Troglitazone inhibits glutamine metabolism in rat mesangial cells.
Troglitazone is a peroxisome proliferator-activated receptor-gamma agonist that has been shown to halt mesangium expansion in experimental models of type 2 diabetes mellitus and to act directly on rat mesangial cells. Because glutamine serves as the precursor for cellular biosynthetic processes, we asked whether troglitazone would inhibit mesangial cell glutamine metabolism under these conditions. Confluent monolayers of rat mesangial cells were incubated in RPMI medium in the presence of troglitazone or vehicle (DMSO). Troglitazone effected a dose-dependent reduction in glutamine utilization and in alanine formation, associated with a decrease in monolayer collagen-glycosaminoglycan content. Despite the reduced glutamine uptake, ammonium formation did not decrease, consistent with increased glutamate flux through the deamination pathway. Assayable activity of the alanine aminotransferase decreased by 63%, whereas assayable glutamate dehydrogenase remained unchanged. In control monolayers, the sum of ammonium plus alanine plus glutamate nitrogen released accounted for <75% of the glutamine nitrogen uptake. In troglitazone-treated monolayers, all of the glutamine nitrogen taken up could be accounted for as ammonium nitrogen released into the medium. These results are consonant with troglitazone reducing glutamine metabolism and specifically the transamination pathway in rat mesangial cells associated with a reduction in collagen-glycosaminoglycan content.
Routh
Robert
R
Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
McCarthy
Kevin
K
Welbourne
Tomas
T
D000409:Alanine / Q000037:antagonists & inhibitors; D000410:Alanine Transaminase / Q000037:antagonists & inhibitors; D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D003094:Collagen / Q000037:antagonists & inhibitors; D003641:Deamination; D004305:Dose-Response Relationship, Drug; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000037:antagonists & inhibitors*; D006025:Glycosaminoglycans / Q000037:antagonists & inhibitors; D008297:Male; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D002839:Chromans; D006025:Glycosaminoglycans; D000644:Quaternary Ammonium Compounds; D013844:Thiazoles; D045162:Thiazolidinediones; D005973:Glutamine; D018698:Glutamic Acid; D003094:Collagen; D000410:Alanine Transaminase; D000077288:Troglitazone; D000409:Alanine