TY - JOUR
T1 - The PPARγagonist pioglitazone prevents TGF-β induced renal fibrosis by repressing EGR-1 and STAT3
AU - Németh, Ágnes
AU - Mózes, Miklós M.
AU - Calvier, Laurent
AU - Hansmann, Georg
AU - Kökény, Gábor
N1 - Funding Information:
The project was funded by the grant of the Hungarian Scientific Research Fund (OTKA PD112960 to GK), and the German Research Foundation (DFG HA4348/2–2 and HA4348/6-1 to GH). None of the funding bodies had any role in the study design, data collection, analysis, interpretation or in writing the manuscript.
Publisher Copyright:
© 2019 The Author(s).
PY - 2019/7/5
Y1 - 2019/7/5
N2 - Background: It has been proposed that peroxisome proliferator-activated receptor-γ(PPARγ) agonists might reduce renal fibrosis, however, several studies had contradictory results. Moreover, the possible interaction of TGF-β1, PPARγ, and transcription factors in renal fibrosis have not been investigated. We hypothesized that oral pioglitazone treatment would inhibit TGF-β-driven renal fibrosis and its progression, by modulating profibrotic transcription factors in TGF-β1 transgenic mice. Methods: Male C57Bl/6 J mice (control, CTL, n = 14) and TGF-β overexpressing transgenic mice (TGFβ, n = 14, having elevated plasma TGF-β1 level) were divided in two sets at 10 weeks of age. Mice in the first set were fed with regular rodent chow (CTL and TGFβ, n = 7/group). Mice in the second set were fed with chow containing pioglitazone (at a dose of 20 mg/kg/day, CTL + Pio and TGFβ+Pio, n = 7/group). After 5 weeks of treatment, blood pressure was assessed and urine samples were collected, and the kidneys were analyzed for histology, mRNA and protein expression. Results: TGF-β1 induced glomerulosclerosis and tubulointerstitial damage were significantly reduced by pioglitazone. Pioglitazone inhibited renal mRNA expression of all the profibrotic effectors: type-III collagen, TGF-β1, CTGF and TIMP-1, and alike transcription factors cFos/cJun and protein expression of EGR-1, and STAT3 protein phosphorylation. Conclusions: Oral administration of PPARγagonist pioglitazone significantly reduces TGF-β1-driven renal fibrosis, via the attenuation of EGR-1, STAT3 and AP-1. This implies that PPARγagonists might be effective in the treatment of chronic kidney disease patients.
AB - Background: It has been proposed that peroxisome proliferator-activated receptor-γ(PPARγ) agonists might reduce renal fibrosis, however, several studies had contradictory results. Moreover, the possible interaction of TGF-β1, PPARγ, and transcription factors in renal fibrosis have not been investigated. We hypothesized that oral pioglitazone treatment would inhibit TGF-β-driven renal fibrosis and its progression, by modulating profibrotic transcription factors in TGF-β1 transgenic mice. Methods: Male C57Bl/6 J mice (control, CTL, n = 14) and TGF-β overexpressing transgenic mice (TGFβ, n = 14, having elevated plasma TGF-β1 level) were divided in two sets at 10 weeks of age. Mice in the first set were fed with regular rodent chow (CTL and TGFβ, n = 7/group). Mice in the second set were fed with chow containing pioglitazone (at a dose of 20 mg/kg/day, CTL + Pio and TGFβ+Pio, n = 7/group). After 5 weeks of treatment, blood pressure was assessed and urine samples were collected, and the kidneys were analyzed for histology, mRNA and protein expression. Results: TGF-β1 induced glomerulosclerosis and tubulointerstitial damage were significantly reduced by pioglitazone. Pioglitazone inhibited renal mRNA expression of all the profibrotic effectors: type-III collagen, TGF-β1, CTGF and TIMP-1, and alike transcription factors cFos/cJun and protein expression of EGR-1, and STAT3 protein phosphorylation. Conclusions: Oral administration of PPARγagonist pioglitazone significantly reduces TGF-β1-driven renal fibrosis, via the attenuation of EGR-1, STAT3 and AP-1. This implies that PPARγagonists might be effective in the treatment of chronic kidney disease patients.
KW - Kidney
KW - PPARγ
KW - Renal fibrosis
KW - TGF-β
KW - Transcription factors
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U2 - 10.1186/s12882-019-1431-x
DO - 10.1186/s12882-019-1431-x
M3 - Article
C2 - 31277592
AN - SCOPUS:85069269365
SN - 1471-2369
VL - 20
JO - BMC nephrology
JF - BMC nephrology
IS - 1
M1 - 245
ER -