Berberine alleviates palmitic acid‑induced podocyte apoptosis by reducing reactive oxygen species‑mediated endoplasmic reticulum stress

Xiang,Xing-Yang; Liu,Ting; Wu,Yue; Jiang,Xu-Shun; He,Jun-Ling; Chen,Xue-Mei; Du,Xiao-Gang

doi:10.3892/mmr.2020.11641

Berberine alleviates palmitic acid‑induced podocyte apoptosis by reducing reactive oxygen species‑mediated endoplasmic reticulum stress

Authors:
- Xing-Yang Xiang
- Ting Liu
- Yue Wu
- Xu-Shun Jiang
- Jun-Ling He
- Xue-Mei Chen
- Xiao-Gang Du
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Affiliations: Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, P.R. China, Department of Nephrology, Chengdu Fifth People's Hospital, Chengdu, Sichuan 611130, P.R. China, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, P.R. China, Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands, Emergency Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, P.R. China
Published online on: November 2, 2020 https://doi.org/10.3892/mmr.2020.11641
Article Number: 3
Copyright: © Xiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lipid accumulation in podocytes can lead to the destruction of cellular morphology, in addition to cell dysfunction and apoptosis, which is a key factor in the progression of chronic kidney disease (CKD). Berberine (BBR) is an isoquinoline alkaloid extracted from medicinal plants such as Coptis chinensis, which has been reported to have a lipid‑lowering effect and prevent CKD progression. Therefore, the present study aimed to investigate the effect of BBR on palmitic acid (PA)‑induced podocyte apoptosis and its specific mechanism using an in vitro model. Cell death was measured using the Cell Counting Kit‑8 colorimetric assay. Cell apoptotic rate was assessed by flow cytometry. The expression of endoplasmic reticulum (ER) stress‑ and apoptosis‑related proteins was detected by western blotting or immunofluorescence. Reactive oxygen species (ROS) were evaluated by 2',7'‑dichlorofluorescein diacetate fluorescence staining. The results of the present study revealed that BBR treatment decreased PA‑induced podocyte apoptosis. In addition, 4‑phenylbutyric acid significantly reduced PA‑induced cell apoptosis and the expression of ER stress‑related proteins, which indicated that ER stress was involved in PA‑induced podocyte apoptosis. In addition, N‑acetylcysteine inhibited PA‑induced excessive ROS production, ER stress and cell apoptosis of podocytes. BBR also significantly reduced PA‑induced ROS production and ER stress in podocytes. These results suggested that PA mediated podocyte apoptosis through enhancing ER stress and the production of ROS. In conclusion, BBR may protect against PA‑induced podocyte apoptosis, and suppression of ROS‑dependent ER stress may be the key mechanism underlying the protective effects of BBR.

