PPAR-gamma agonist protects podocytes from injury.
Podocyte injury and loss contribute to progressive glomerulosclerosis. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear hormone receptor, which we have found to be increased in podocytes in a variety of kidney diseases. It is not known if PPAR-gamma contributes to renal injury or if it serves as a countermeasure to limit renal injury during disease progression. We tested these possibilities utilizing the puromycin aminonucleoside (PAN) model of renal injury in immortalized mouse podocytes. The cultured podocytes expressed PPAR-gamma mRNA at baseline but this was decreased by PAN. Pioglitazone, a pharmacologic agonist of PPAR-gamma, increased both PPAR-gamma mRNA and activity in injured podocytes, as assessed by a reporter plasmid assay. Further, pioglitazone significantly decreased PAN-induced podocyte apoptosis and necrosis while restoring podocyte differentiation. The PPAR-gamma agonist significantly restored expression of the cyclin-dependent kinase inhibitor p27 and the antiapoptotic molecule Bcl-xL while significantly decreasing proapoptotic caspase-3 activity. Pioglitazone tended to decrease PAN-induced transforming growth factor-beta (TGF-beta) mRNA expression. Our study shows that PPAR-gamma is normally expressed by podocytes and its activation is protective against PAN-induced apoptosis and necrosis. We postulate that this protective effect may be mediated in part by effects on p27 and TGF-beta expression.
Kanjanabuch
T
T
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Ma
L-J
LJ
Chen
J
J
Pozzi
A
A
Guan
Y
Y
Mundel
P
P
Fogo
A B
AB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology*; D051379:Mice; D009336:Necrosis; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D010957:Plasmids / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D011692:Puromycin Aminonucleoside / Q000633:toxicity; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D061945:Caspase Inhibitors; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D051020:bcl-X Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011692:Puromycin Aminonucleoside; D000077205:Pioglitazone