p38, ERK 1/2, JNK-1) and IkappaB kinase and IkappaB-alpha, respectively. Inhibitors of protein kinase C and tyrosine kinase, anti-oxidants and intracellular calcium chelator suppressed the FA(+) albumin-induced activation of c-Src kinase. L-Carnitine suppressed the FA(+) albumin-induced VCAM-1 expression via inhibition of c-Src kinase.


CONCLUSIONS
VCAM-1 expression with activation of c-Src kinase-AP-1/NFkappaB pathways might be one of the possible mechanisms that linked FA(+) albumin to tubulointerstitial injury. L-Carnitine might be beneficial in attenuating FA(+) albumin-induced tubular injury.
Baek
Joo Eun
JE
Department of Internal Medicine, Asan Institute for Life Sciences, College of Medicine, University of Ulsan, Seoul, Korea.
Yang
Won Suk
WS
Chang
Jai Won
JW
Kim
Soon Bae
SB
Park
Su Kil
SK
Park
Jung Sik
JS
Lee
Sang Koo
SK
D000418:Albumins / Q000378:metabolism / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D002331:Carnitine / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000502:physiology*; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*; D014803:Vitamin B Complex / Q000378:metabolism / Q000494:pharmacology; D019061:src-Family Kinases
D000418:Albumins; D005227:Fatty Acids; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D019010:Vascular Cell Adhesion Molecule-1; D014803:Vitamin B Complex; D000072000:NF-KappaB Inhibitor alpha; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D002331:Carnitine