The PPARγ agonist pioglitazone prevents TGF-β induced renal fibrosis by repressing EGR-1 and STAT3.

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 PPARγ agonist pioglitazone significantly reduces TGF-β1-driven renal fibrosis, via the attenuation of EGR-1, STAT3 and AP-1. This implies that PPARγ agonists might be effective in the treatment of chronic kidney disease patients.

• Authors: Ágnes Németh, Miklós M Mózes, Laurent Calvier, Georg Hansmann, Gábor Kökény
• Journal: BMC nephrology (BMC Nephrol) Vol. 20 Issue 1 Pg. 245 (07 05 2019) ISSN: 1471-2369 [Electronic] England
• PMID: 31277592 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Early Growth Response Protein 1
• Egr1 protein, mouse
• PPAR gamma
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Transforming Growth Factor beta
• Pioglitazone

Topics

• Animals
• Early Growth Response Protein 1 (antagonists & inhibitors, metabolism)
• Fibrosis
• Kidney Diseases (chemically induced, metabolism, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• PPAR gamma (agonists)
• Pioglitazone (pharmacology, therapeutic use)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Transforming Growth Factor beta (antagonists & inhibitors, toxicity)