Abstract
BackgroundIt 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.MethodsMale 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.ResultsTGF-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.ConclusionsOral 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.
Highlights
It has been proposed that peroxisome proliferator-activated receptor-γ (PPARγ) agonists might reduce renal fibrosis, several studies had contradictory results
In Transforming growth factor-β1 (TGF-β1) transgenic mice, the transgene construct consists of the full-length porcine TGF-β1 cDNA driven by the albumin promoter and enhancer, and the transgene was incorporated into the Y chromosome only male mice are transgenic
The plasma TGF-β1 levels of transgenic mice was significantly elevated as compared to control mice (Additional file 1: Figure S1). Both control and TGF-β1 transgenic mice had similar body weight regardless of the treatment (Fig. 1b), and the mean arterial blood pressure was similar in all groups (Fig. 1a)
Summary
It has been proposed that peroxisome proliferator-activated receptor-γ (PPARγ) agonists might reduce renal fibrosis, several studies had contradictory results. 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. In fibrosis that occurs in multiple organs, this MMP/TIMP balance is disrupted. Among the several profibrotic transcription factors, early growth response factor-1 (EGR-1) contributes to fibrosis by directly stimulating collagen synthesis [6] and myofibroblast differentiation [7]. STAT3 influences cell proliferation [11,12,13] and fibrosis [14] by inducing the expression of multiple genes, including
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