Login Register Cart 0
Generic placeholder image

Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
General Research Article

Thalidomide Mitigates Apoptosis via Endoplasmic Reticulum Stress in Diabetic Nephropathy

Author(s): Hong-Xia Zhang, Jie Yuan and Rong-Shan Li*

Volume 22, Issue 7, 2022

Published on: 29 April, 2022

Page: [787 - 794] Pages: 8

DOI: 10.2174/1871530322666211230115743

Price: $65

Abstract

Background: Previous studies have shown that endoplasmic reticulum (ER) stress is related to the apoptosis in the development of diabetic nephropathy (DN) and thalidomide (Thd) has renalprotective effects by suppressing inflammation and proliferation of MCs in DN. However, the effect of Thd on the apoptosis of MCs in DN remains largely unclear. The present research is designed to explore the effect of Thd on apoptosis in DN and the related mechanisms.

Objective: The study is designed to examine the effect and mechanism of Thd on apoptosis in type 2 diabetic mice and high glucose (HG)-induced MCs.

Methods: We first evaluated the ER stress markers and apoptosis-related proteins with the treatment of Thd in type 2 diabetic mice and MCs in vitro under HG conditions. MTT assay was used to assess cell viability. Additionally, we evaluated the effect of Thd treatment upon MC apoptosis through flow cytometry. Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to evaluate genes and protein expression related to ER stress and apoptosis.

Results: The levels of blood urea BUN, CREA, Urine albumin, and UACR in diabetic mice were observed to be significantly reduced after 8 weeks of intervention with Thd. And also, there were upregulated glucose-regulated protein 78 (GRP78), Caspase-12, and downregulated B-cell lymphoma 2 (Bcl-2) in glomeruli of DN mice. In vitro, compared with the HG group, MC apoptosis reduced dramatically with Thd treatment along with upregulation of Bcl-2 and downregulation of Bax. At the same time, ER stress markers GRP78, C/EBP homologous protein (CHOP), and Caspase-12 were also mitigated following the Thd treatment.

Conclusion: The present study indicates that Thd might reduce the ER stress in DN via downregulating GRP78, CHOP, and Caspase12 expressions, ultimately mitigating MCs apoptosis.

Keywords: Diabetic nephropathy, thalidomide, mesangial cell, apoptosis, endoplasmic reticulum stress, mechanism.

