Peroxisome proliferator-activated receptor-gamma activity is associated with renal microvasculature.
Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a nuclear transcription factor and the pharmacological target for antidiabetic thiazolidinediones (TZDs). TZDs ameliorate diabetic nephropathy and have direct effects on cultured mesangial cells (MCs); however, in situ hybridization failed to detect expression of PPAR gamma in glomeruli in vivo. The purpose of this study was to determine whether PPAR gamma is expressed in renal glomeruli. Two rabbit PPAR gamma isoforms were cloned. Nuclease protection assays demonstrate that both PPAR gamma isoforms are expressed in freshly isolated glomeruli. Treatment of rabbits with the TZD troglitazone selectively induced expression of an endogenous PPAR gamma target gene, adipocyte fatty acid-binding protein (A-FABP), in renal glomerular cells and renal medullary microvascular endothelial cells, demonstrated by both in situ hybridization and immunostain. Troglitazone also dramatically increased A-FABP expression in cultured MCs. Constitutive PPAR gamma expression was detected in cultured rabbit MCs. Endogenous MC PPAR gamma can also drive PPAR gamma reporter. Troglitazone and 15-deoxy-Delta 12,14 prostaglandin J(2) at low concentrations reduced mesangial cell [(3)H]thymidine incorporation without affecting viability. These data suggest that constitutive PPAR gamma activity exists in renal glomeruli in vivo and could provide a pharmacological target to directly modulate glomerular injury.
Guan
Y
Y
Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37212, USA. youefi.guan@mcmail.vanderbilt.edu
Zhang
Y
Y
Schneider
A
A
Davis
L
L
Breyer
R M
RM
Breyer
M D
MD
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D003001:Cloning, Molecular; D004730:Endothelium, Vascular / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000077288:Troglitazone
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002352:Carrier Proteins; D002839:Chromans; D050556:Fatty Acid-Binding Proteins; D007004:Hypoglycemic Agents; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077288:Troglitazone; D015230:Prostaglandin D2