Abstract
BackgroundThe histone deacetylase (HDAC) inhibitor, which has potential effects on epigenetic modifications, had been reported to attenuate renal fibrosis. CD4+ forkhead box P3 (FOXP3)+ T regulatory (Treg) cells may be converted to inflammation-associated T helper 17 cells (Th17) with tissue fibrosis properties. The association between FOXP3+IL-17+ T cells and the attenuation of renal fibrosis by the HDAC inhibitor is not clear.MethodsThis study evaluated the roles of the HDAC inhibitor, Treg cells and their differentiation into Th17 cells, which aggravate chronic inflammation and renal fibrosis in a unilateral ureteral obstruction (UUO) mouse model. The study groups included control and UUO mice that were monitored for 7, 14 or 21 days.ResultsJuxtaglomerular (JG) hyperplasia, angiotensin II type 1 receptor (AT1R) expression and lymphocyte infiltration were observed in renal tissues after UUO but were decreased after trichostatin A (TSA) treatment, a HDAC inhibitor. The number of CD4+FOXP3+ T cells increased progressively, along with the number of FOXP3+interleukin (IL)-17+ T cells, after 14 days, and their numbers then progressively decreased with increasing CD4+IL-17+ T cell numbers, as demonstrated by double immunohistochemistry. Progressive renal fibrosis was associated with the loss of CD4+FOXP3+IL-17+ T cells in splenic single-cell suspensions. FOXP3+IL-17+ T cells expressed TGF-β1 both in vitro and in vivo, and TGF-β1 expression was significantly knockdown by IL-17 siRNA in vitro. These cells were found to play a role in converting Tregs into IL-17- and TGF-β1-producing cells.ConclusionsTSA treatment decreased JG hyperplasia, the percentage of FOXP3+IL-17+ cells and the degree of fibrosis, suggesting that therapeutic benefits may result from epigenetic modifications.
Highlights
The histone deacetylase (HDAC) inhibitor, which has potential effects on epigenetic modifications, had been reported to attenuate renal fibrosis
The numbers of CD4+forkhead box P3 (FOXP3)+, CD4+IL-17+ and FOXP3+IL17+ T cells are increased in renal tissue after ureteral obstruction (UUO) A previous study has reported a pivotal role of CD4+ T cells in renal fibrosis; in addition, we observed lymphocyte infiltration in kidney tissues after UUO
The TGF-β1 and IL-17 mRNA levels increased with duration of UUO We examined the expression of TGF-β1 and IL-17 mRNA in obstructed kidneys induced by UUO
Summary
The histone deacetylase (HDAC) inhibitor, which has potential effects on epigenetic modifications, had been reported to attenuate renal fibrosis. CD4+ forkhead box P3 (FOXP3)+ T regulatory (Treg) cells may be converted to inflammation-associated T helper 17 cells (Th17) with tissue fibrosis properties. The association between FOXP3+IL-17+ T cells and the attenuation of renal fibrosis by the HDAC inhibitor is not clear. The unilateral ureteral obstruction (UUO) model presents renal fibrosis unrelated to hypertension or systemic immune disease [3, 4]. Kidney obstruction after UUO results in tubular injury and cell death by apoptosis or necrosis [5,6,7]. One prior study has revealed the pivotal role of CD4+ T cells in renal fibrosis following ureteric obstruction [8]. One UUO study has identified intra-renal dendritic cells as an early source of proinflammatory mediators after acute urinary obstruction and has found that they play
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