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Emodin Mitigates Podocytes Apoptosis Induced by Endoplasmic Reticulum Stress Through the Inhibition of the PERK Pathway in Diabetic Nephropathy

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Emodin Mitigates Podocytes Apoptosis Induced by Endoplasmic Reticulum Stress Through the Inhibition of the PERK Pathway in Diabetic Nephropathy Journal name: Drug Design, Development and Therapy Article Designation: Original Research Year: 2018 Volume: 12 Drug Design, Development and Therapy Dovepress Running head verso: Tian et al Running head recto: Emodin protects podocytes against apoptosis induced by ER stress open access to scientific and medical research DOI: 167405 Open Access Full Text Article ORIGINAL RESEARCH Emodin mitigates podocytes apoptosis induced by endoplasmic reticulum stress through the inhibition of the PERK pathway in diabetic nephropathy Nianxiu Tian1 Background: Endoplasmic reticulum stress is associated with podocyte apoptosis in the Yanbin Gao1 pathogenesis of diabetic nephropathy (DN). A previous study has demonstrated that emodin has Xiaolei Wang1 a protective effect in the kidney by suppressing proliferation of mesangial cells and inhibiting Xiaoming Wu2 the renal tubular epithelial-to-mesenchymal transition. However, the effects of emodin on the Dawei Zou3 podocyte apoptosis in DN and its mechanisms are unknown. Zhiyao Zhu3 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. ZheJi Han1 Methods: KK-Ay mice model of DN were treated with emodin at dose of 40 and 80 mg/kg/day Tao Wang1 for 8 weeks. Urine albumin, serum creatinine, blood urea nitrogen levels and the renal histopa- 1 Yimin Shi thology in mice were performed. In vitro, conditionally immortalized mouse podocytes exposed 1Department of Endocrinology, School to HG (30mM) were incubated with emodin. Cell viability was measured by CCK-8 assay. of Traditional Chinese Medicine, Additionally, we performed RNA interference and measured the apoptosis in cultured podocytes Capital Medical University, Fengtai District, Beijing, China; 2Department treated with emodin. Immunohistochemistry, immunofluorescence, western blot, and real-time of Paediatrics, Beijing Children’s PCR were used to detect gene and protein expression both in vivo and in vitro. Hospital, Capital Medical University, Xicheng District, Beijing, China; Results: The results showed that emodin treatment ameliorated urine albumin, serum creatinine, 3Department of Endocrinology, Beijing and blood urea nitrogen of DN mice. The pathological damage of kidney tissue was also improved Key Lab of TCM Collateral Disease after treatment with emodin. Moreover, emodin increased nephrin expression. Podocytes theory Research, Fengtai District, Beijing, China 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 inhib- ited 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 Correspondence: Yanbin Gao Department of Endocrinology, School Introduction of Traditional Chinese Medicine, Capital Diabetic nephropathy (DN) is a progressive microvascular complication occurring Medical University, 10 Youanmenwai, Xitoutiao, Fengtai District, Beijing among people with diabetes mellitus and has become a prime cause of end-stage renal 100069, China disease (ESRD) in the USA.1 This disease is initially characterized by the appearance Tel/fax +86 10 8391 1720 Email [email protected] of moderately increased albuminuria, followed by overt proteinuria and a gradual submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2018:12 2195–2211 2195 Dovepress © 2018 Tian et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/DDDT.S167405 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Tian et al Dovepress decline in glomerular filtration rate.2,3 Accumulating evidence kinase (PERK)/eukaryotic initiation factor 2α (eIf2α) has demonstrated that podocytes apoptosis is an important signaling pathway, which is activated during the UPR.28 factor in the pathogenesis of proteinuria in DN,4–6 and inhibi- tion of podocytes apoptosis is a potential therapeutic target Methods in DN.7 However, the mechanisms of podocytes apoptosis Chemicals in DN have not been fully clarified yet. Emodin (Figure 1, C15H10O5, molecular weight=270.23, purity The endoplasmic