Collectively, our data suggest that loss of Chop protects mice against UUO-induced renal fibrosis by preventing tubular apoptosis and secondary necrosis, and by which Chop deficiency represses Hmgb1 passive release and active secretion, which then inhibits Hmgb1/TLR4/NFκB signaling along with attenuated production of IL-1β; whereas reduced IL-1β production following UUO insult would not only limit the secretion of TGF-β but also the activation of PI3K/AKT signaling, which then attenuates the initiation and progression of renal fibrosis. Here, TLR4 is linked to renal fibrosis.