Differential regulation of glomerular arginine transporters (CAT-1 and CAT-2) in lipopolysaccharide-treated rats

The decrease in glomerular filtration rate (GFR) that is characteristic of sepsis has been shown to result from inhibition of glomerular endothelial nitric oxide synthase (eNOS) by nitric oxide (NO) generated from the inducible isoform of NOS (iNOS). Although l-arginine is the sole precursor for NO...

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Published in:American journal of physiology. Renal physiology 2003-04, Vol.284 (4), p.F788-F795
Main Authors: Schwartz, Doron, Schwartz, Idit F, Gnessin, Ehud, Wollman, Yoram, Chernichovsky, Tamara, Blum, Miriam, Iaina, Adrian
Format: Article
Language:English
Subjects:
Animals
Arginine - pharmacokinetics
Cationic Amino Acid Transporter 1 - genetics
Cationic Amino Acid Transporter 1 - metabolism
Cationic Amino Acid Transporter 2 - genetics
Cationic Amino Acid Transporter 2 - metabolism
Cells, Cultured
Disease Models, Animal
Dose-Response Relationship, Drug
Gene Expression Regulation - drug effects
Glomerular Mesangium - cytology
Glomerular Mesangium - drug effects
Glomerular Mesangium - metabolism
In Vitro Techniques
Ion Transport - drug effects
Kidney Glomerulus - drug effects
Kidney Glomerulus - metabolism
Lipopolysaccharides
Lysine - pharmacology
Male
Nitric Oxide Synthase - metabolism
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Rats
Rats, Wistar
RNA, Messenger - metabolism
Sepsis - chemically induced
Sepsis - metabolism
Sodium - pharmacology
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Summary:The decrease in glomerular filtration rate (GFR) that is characteristic of sepsis has been shown to result from inhibition of glomerular endothelial nitric oxide synthase (eNOS) by nitric oxide (NO) generated from the inducible isoform of NOS (iNOS). Although l-arginine is the sole precursor for NO biosynthesis, its intracellular availability in glomeruli from septic animals has never been investigated. Arginine uptake was measured in freshly harvested glomeruli from the following experimental groups: 1) untreated rats; 2) rats pretreated with LPS (4 mg/kg body wt, 4 h before experiments); 3) rats treated with LPS as above with either l-N(6)-(1-iminoethyl)lysine hydrochloride (l-NIL), a selective iNOS antagonist, or 7-nitroindazole, a selective neuronal NOS antagonist; and 4) rats treated with l-NIL only. Both glomeular and mesangial arginine transport characteristics were found compatible with a y(+) system. Arginine uptake was augmented in glomeruli from LPS-treated rats. Treatment with l-NIL completely abolished this effect whereas l-NIL alone had no effect. Similar results were obtained when primary cultures of rat mesangial cells were preincubated with LPS (10 microg/ml for 24 h) with or without l-NIL. Using RT-PCR, we found that in vivo administration of LPS resulted in a significant increase in glomerular cationic amino acid transporter-2 (CAT-2) mRNA expression whereas CAT-1 mRNA was undetected. Northern blotting further confirmed a significant increase in glomerular CAT-2 by LPS. In mesangial cells, the expression of both CAT-1 and CAT-2 mRNA was augmented after incubation with LPS. In conclusion, in vivo administration of LPS augments glomerular arginine transport through upregulation of steady-state CAT-2 mRNA while downregulating CAT-1 mRNA. These results may correspond to the changes in glomerular iNOS and eNOS activity in sepsis.
ISSN:1931-857X
1522-1466
DOI:10.1152/ajprenal.00221.2002