reticulum (ER) is a central organelle by high-performance liquid chromatography [HPLC]$98%) in which proteins are synthesized, folded, and modified, was purchased from Pufei De Biotech. Co. Ltd (Chengdu, and where calcium, a crucial factor for cellular homeo- China). stasis, is stored.8–10 Within the ER, an imbalance between protein folding and transfer of properly folded proteins to Animals and treatment other organelles can cause the accumulation of unfolded or Male C57BL/6J and KK-Ay mice (8 weeks old) were pur- misfolded proteins, triggering the activation of the unfolded chased from Beijing Huafukang Bioscience Co. Inc (Beijing, 11,12 protein response (UPR) and ER stress. Sustained or aber- China). All experiments were performed in accordance with rant ER stress is cytotoxic, and might lead to cell injury or the National Institutes of Health guideline (NIH Pub. No. 13–15 death. A growing body of evidence demonstrates that 85-23, revised 1996). The study protocol was approved by ER stress has a main function in the progression of diabetes the Institutional Animal Care and Use Committee of the 16–19 complications, including DN. Some studies also indi- Capital Medical University (Permission number: AEEI- cate that the reduction of ER stress with 4-phenylbutyric 2016-124). All animals were housed at a constant tempera- acid (PBA) or tauroursodeoxycholic acid (TUDCA) can ture (24°C±1°C) and humidity (50%–60%), with a regular protect the kidneys from functional degradation by inhibit- 12-h light and 12-h dark cycle in a specific-pathogen-free 10 ing the overexpression of lipocalin-2 (LCN2) in DN. In (SPF) room. C57BL/6J mice were fed with common for- addition, metformin treatment can ameliorate ER stress age, and KK-Ay mice were fed with research forage for 4 and renal fibrosis induced by high glucose in the renal weeks, as previously described.29 Random blood glucose tubular epithelial cell line HK-2, through the activation (RBG) levels were measured in blood obtained from the of the adenosine monophosphate-activated protein kinase caudal vein of each animal with a portable glucometer (One 20 (AMPK) pathway. Touch® Ultra, LifeScan, Johnson & Johnson, CA, USA). The anthraquinone emodin (1,3,8-trihydroxy-6-methy- KK-Ay mice with RBG higher than 16.7 mM and a urine lanthraquinone) is an orange crystalline phenolic compound albumin creatinine ratio (ACR) over 300 μg/mg showed kid- extracted from the roots and rhizome of several plants, such as ney damage closely resembling human DN30 and represented the traditional Chinese herbs Rheum palmatum, Polygonum a DN model, according to a previous study.29 21,22 cuspidatum, and Cascara buckthorn. Emodin has been C57BL/6J mice were considered as the normal (control) widely used to reduce inflammation, to inhibit cell prolif- group (n=8). KK-Ay mice were randomly divided into three eration and ER stress, and to prevent obesity.23–26 This study groups: DN mice (model group, n=8), DN mice treated investigates the therapeutic use of emodin in DN. Previous with low-dose emodin (n=8, 40 mg/kg/day), and DN mice studies have indicated that emodin can protect the cells from treated with high-dose emodin (n=8, 80 mg/kg/day). This oxidative stress in HK-2 cells by regulating the mitogen- dose of emodin has been proved to be effective and safe.25,31 activated protein kinases (MAPK) signaling pathway.27 Additionally, in podocytes, emodin ameliorates the tubular epithelial-to-mesenchymal transition (EMT) induced by OH O OH high glucose, through the inhibition of integrin-linked kinase (ILK) and desmin in streptozotocin (STZ)-induced diabetic rats.21 However, the effect of emodin on ER stress-triggered podocytes apoptosis remains unclear. This study investi- gates whether emodin suppresses the ER stress-induced OH podocytes apoptosis in DN and highlights the possible thera- H3C peutic use of emodin in DN. Additionally, we explored the mechanism of the effect of emodin and tested if emodin can O inhibit the protein kinase RNA-like endoplasmic reticulum Figure 1 Chemical structure of emodin. 2196 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2018:12 Dovepress Dovepress Emodin protects podocytes against apoptosis induced
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