Taken together,our results imply that PGI2 has effects on TNF-α
transcription and translation by dual antiapoptotic pathways: the exogenous PGI2/IP/cAMP pathway and the endogenous PGI2/PPAR-α pathway.
Strategies to overexpression of PGI2 and PPAR-α at different levels can be developed to attenuate renal injury from I/R and carboplatin are feasible.
49
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Tables and Figures:
1A
Fig. 1A: Expression of PPAR-α protein in NRK-52E cells with a Flag-tag containing PPAR-α cDNA transformation. PPAR-α
overexpressed in NRK-52E cells transfected by a Flag-tag containing PPAR-α cDNA plasmid.1B
Fig. 1B: Levels of cleaved caspase-3 and caspase-8 proteins in NRK-52E cells transfected with the Flag-PPAR-α plasmid
following H/R (Western blotting). After H/R treatment, the cleaved
caspase-3 and -8 were both significantly reduced by overexpression of PPAR-α.1C
1D
Fig. 1C and D: Levels of PPAR-α mRNA and protein in NRK-52E cells transfected with PPAR-α siRNA. Cells were cotransfected with lipofectamine and PPAR-α for 24 h and assayed by RT-PCR (C) and Western blotting (D). PPAR-α siRNA specifically and dose-
dependently reduced the expression of PPAR-α in PPAR-α transfected NRK-52E cells.65
1E
Fig. 1E: Protein levels of cleaved caspase-3 and -8 in short interference RNA (siRNA)-transfected NRK-52E cells following H/R (Western blotting). PPAR-α-transfected NRK-52E cells expressed less
caspase-3 and -8 after H/R. These effects were abolished by cotransfection with PPAR-α siRNA.
2A
Fig. 2A: Effects of PPAR-α on TNF-α promoter activity. H/R
elevated TNF-α promoter activity in NRK-52E cells and the effect was attenuated by infection with PPAR-α. *P< 0.05.67
2B
Fig. 2B: Effect of PPAR-α on H/R-induced TNF-α expression in
NRK-52E cells. H/R elevated the concentration of TNF-α in
NRK-52E cells and the effect was attenuated by infection with PPAR-α. C, no transfection; H, infection with HPGK plasmid; P,infection with PPAR-α plasmid. *P<0.05.
2C
Fig. 2C: Effect of PPAR-α on NF-κB nuclear translocation and IκB degradation. H/R increased the NF-κB DNA binding activity in the
nuclear extracts of renal tubular cells, but this was markedlysuppressed in PPAR-α-transfected cells. We also verified the identity of the gel shift band by competition analysis using unlabeled DNA fragments (lanes 25x and 50x). C, sham operatio
n；M, mock transfection, or PPAR-α transfection.
69
2D
Fig. 2D: Effects of PPAR-α on the NF-κB activation. In H/R-treated
PPAR-α-transfected NRK-52E cells, the level of nucleic NF-κB was reduced and cytosolic IκB was elevated. C, control; M, control plasmidtransfection. Results are from 3 independent experiments. Scanning
densitometry was used for semiquantitative analysis and compared with
-actin levels. *P < 0.05.
3A
Fig. 3A: Effects of DHA on PPAR-α expression, serum urea nitrogen, and creatinine levels following I/R. I/R injured mice showed increased
serum urea and creatininelevels. Treatment with DHA increasedintracellular PPAR-α expression and improved serum urea and creatinine levels. C, saline; D, DHA; NS, not significant; *P < 0.05; n= 6/group.
71
3B
Fig. 3B. Detection of apoptotic kidney cells using in vivo TUNEL staining. TUNEL-positive cells were virtually undetectable in the
kidneys of sham-operated mice and DHA-treated mice without I/R.Following I/R, we observed large numbers of TUNEL-positive cells in untreated mice but significantly fewer TUNEL-positive cells in DHA-treated mice. Control, left column; DHA-treated, right column;
sham operation, top; I/R, bottom; *P < 0.05; n = 5/group.
3C
Fig. 3C: Effect of DHA on expressions of caspase-3 and -8.
DHA-treated mice under I/R showed significantly less caspase-8 and -3 activation than untreated mice. Experiments were