The PPARγagonist pioglitazone prevents TGF-β induced renal fibrosis by repressing EGR-1 and STAT3

Ágnes Németh, Miklós M. Mózes, Laurent Calvier, Georg Hansmann, Gábor Kökény

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number245
JournalBMC Nephrology
Volume20
Issue number1
DOIs
StatePublished - Jul 5 2019
Externally publishedYes

Fingerprint

pioglitazone
Fibrosis
Kidney
Peroxisome Proliferator-Activated Receptors
Transcription Factors
Transgenic Mice
STAT3 Transcription Factor
Messenger RNA
Tissue Inhibitor of Metalloproteinase-1
Collagen Type III
Transcription Factor AP-1
Chronic Renal Insufficiency
Oral Administration
Rodentia
Histology
Proteins
Therapeutics
Phosphorylation
Urine

Keywords

  • Kidney
  • PPARγ
  • Renal fibrosis
  • TGF-β
  • Transcription factors

ASJC Scopus subject areas

  • Nephrology

Cite this

The PPARγagonist pioglitazone prevents TGF-β induced renal fibrosis by repressing EGR-1 and STAT3. / Németh, Ágnes; Mózes, Miklós M.; Calvier, Laurent; Hansmann, Georg; Kökény, Gábor.

In: BMC Nephrology, Vol. 20, No. 1, 245, 05.07.2019.

Research output: Contribution to journalArticle

Németh, Ágnes ; Mózes, Miklós M. ; Calvier, Laurent ; Hansmann, Georg ; Kökény, Gábor. / The PPARγagonist pioglitazone prevents TGF-β induced renal fibrosis by repressing EGR-1 and STAT3. In: BMC Nephrology. 2019 ; Vol. 20, No. 1.
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AU - Németh, Ágnes

AU - Mózes, Miklós M.

AU - Calvier, Laurent

AU - Hansmann, Georg

AU - Kökény, Gábor

PY - 2019/7/5

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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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