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Emodin mitigates podocytes apoptosis induced by endoplasmic reticulum stress through the inhibition of the PERK pathway in diabetic nephropathy

Authors Tian N, Gao Y, Wang X, Wu X, Zou D, Zhu Z, Han ZJ, Wang T, Shi Y

Received 6 March 2018

Accepted for publication 13 May 2018

Published 13 July 2018 Volume 2018:12 Pages 2195—2211

DOI https://doi.org/10.2147/DDDT.S167405

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Jianbo Sun


Nianxiu Tian,1 Yanbin Gao,1 Xiaolei Wang,1 Xiaoming Wu,2 Dawei Zou,3 Zhiyao Zhu,3 ZheJi Han,1 Tao Wang,1 Yimin Shi1

1Department of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, Fengtai District, Beijing, China; 2Department of Paediatrics, Beijing Children’s Hospital, Capital Medical University, Xicheng District, Beijing, China; 3Department of Endocrinology, Beijing Key Lab of TCM Collateral Disease theory Research, Fengtai District, Beijing, China

Background: Endoplasmic reticulum stress is associated with podocyte apoptosis in the pathogenesis of diabetic nephropathy (DN). A previous study has demonstrated that emodin has a protective effect in the kidney by suppressing proliferation of mesangial cells and inhibiting the renal tubular epithelial-to-mesenchymal transition. However, the effects of emodin on the podocyte apoptosis in DN and its mechanisms are unknown.
Aim: This study aimed to explore the effect of emodin on DN model KK-Ay mice and high glucose induced podocytes apoptosis via the PERK–eIF2α pathway.
Methods: KK-Ay mice model of DN were treated with emodin at dose of 40 and 80 mg/kg/day for 8 weeks. Urine albumin, serum creatinine, blood urea nitrogen levels and the renal histopathology in mice were performed. In vitro, conditionally immortalized mouse podocytes exposed to HG (30mM) were incubated with emodin. Cell viability was measured by CCK-8 assay. Additionally, we performed RNA interference and measured the apoptosis in cultured podocytes treated with emodin. Immunohistochemistry, immunofluorescence, western blot, and real-time PCR were used to detect gene and protein expression both in vivo and in vitro.
Results: The results showed that emodin treatment ameliorated urine albumin, serum creatinine, and blood urea nitrogen of DN mice. The pathological damage of kidney tissue was also improved after treatment with emodin. Moreover, emodin increased nephrin expression. Podocytes apoptosis and endoplasmic reticulum stress markers (GRP78) were significantly reduced upon emodin treatment. Furthermore, emodin treatment decreased the expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (P-PERK), phosphorylated P-eIF2α, ATF4, and CHOP. In vitro, emodin treatment was further found to decrease the GRP78 level induced by high glucose or tunicamycin (TM). Besides, emodin and PERK knockdown inhibited the apoptosis of podocytes cultured in high glucose by counteracting the upregulation of phosphorylated PERK, phosphorylated eIF2α, ATF4, and CHOP.
Conclusion: Overall, the findings indicate that emodin mitigates podocytes apoptosis by inhibiting the PERK-eIF2α signaling pathway in vivo and in vitro, and, therefore, exerts a protective action on podocytes in DN.

Keywords: emodin, diabetic nephropathy, endoplasmic reticulum stress, podocyte apoptosis, PERK-eIF2α

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