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c‑Jun N‑terminal kinase/transforming growth factor‑β/Smad3 pathway: Is it associated with endoplasmic reticulum stress‑mediated renal interstitial fibrosis?

Molecular medicine reports (2019-06-11)
Yuyuan Liu, Ping Shen, Yongmei Zhou, Li Tang, Huaqi Chai
ABSTRACT

The present study investigated the role of the c‑Jun N‑terminal kinase (JNK)/transforming growth factor‑β (TGF‑β)/Smad3 pathway in endoplasmic reticulum stress (ERS)‑mediated renal interstitial fibrosis, which would be beneficial for chronic kidney disease (CKD) therapy. In human renal biopsy tissue, the expression levels of glucose‑regulated protein 78 (GRP78) and phosphorylated (p)‑JNK were examined by immunohistochemical analysis. In renal tubular HK‑2 cells, tunicamycin (TM) was used to induce ERS, and the cells were then treated with the chemical ERS inhibitor 4‑phenylbutyrate (4‑PBA) or the chemical JNK pathway inhibitor SP600125, respectively. Western blotting was then performed in the cells to determine the expression levels of GRP78 and p‑JNK proteins, as well as TGF‑β/Smad3 pathway‑associated proteins, including TGF‑β1, p‑Smad3, connective tissue growth factor and α‑smooth muscle actin. The results revealed that GRP78 and p‑JNK were evidently expressed in the renal tissues of patients with CKD, and these expression levels were significantly higher in renal tissues with severe interstitial fibrosis compared with glomerular minor lesion tissues (P<0.01 and P<0.05, respectively). Furthermore, ERS and JNK pathway inhibition decreased the expression levels of TGF‑β/Smad3 pathway signals in cells incubated with TM. ERS pathway inhibition also attenuated the expression levels of p‑JNK in HK‑2 cells. In conclusion, ERS was observed to serve an important role in the pathogenesis of CKD and may induce renal interstitial fibrosis via the JNK/TGF‑β/Smad3 pathway.

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Sodium phenylbutyrate, ≥98% (HPLC)