Abstract
Renal fibrosis, particularly tubulointerstitial fibrosis is considered to be the final manifestation of almost all chronic kidney diseases (CKDs). Herein we demonstrated evidence that CHOP-related ER stress is associated with the development of renal fibrosis in both CKD patients and unilateral ureteral obstruction (UUO)-induced animals, and specifically, mice deficient in Chop were protected from UUO-induced renal fibrosis. Mechanistic studies revealed that loss of Chop protected tubular cells from UUO-induced apoptosis and secondary necrosis along with attenuated Hmgb1 passive release and active secretion. As a result, Chop deficiency suppressed Hmgb1/TLR4/NFκB signaling, which then repressed UUO-induced IL-1β production. Consequently, the IL-1β downstream Erk1/2 activity and its related c-Jun transcriptional activity were reduced, leading to attenuated production of TGF-β1 following UUO insult. It was further noted that reduced IL-1β production also inhibited UUO-induced PI3K/AKT signaling, and both of which ultimately protected mice from UUO-induced renal fibrosis. Together, our data support that suppression of CHOP expression could be a viable therapeutic strategy to prevent renal fibrosis in patients with CKDs.
Highlights
Endoplasmic reticulum (ER) is crucial for protein biosynthesis, folding, trafficking and modification, and disturbances of ER homeostasis by extracellular stimuli such as oxidative stress would affect protein folding and cause ER stress
Recent studies demonstrated feasible evidence suggesting a role for ER stress in the development of renal fibrosis in the setting of patients with chronic kidney diseases (CKD).[18]
Given the role of CCAAT/enhancer-binding protein homologous protein (CHOP) had in the induction of ER stress, we hypothesized that CHOP may have a critical role in the pathogenesis of renal fibrosis secondary to CKDs
Summary
Endoplasmic reticulum (ER) is crucial for protein biosynthesis, folding, trafficking and modification, and disturbances of ER homeostasis by extracellular stimuli such as oxidative stress would affect protein folding and cause ER stress. Chiang et al.[12] provided feasible evidence suggesting the involvement of ER stress in renal apoptosis and fibrosis, and studies in albumin-overloaded renal tubular cells further revealed that suppression of oxidative stress attenuates EMT and reduces ER stress.[13] Based on these observations, we first conducted studies in CKD patients to demonstrate the presence of ER stress during the course of renal fibrosis, unilateral ureteral obstruction (UUO) was induced in mice deficient in CCAAT/ enhancer-binding protein (C/EBP) homologous protein (Chop) to dissect the cellular and molecular events relevant to ER stress in renal fibrosis. Extracellular Hmgb[1] bound to TLR4, and by which, it activated MyD88-NFκB pathway to enhance IL-1β expression, which in turn promoted TGF-β/Smad2/3 and Pi3k/Akt signaling to exacerbate renal fibrosis
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