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

摘要

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. 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. 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. 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.