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1	Hager MR, Narla AD and Tannock LR: Dyslipidemia in patients with chronic kidney disease. Rev Endocr Metab Disord. 18:29–40. 2017. View Article : Google Scholar : PubMed/NCBI
2	Keane WF, Tomassini JE and Neff DR: Lipid abnormalities in patients with chronic kidney disease: Implications for the pathophysiology of atherosclerosis. J Atheroscler Thromb. 20:123–133. 2013. View Article : Google Scholar : PubMed/NCBI
3	Kasiske BL and Wheeler DC: The management of dyslipidemia in CKD: New analyses of an expanding dataset. Am J Kidney Dis. 61:371–374. 2013. View Article : Google Scholar : PubMed/NCBI
4	Kowalski A, Krikorian A and Lerma EV: Dyslipidemia in chronic kidney disease. Dis Mon. 61:396–402. 2015. View Article : Google Scholar : PubMed/NCBI
5	Izquierdo-Lahuerta A, Martinez-Garcia C and Medina-Gómez G: Lipotoxicity as a trigger factor of renal disease. J Nephrol. 29:603–610. 2016. View Article : Google Scholar : PubMed/NCBI
6	Dai H, Liu Q and Liu B: Research progress on mechanism of podocyte depletion in diabetic nephropathy. J Diabetes Res. 2017:26152862017. View Article : Google Scholar : PubMed/NCBI
7	Dalla Vestra M, Masiero A, Roiter AM, Saller A, Crepaldi G and Fioretto P: Is podocyte injury relevant in diabetic nephropathy? Studies in patients with type 2 diabetes. Diabetes. 52:1031–1035. 2003. View Article : Google Scholar : PubMed/NCBI
8	Zhang Y, Ma KL, Liu J, Wu Y, Hu ZB, Liu L and Liu BC: Dysregulation of low-density lipoprotein receptor contributes to podocyte injuries in diabetic nephropathy. Am J Physiol Endocrinol Metab. 308:E1140–E1148. 2015. View Article : Google Scholar : PubMed/NCBI
9	Szeto HH, Liu S, Soong Y, Alam N, Prusky GT and Seshan SV: Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury. Kidney Int. 90:997–1011. 2016. View Article : Google Scholar : PubMed/NCBI
10	Martinez-Garcia C, Izquierdo-Lahuerta A, Vivas Y, Velasco I, Yeo TK, Chen S and Medina-Gomez G: Renal lipotoxicity-associated inflammation and insulin resistance affects actin cytoskeleton organization in podocytes. PLoS One. 10:e01422912015. View Article : Google Scholar : PubMed/NCBI
11	Xu S, Nam SM, Kim JH, Das R, Choi SK, Nguyen TT, Quan X, Choi SJ, Chung CH, Lee EY, et al: Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress. Cell Death Dis. 6:e19762015. View Article : Google Scholar : PubMed/NCBI
12	Tao JL, Wen YB, Shi BY, Zhang H, Ruan XZ, Li H, Li XM, Dong WJ and Li XW: Endoplasmic reticulum stress is involved in podocyte apoptosis induced by saturated fatty acid palmitate. Chin Med J (Engl). 125:3137–3142. 2012.PubMed/NCBI
13	Hua W, Huang HZ, Tan LT, Wan JM, Gui HB, Zhao L, Ruan XZ, Chen XM and Du XG: CD36 mediated fatty acid-induced podocyte apoptosis via oxidative stress. PLoS One. 10:e01275072015. View Article : Google Scholar : PubMed/NCBI
14	Rabbani GH, Butler T, Knight J, Sanyal SC and Alam K: Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerae. J Infect Dis. 155:979–984. 1987. View Article : Google Scholar : PubMed/NCBI
15	Taylor CE and Greenough WB III: Control of diarrheal diseases. Annu Rev Public Health. 10:221–244. 1989. View Article : Google Scholar : PubMed/NCBI
16	Lan J, Zhao Y, Dong F, Yan Z, Zheng W, Fan J and Sun G: Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol. 161:69–81. 2015. View Article : Google Scholar : PubMed/NCBI
17	Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, et al: Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 10:1344–1351. 2004. View Article : Google Scholar : PubMed/NCBI
18	Ni WJ, Ding HH and Tang LQ: Berberine as a promising anti-diabetic nephropathy drug: An analysis of its effects and mechanisms. Eur J Pharmacol. 760:103–112. 2015. View Article : Google Scholar : PubMed/NCBI
19	Zhang Z, Li B, Meng X, Yao S, Jin L, Yang J, Wang J, Zhang H, Zhang Z, Cai D, et al: Berberine prevents progression from hepatic steatosis to steatohepatitis and fibrosis by reducing endoplasmic reticulum stress. Sci Rep. 6:208482016. View Article : Google Scholar : PubMed/NCBI
20	Wang B, Xu X, He X, Wang Z and Yang M: Berberine improved aldo-induced podocyte injury via inhibiting oxidative stress and endoplasmic reticulum stress pathways both in vivo and in vitro. Cell Physiol Biochem. 39:217–228. 2016. View Article : Google Scholar : PubMed/NCBI
21	Jiang XS, Chen XM, Wan JM, Gui HB, Ruan XZ and Du XG: Autophagy protects against palmitic acid-induced apoptosis in podocytes in vitro. Sci Rep. 7:427642017. View Article : Google Scholar : PubMed/NCBI
22	Liu T, Chen XM, Sun JY, Jiang XS, Wu Y, Yang S, Huang HZ, Ruan XZ and Du XG: Palmitic acid-induced podocyte apoptosis via the reactive oxygen species-dependent mitochondrial pathway. Kidney Blood Press Res. 43:206–219. 2018. View Article : Google Scholar : PubMed/NCBI
