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 Chop gene-deleted (Chop-/-) mice and their wild-type littermates (Chop+/+). UUO-induced kidney
fibrosis was reduced in the Chop-/- than Chop+/+ 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 Chop-/- mice. Furthermore, Chop 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 Chop-/- than Chop+/+ 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 Chop-/- mouse kidney cells than in Chop+/+ mice. Thus, the ablation of Chop 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.