Targeted inhibition of endoplasmic reticulum stress: New hope for renal fibrosis (Review)

Abstract

Chronic kidney disease (CKD) has a very high mortality rate and remains a global health challenge. Inhibiting renal fibrosis is one of the most promising therapeutic strategies for CKD. Recent studies have indicated that endoplasmic reticulum stress (ERS) serves an active role in the development of acute and chronic kidney disease, especially with regards to renal fibrosis. In the current review, the authors summarize the latest understanding of the role of ERS during the onset of renal fibrosis. ERS promotes renal fibrosis through multiple signaling pathways, such as transforming growth factor‑β, epithelial‑mesenchymal transition and oxidative stress. In addition, ERS also causes podocyte damage, leading to increased proteinuria and the development of renal fibrosis in rat models. In conclusion, targeted inhibition of ERS may become a promising therapeutic strategy for renal fibrosis.

Figure 1.

TGF-β signaling induced apoptosis is modulated by the UPR cascade. Under severe or prolonged endoplasmic reticulum stress caused by TGF-β signaling, UPR stimulates apoptosis through the following 3 proteins: PERK, IRE1 and ATF4. These proteins increase the expression of transcription factors CHOP, XBP1 and ATF4, which promote apoptosis and upregulate TGF-β1 expression, thus augmenting TGF-β signaling. Additionally, UPR propagates apoptosis via the JNK signaling pathway, which can also be induced by TGF-β. TGF-β, transforming growth factor-β; UPR, unfolded protein response; PERK, protein kinase RNA-like endoplasmic reticulum kinase; IRE1, inositol-requiring enzyme 1; ATF, activating transcription factor; CHOP, CCAAT-enhancer-binding protein homologous protein; XBP1, X-box-binding protein-1; JNK, c-Jun N-terminal kinase; α-SMA, α-smooth muscle actin.

Figure 2.

The possible mechanism by which ERS induces EMT. UPR impacts EMT both directly and indirectly. In the former case, GRP78 can increase the expression of α-SMA and decrease the expression of E-cadherin, both biomarkers of EMT. In the latter case, ERS stimulates the expression of α-SMA through autophagy induced by C-Src. ERS, endoplasmic reticulum stress; EMT, epithelial-mesenchymal transition; UPR, unfolded protein response; GRP78, glucose-regulated protein 78; α-SMA, α-smooth muscle actin.

Figure 3.

The possible mechanism by which ERS results in podocyte damage. Proteinuria causes ERS via Ca²⁺, resulting in increased expression of ATF4 and CHOP, which interact to induce LCN2 expression and cause podocyte apoptosis. Additionally, increasing Ca²⁺ levels can promote podocyte UPR by inhibiting CD2AP, which serves a critical role in podocyte biology. ERS, endoplasmic reticulum stress; ATF, activating transcription factor; CHOP, CCAAT-enhancer-binding protein homologous protein; LCN2, lipocalin 2; UPR, unfolded protein response; CD2AP, CD2-associated protein; TRPC6, transient receptor potential C6; PERK, protein kinase RNA-like endoplasmic reticulum kinase.