PPARgamma agonists inhibit TGF-beta-PKA signaling in glomerulosclerosis.
OBJECTIVE
To study the probable mechanisms of the anti-glomerulosclerosis effects induced by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists in rat intraglomerular mesangial cells (MCs).


METHODS
Cells were transfected with the pTAL-PPRE-tk-Luc(+) plasmid and then treated with different concentrations of PPARgamma agonist, either troglitazone or telmisartan, for the indicated times. Promega luciferase assays were subsequently used for the detection of PPARgamma activation. Protein expression levels were assessed by Western blot, and PepTag assays were used for the non-radioactive detection of protein kinase A (PKA) activity. The deposition of alpha-smooth muscle actin (alpha-SMA) and p-cyclic AMP responsive element binding protein (pCREB) were analyzed by confocal laser scanning.


RESULTS
Both troglitazone and telmisartan remarkably inhibit the PKA activation and pCREB expression that is stimulated by TGF-beta. The PPARgamma agonists also inhibited alpha-SMA and collagen IV protein expression by blocking PKA activation.


CONCLUSIONS
PPARgamma ligands effectively suppress the activation of MCs and the accumulation of collagen IV stimulated by TGF-beta in vitro. The renal protection provided by PPARgamma agonists is partly mediated via their blockade of TGF-beta/PKA signaling.
Zou
Rong
R
Department of Nephrology, Wuhan Integrated TCM & Western Medicine Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xu
Gang
G
Liu
Xiao-cheng
XC
Han
Min
M
Jiang
Jing-jing
JJ
Huang
Qian
Q
He
Yong
Y
Yao
Ying
Y
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D024141:Collagen Type IV / Q000187:drug effects / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D000077333:Telmisartan; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000077288:Troglitazone
D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D002839:Chromans; D024141:Collagen Type IV; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D000077333:Telmisartan; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D000077288:Troglitazone; C498862:Acta2 protein, rat