The role of TGF-β in diabetes-induced renal fibrosis remains incompletely understood. We showed decreased NFE2 expression in TGFβ-treated renal proximal tubule cells and in diabetic mouse kidneys. TGF-β treatment increased NFE2 mRNA level in HK11 cells suggesting a role for NFE2 degradation. ERK and p38 MAPKs promoted TGFβ-induced NFE2 degradation, CTGF and FN expression. NFE2 over-expression/silencing inhibited exacerbated TGFβ-induced CTGF. Proteasome inhibitor MG132 preserved TGFβ-induced NFE2 expression and inhibited CTGF and FN expression. Current study examined role of JNK MAPK and HDAC inhibition on NFE2 and CTGF expression in TGF-β treated HK-11 cells and effects of MG132 on JNK activation in OVE26 mouse kidneys and in TGFβ-treated HK-11 cells.HK11 cells were pre-treated with/without JNK inhibitor SP600125, HDAC inhibitor trichostatin A, and MG132, for an hour prior to treatment with TGFβ for 24 h.JNK blockade inhibited TGFβ-induced CTGF expression but not NF-E2 expression. MG132 blocked TGFβ-induced JNK activation in HK11 cells and in OVE26 mice. HDAC inhibition exacerbated TGFβ-induced NFE2 degradation and induced CTGF expression. ERK, p38 and JNK pathways contribute to enhanced CTGF expression but only p38 and ERK MAPK pathways contribute to NFE2 degradation. MG132 blocked TGFβ-induced JNK activation, suggesting that proteasome function is necessary for JNK activation and therefore, blocking JNK had no effect on preserving NF-E2 expression. Blocking HDAC activation possibly promoted HAT activity, NFE2 acetylation and enhanced degradation. Thus, proteasome inhibition plus TGFβ preserved NFE2 expression and prevented JNK activation and CTGF. HDAC inhibition plus TGFβ exacerbated NFE2 degradation and enhanced JNK activation and CTGF. We identified NFE2 as a potential anti-fibrotic protein in the kidney.

Disclosure

J. Li: None. M. Rane: None. L. Cai: None. Y. Tan: None.

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