Ablation of C/EBP homologous protein attenuates renal fibrosis after ureteral obstruction by reducing autophagy and microtubule disruption

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>Fibrosis is an undesirable consequence of injury and a critical problem in many diseases. Recent studies have demonstrated an association of C/EBP homologous protein (CHOP) with fibrosis. We investigated the mechanism of CHOP in kidney fibrosis progression after unilateral ureteral obstruction (UUO) using <I>Chop</I> gene-deleted (<I>Chop</I> <SUP>−/−</SUP>) mice and their wild-type littermates (<I>Chop</I> <SUP>+/+</SUP>). UUO-induced kidney fibrosis was reduced in the <I>Chop</I> <SUP>−/−</SUP> than <I>Chop</I> <SUP>+/+</SUP> mice. After UUO, CHOP expression was detected in the cytosol and nucleus of distal tubule cells and collecting duct cells of the kidney. UUO formed the autophagosome and increased the expression of autophagy proteins, Beclin-1, LC3-I and II, and p62 in the kidneys. These UUO-induced changes were significantly reduced in <I>Chop</I> <SUP>−/−</SUP> mice. Furthermore, <I>Chop</I> gene deletion attenuated mitochondrial fragmentation with lower expression of Fis-1, a mitochondrial fission protein, but higher expression of Opa-1, a mitochondrial fusion protein, than that seen in the wild-type mice. UUO disrupted the microtubule, which is involved in autophagosome formation, and this disruption was milder in the <I>Chop</I> <SUP>−/−</SUP> than <I>Chop</I> <SUP>+/+</SUP> mouse kidney, with less reduction of histone deacetylase 6 and α‑tubulin acetyl transferase, which acetylates tubulin, a component of the microtubule. After UUO, apoptosis, a consequence of autophagy and mitochondrial damage, was reduced in the <I>Chop</I> <SUP>−/−</SUP> mouse kidney cells than in <I>Chop</I> <SUP>+/+</SUP> mice. Thus, the ablation of <I>Chop</I> attenuates renal fibrosis, accompanied by reduced autophagy, mitochondrial fragmentation, microtubule disruption, and apoptosis. Overall, these results suggest that CHOP plays a critical role in the progression of kidney fibrosis, likely through regulation of autophagy and apoptosis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Unilateral ureteral obstruction (UUO) induces kidney fibrosis with CHOP expression. </LI> <LI> <I>Chop</I> gene deletion attenuates UUO-induced autophagy, apoptosis, and fibrosis. </LI> <LI> <I>Chop</I> gene deletion mitigates UUO-induced disruption of the microtubule. </LI> <LI> CHOP plays a critical role on fibrosis likely through autophagy regulation. </LI> </UL> </P>