Abstract
Renal tubulointerstitial fibrosis is an important pathogenic feature in chronic kidney disease and end-stage renal disease, regardless of the initiating insults. A recent study has shown that CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) is involved in acute ischemia/reperfusion-related acute kidney injury through oxidative stress induction. However, the influence of CHOP on chronic kidney disease-correlated renal fibrosis remains unclear. Here, we investigated the role of CHOP in unilateral ureteral obstruction (UUO)-induced experimental chronic tubulointerstital fibrosis. The CHOP knockout and wild type mice with or without UUO were used. The results showed that the increased expressions of renal fibrosis markers collagen I, fibronectin, α-smooth muscle actin, and plasminogen activator inhibitor-1 in the kidneys of UUO-treated wild type mice were dramatically attenuated in the kidneys of UUO-treated CHOP knockout mice. CHOP deficiency could also ameliorate lipid peroxidation and endogenous antioxidant enzymes depletion, tubular apoptosis, and inflammatory cells infiltration in the UUO kidneys. These results suggest that CHOP deficiency not only attenuates apoptotic death and oxidative stress in experimental renal fibrosis, but also reduces local inflammation, leading to diminish UUO-induced renal fibrosis. Our findings support that CHOP may be an important signaling molecule in the progression of chronic kidney disease.
Highlights
Renal tubulointerstitial fibrosis is an important hallmark during the progression from chronic kidney disease (CKD) to the end-stage renal disease (ESRD)
The results showed that the increased expressions of renal fibrosis markers collagen I, fibronectin, α-smooth muscle actin, and plasminogen activator inhibitor-1 in the kidneys of ureteral obstruction (UUO)-treated wild type mice were dramatically attenuated in the kidneys of UUO-treated CHOP knockout mice
Kidneys were significantly reversed in the CHOP KO mice (Figure 3). These results suggest that CHOP deficiency effectively restores the UUO-induced renal fibrosis
Summary
Renal tubulointerstitial fibrosis is an important hallmark during the progression from chronic kidney disease (CKD) to the end-stage renal disease (ESRD). Renal tubulointerstitial fibrosis reflects the imbalance of different mechanisms including renal cells apoptosis, inflammatory cells infiltration, and oxidative stress generation. Studies aiming to elucidate the potential mechanisms of renal fibrosis are urgently needed to facilitate the discovery of therapies capable of reversing renal fibrosis and improving CKD and ESRD. Endoplasmic reticulum (ER) stress has been shown to be triggered by cellular insults including starvation, genetic mutation, disturbance of protein turnover, and inflammation, and may be www.impactjournals.com/oncotarget associated with diseases such as diabetes, cardiomyopathy, and neuron degeneration disease [4,5,6,7,8]. Several studies identified that ER stress might take part in the process of cholestasis-induced liver fibrosis, cystic fibrosis, pulmonary fibrosis, and renal fibrosis [4, 9,10,11]
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