The attenuation of renal fibrosis by histone deacetylase inhibitors is associated with the plasticity of FOXP3⁺IL-17⁺ T cells

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.

This 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.

Juxtaglomerular (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.

TSA 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.