Abstract
Pathophysiological states cause misfolded protein accumulation in the endoplasmic reticulum (ER). Then, ER stress and the unfolded protein response (UPR) are activated. Targeting ER stress may enhance the adaptive UPR and then protect the cell against pathogenic environments. In the present study, we utilized nanotechnology to synthesize thapsigargin nanoparticles (TG NPs) which induced ER stress and the UPR pathway, to study the role of ER stress and autophagy in chronic kidney disease (CKD). We found that the mRNA levels of ER stress- and autophagy-related molecules were elevated in the renal tissue of CKD patients compared to those of healthy individuals. Furthermore, TG NPs induced the UPR pathway and autophagy in HK-2 human kidney tubular epithelial cells. TG NPs protected HK-2 cells against oxidative stress-induced cell death through the activation of Nrf2 and FoxO1. The siRNA-mediated inhibition of Nrf2 or FoxO1 resulted in enhanced oxidative stress-induced cytotoxicity in HK-2 cells. In a mouse model of adenine diet-induced CKD, TG NPs and KIM-1-TG NPs ameliorated renal injury through the stimulation of ER stress and its downstream pathways. Our findings suggest that the induction of ER stress using pharmacological agents may offer a promising therapeutic strategy for preventing or interfering with CKD progression.
Highlights
The global prevalence of chronic kidney disease (CKD) is rising in older people and treatment for CKD is important to affect the health of aging population [1]
The results indicated that the expression of BECN1 and ATG5 was elevated in the renal tissue of the CKD patients in the discovery set (Figure 1B)
These results showed that the regulation of endoplasmic reticulum (ER) stress and autophagy may participate in CKD progression
Summary
The global prevalence of chronic kidney disease (CKD) is rising in older people and treatment for CKD is important to affect the health of aging population [1]. Previous studies have demonstrated that the endoplasmic reticulum (ER) functions in the regulation of protein homeostasis in the kidneys [4]. ER stress and the unfolded protein response (UPR) are activated [6, 7]. The UPR has three major signaling pathways including the PRKR-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α) and activating transcription factor 6 (ATF6) pathways [4]. Previous studies have indicated that activation of the UPR maintains ER function and may be protective against additional stresses [6, 8]. Recent studies have reported that the PERK pathway of the UPR induces the transcription factor, nuclear factor erythroid-derived-2related factor-2 (Nrf2) and regulates redox homeostasis to ensure cell survival [12]. Targeting ER stress may enhance the adaptive UPR and protect the cell more effectively against pathogenic conditions
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