« Previous
Graphical Abstract

[1]
Ivanac-Janković R.; Lovčić V.; Magaš, S.; Šklebar, D.; Kes, P. The novella about diabetic nephropathy. Acta Clin. Croat., 2015, 54(1), 83-91. Available from: med.ncbi.nlm.nih.gov/26058248/
[2]
Wu, J-P.; Zhang, W.; Wu, F.; Zhao, Y.; Cheng, L-F.; Xie, J-J.; Yao, H-P. Honokiol: an effective inhibitor of high-glucose-induced upregulation of inflammatory cytokine production in human renal mesangial cells. Inflamm. Res., 2010, 59(12), 1073-1079.
[http://dx.doi.org/10.1007/s00011-010-0227-z]
[3]
Tsai, Y-C.; Kuo, M-C.; Hung, W-W.; Wu, L-Y.; Wu, P-H.; Chang, W-A.; Kuo, P-L.; Hsu, Y-L. High glucose induces mesangial cell apoptosis through mir-15b-5p and promotes diabetic nephropathy by extracellular vesicle delivery. Mol. Ther., 2020, 28(3), 963-974.
[http://dx.doi.org/10.1016/j.ymthe.2020.01.014]
[4]
Wang, Y.; He, Z.; Yang, Q.; Zhou, G. XBP1 inhibits mesangial cell apoptosis in response to oxidative stress via the PTEN/AKT pathway in diabetic nephropathy. FEBS Open Bio, 2019, 9(7), 1249-1258.
[http://dx.doi.org/10.1002/2211-5463.12655] [PMID: 31077568]
[5]
Huang, S.; Tan, M.; Guo, F.; Dong, L.; Liu, Z.; Yuan, R.; Dongzhi, Z.; Lee, D-S.; Wang, Y.; Li, B. Nepeta angustifolia c. y. wu improves renal injury in hfd/stz-induced diabetic nephropathy and inhibits oxidative stress-induced apoptosis of mesangial cells. J. Ethnopharmacol., 2020, 255, 112771.
[6]
Tian, N.; Gao, Y.; Wang, X.; Wu, X.; Zou, D.; Zhu, Z.; Han, Z.; Wang, T.; Shi, Y. Emodin mitigates podocytes apoptosis induced by endoplasmic reticulum stress through the inhibition of the PERK pathway in diabetic nephropathy. Drug Des. Devel. Ther., 2018, 12, 2195-2211.
[http://dx.doi.org/10.2147/DDDT.S167405] [PMID: 30034224]
[7]
El Karoui, K.; Viau, A.; Dellis, O.; Bagattin, A.; Nguyen, C.; Baron, W.; Burtin, M.; Broueilh, M.; Heidet, L.; Mollet, G.; Druilhe, A.; Antignac, C.; Knebelmann, B.; Friedlander, G.; Bienaimé, F.; Gallazzini, M.; Terzi, F. Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2. Nat. Commun., 2016, 7(1), 10330.
[http://dx.doi.org/10.1038/ncomms10330] [PMID: 26787103]
[8]
Bravo, R.; Parra, V.; Gatica, D.; Rodriguez, A.E.; Torrealba, N.; Paredes, F.; Wang, Z.V.; Zorzano, A.; Hill, J.A.; Jaimovich, E.; Quest, A.F.G.; Lavandero, S. Endoplasmic reticulum and the unfolded protein response. Int. Rev. Cell Mol. Biol., 2013, 301, 215-290.
[http://dx.doi.org/10.1016/B978-0-12-407704-1.00005-1]
[9]
Cybulsky, A.V. Endoplasmic reticulum stress in proteinuric kidney disease. Kidney Int., 2010, 77(3), 187-193.
[http://dx.doi.org/10.1038/ki.2009.389] [PMID: 19812538]
[10]
Hetz, C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell Biol., 2012, 13(2), 89-102.
[http://dx.doi.org/10.1038/nrm3270] [PMID: 22251901]
[11]
Cybulsky, A.V. Endoplasmic reticulum stress, the unfolded protein response and autophagy in kidney diseases. Nat. Rev. Nephrol., 2017, 13(11), 681-696.
[http://dx.doi.org/10.1038/nrneph.2017.129] [PMID: 28970584]
[12]
Hu, W-K.; Liu, R.; Pei, H.; Li, B. Endoplasmic reticulum stress-related factors protect against diabetic retinopathy. Exp. Diabetes Res., 2012, 2012, 507986.
[http://dx.doi.org/10.1155/2012/507986] [PMID: 22203836]
[13]
Liu, G.C.; Fang, F.; Zhou, J.; Koulajian, K.; Yang, S.; Lam, L.; Reich, H.N.; John, R.; Herzenberg, A.M.; Giacca, A.; Oudit, G.Y.; Scholey, J.W. Deletion of p47phox attenuates the progression of diabetic nephropathy and reduces the severity of diabetes in the Akita mouse. Diabetologia, 2012, 55(9), 2522-2532.
[http://dx.doi.org/10.1007/s00125-012-2586-1] [PMID: 22653270]
[14]
Shah, M.S.; Brownlee, M. Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ. Res., 2016, 118(11), 1808-1829.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.306923] [PMID: 27230643]
[15]
Raje, N.; Anderson, K. Thalidomide-a revival story. N. Engl. J. Med., 1999, 341(21), 1606-1609.
[http://dx.doi.org/10.1056/NEJM199911183412110] [PMID: 10564693]
