NF-kappaB inhibitors significantly attenuate the transcription of high affinity type-2 cationic amino acid transporter in LPS-stimulated rat kidney.
BACKGROUND
Sepsis-induced renal failure is closely related to inducible nitric oxide synthase (iNOS) upregulation and nitric oxide (NO) overproduction. Trans-membrane L-arginine transportation mediated by type-2 cationic amino acid transporter (CAT-2) isozymes, including CAT-2, CAT-2A, and CAT-2B, is one of the crucial mechanisms that regulate NO biosynthesis by iNOS. We previously had shown that endotoxemia significantly upregulated renal CAT-2 and CAT-2B but not CAT-2A expression. This study was, thus, conducted to further explore the role of nuclear factor-kappaB (NF-kappaB) in regulating the expression of CAT-2 isozymes in lipopolysaccharide (LPS)-treated rat kidney.


METHODS
Adult male Sprague-Dawley rats were randomly given intra-peritoneal injections of normal saline (N/S), LPS, LPS plus NF-kappaB inhibitor pre-treatment (PDTC, dexamethasone, or salicylate), or an NF-kappaB inhibitor alone. The rats were sacrificed at 6 hours after LPS injection and enzyme expression and renal injury were examined.


RESULTS
Renal iNOS, CAT-2, and CAT-2B were significantly upregulated in LPS-stimulated rat kidney. NF-kappa B inhibitors significantly attenuated this upregulation induced by LPS and resultantly attenuated renal NO biosynthesis and renal injury induced by LPS. In contrast, renal CAT-2A expression was not affected by either LPS or NF-kappaB inhibitors.


CONCLUSIONS
LPS co-induces iNOS, CAT-2 and CAT-2B expression in LPS-stimulated rat kidney. Furthermore, inhibition of NF-kappaB significantly attenuates NO biosynthesis through inhibition of iNOS, CAT-2, and CAT-2B, and, in turn, significantly reduces endotoxemia-induced renal injury.
Chu
Li-Chuan
LC
Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan, ROC.
Tsai
Pei-Shan
PS
Lee
Jie-Jen
JJ
Yen
Chia-Hsiang
CH
Huang
Chun-Jen
CJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D027202:Cationic Amino Acid Transporter 2 / Q000235:genetics*; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects*
D027202:Cationic Amino Acid Transporter 2; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009569:Nitric Oxide