[16]
Zhang, H.; Yuan, J.; Li, Y.; Li, R. Thalidomide decrea- ses high glucose induced extracellular matrix protein synthesis in mesangial cells via the ampk pathway. Exp. Ther. Med., 2018, 17(1), 927-934.
[http://dx.doi.org/10.3892/etm.2018.6995]
[17]
Zhao, J.; Wang, H.; Song, T.; Yang, Y.; Gu, K.; Ma, P.; Zhang, Z.; Shen, L.; Liu, J.; Wang, W. Thalidomide promotes morphine efficacy and prevents morphine-induced tolerance in rats with diabetic neuropathy. Neurochem. Res., 2016, 41(12), 3171-3180.
[http://dx.doi.org/10.1007/s11064-016-2041-7] [PMID: 27573481]
[18]
Behl, T.; Kaur, I.; Goel, H.; Kotwani, A. Significance of the antiangiogenic mechanisms of thalidomide in the therapy of diabetic retinopathy. Vascul. Pharmacol., 2017, 92, 6-15.
[http://dx.doi.org/10.1016/j.vph.2015.07.003] [PMID: 26196302]
[19]
Kim, D-H.; Kim, Y-J.; Chang, S-A.; Lee, H-W.; Kim, H-N.; Kim, H-K.; Chang, H-J.; Sohn, D-W.; Park, Y-B. The protective effect of thalidomide on left ventricular function in a rat model of diabetic cardiomyopathy. Eur. J. Heart Fail., 2010, 12(10), 1051-1060.
[http://dx.doi.org/10.1093/eurjhf/hfq103]
[20]
Bosco, A.A.; Lerario, A.C.; Santos, R.F.; Wajchenberg, B.L. Effect of thalidomide and rosiglitazone on the prevention of diabetic retinopathy in streptozotocin-induced diabetic rats. Diabetologia, 2003, 46(12), 1669-1675.
[http://dx.doi.org/10.1007/s00125-003-1234-1] [PMID: 14598030]
[21]
Zhang, H.; Yang, Y.; Wang, Y.; Wang, B.; Li, R. Renal-protective effect of thalidomide in streptozotocin-induced diabetic rats through anti-inflammatory pathway. Drug Des. Devel. Ther., 2018, 12, 89-98.
[http://dx.doi.org/10.2147/DDDT.S149298] [PMID: 29386886]
[22]
Japanese Society of Nephrology. Japan association of renal pathology kidney biopsy-atlas and text, 2nd ed; Tokyo Medical Club, 2011, pp. 85-149.
[23]
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method. Methods, 2001, 25(4), 402-408.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[24]
Mishra, R.; Emancipator, S.N.; Kern, T.; Simonson, M.S. High glucose evokes an intrinsic proapoptotic signaling pathway in mesangial cells. Kidney Int., 2005, 67(1), 82-93.
[http://dx.doi.org/10.1111/j.1523-1755.2005.00058.x] [PMID: 15610231]
[25]
Busch, A.K.; Cordery, D.; Denyer, G.S.; Biden, T.J. Expression profiling of palmitate- and oleate-regulated genes provides novel insights into the effects of chronic lipid exposure on pancreatic beta-cell function. Diabetes, 2002, 51(4), 977-987.
[http://dx.doi.org/10.2337/diabetes.51.4.977] [PMID: 11916915]
[26]
Yao, F.; Li, Z.; Ehara, T.; Yang, L.; Wang, D.; Feng, L.; Zhang, Y.; Wang, K.; Shi, Y.; Duan, H.; Zhang, L. Fatty acid-binding protein 4 mediates apoptosis via endoplasmic reticulum stress in mesangial cells of diabetic nephropathy. Mol. Cell. Endocrinol., 2015, 411, 232-242.
[http://dx.doi.org/10.1016/j.mce.2015.05.003] [PMID: 25958041]
[27]
Kim, H.; Moon, S.Y.; Kim, J-S.; Baek, C.H.; Kim, M.; Min, J.Y.; Lee, S.K. Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis. Am. J. Physiol. Renal Physiol., 2015, 308(3), F226-F236.
[http://dx.doi.org/10.1152/ajprenal.00495.2014] [PMID: 25428127]
[28]
Cunard, R.; Sharma, K. The endoplasmic reticulum stress response and diabetic kidney disease. Am. J. Physiol. Renal Physiol., 2011, 300(5), F1054-F1061.
[http://dx.doi.org/10.1152/ajprenal.00021.2011] [PMID: 21345978]
[29]
Oyadomari, S.; Mori, M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ., 2003, 11(4), 381-389.
[30]
Guo, J.; Zhu, J.; Ma, L.; Shi, H.; Hu, J.; Zhang, S.; Hou, L.; Xu, F.; An, Y.; Yu, H.; Ge, J. Chronic kidney disease exacerbates myocardial ischemia reperfusion injury: role of endoplasmic reticulum stress-mediated apoptosis. Shock, 2018, 49(6), 712-720.
[http://dx.doi.org/10.1097/SHK.0000000000000970] [PMID: 28846567]

Rights & Permissions Print Cite
Article Metrics
21
1
© 2024 Bentham Science Publishers | Privacy Policy