23	Rashid HO, Yadav RK, Kim HR and Chae HJ: ER stress: Autophagy induction, inhibition and selection. Autophagy. 11:1956–1977. 2015. View Article : Google Scholar : PubMed/NCBI
24	Lukas J, Pospech J, Oppermann C, Hund C, Iwanov K, Pantoom S, Petters J, Frech M, Seemann S, Thiel FG, et al: Role of endoplasmic reticulum stress and protein misfolding in disorders of the liver and pancreas. Adv Med Sci. 64:315–323. 2019. View Article : Google Scholar : PubMed/NCBI
25	Maamoun H, Abdelsalam SS, Zeidan A, Korashy HM and Agouni A: Endoplasmic reticulum stress: A critical molecular driver of endothelial dysfunction and cardiovascular disturbances associated with diabetes. Int J Mol Sci. 20:16582019. View Article : Google Scholar
26	Vaziri ND: HDL abnormalities in nephrotic syndrome and chronic kidney disease. Nat Rev Nephrol. 12:37–47. 2016. View Article : Google Scholar : PubMed/NCBI
27	Reiss AB, Voloshyna I, De Leon J, Miyawaki N and Mattana J: Cholesterol metabolism in CKD. Am J Kidney Dis. 66:1071–1082. 2015. View Article : Google Scholar : PubMed/NCBI
28	Ferro CJ, Mark PB, Kanbay M, Sarafidis P, Heine GH, Rossignol P, Massy ZA, Mallamaci F, Valdivielso JM, Malyszko J, et al: Lipid management in patients with chronic kidney disease. Nat Rev Nephrol. 14:727–749. 2018. View Article : Google Scholar : PubMed/NCBI
29	Reiser J and Sever S: Podocyte biology and pathogenesis of kidney disease. Annu Rev Med. 64:357–366. 2013. View Article : Google Scholar : PubMed/NCBI
30	Sieber J and Jehle AW: Free fatty acids and their metabolism affect function and survival of podocytes. Front Endocrinol (Lausanne). 5:1862014. View Article : Google Scholar : PubMed/NCBI
31	Zou K, Li Z, Zhang Y, Zhang HY, Li B, Zhu WL, Shi JY, Jia Q and Li YM: Advances in the study of berberine and its derivatives: A focus on anti-inflammatory and anti-tumor effects in the digestive system. Acta Pharmacol Sin. 38:157–167. 2017. View Article : Google Scholar : PubMed/NCBI
32	Cheng F, Wang Y, Li J, Su C, Wu F, Xia WH, Yang Z, Yu BB, Qiu YX and Tao J: Berberine improves endothelial function by reducing endothelial microparticles-mediated oxidative stress in humans. Int J Cardiol. 167:936–942. 2013. View Article : Google Scholar : PubMed/NCBI
33	Saha SK and Khuda-Bukhsh AR: Berberine alters epigenetic modifications, disrupts microtubule network, and modulates HPV-18 E6-E7 oncoproteins by targeting p53 in cervical cancer cell HeLa: A mechanistic study including molecular docking. Eur J Pharmacol. 744:132–146. 2014. View Article : Google Scholar : PubMed/NCBI
34	Zhang Y, Li X, Zou D, Liu W, Yang J, Zhu N, Huo L, Wang M, Hong J, Wu P, et al: Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab. 93:2559–2565. 2008. View Article : Google Scholar : PubMed/NCBI
35	Wu U, Cha Y, Huang X, Liu J, Chen Z, Wang F, Xu J, Sheng L and Ding H: Protective effects of berberine on high fat-induced kidney damage by increasing serum adiponectin and promoting insulin sensitivity. Int J Clin Exp Pathol. 8:14486–14492. 2015.PubMed/NCBI
36	Sun Y, Yuan X, Zhang F, Han Y, Chang X, Xu X, Li Y and Gao X: Berberine ameliorates fatty acid-induced oxidative stress in human hepatoma cells. Sci Rep. 7:113402017. View Article : Google Scholar : PubMed/NCBI
37	Qin X, Zhao Y, Gong J, Huang W, Su H, Yuan F, Fang K, Wang D, Li J, Zou X, et al: Berberine protects glomerular podocytes via inhibiting Drp1-mediated mitochondrial fission and dysfunction. Theranostics. 9:1698–1713. 2019. View Article : Google Scholar : PubMed/NCBI
38	Kaufman RJ: Stress signaling from the lumen of the endoplasmic reticulum: Coordination of gene transcriptional and translational controls. Genes Dev. 13:1211–1233. 1999. View Article : Google Scholar : PubMed/NCBI
39	Begum G, Harvey L, Dixon CE and Sun D: ER stress and effects of DHA as an ER stress inhibitor. Transl Stroke Res. 4:635–642. 2013. View Article : Google Scholar : PubMed/NCBI
40	Gardner BM, Pincus D, Gotthardt K, Gallagher CM and Walter P: Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb Perspect Biol. 5:a0131692013. View Article : Google Scholar : PubMed/NCBI
41	Verfaillie T, Garg AD and Agostinis P: Targeting ER stress induced apoptosis and inflammation in cancer. Cancer Lett. 332:249–264. 2013. View Article : Google Scholar : PubMed/NCBI
42	Chen Y, Wu Z, Zhao S and Xiang R: Chemical chaperones reduce ER stress and adipose tissue inflammation in high fat diet-induced mouse model of obesity. Sci Rep. 6:274862016. View Article : Google Scholar : PubMed/NCBI
43	Cabral-Miranda F and Hetz C: ER stress and neurodegenerative disease: A cause or effect relationship? Curr Top Microbiol Immunol. 414:131–157. 2018.PubMed/NCBI
44	Ariyasu D, Yoshida H and Hasegawa Y: Endoplasmic reticulum (ER) stress and endocrine disorders. Int J Mol Sci. 18:3822017. View Article : Google Scholar
45	Cybulsky AV: Endoplasmic reticulum stress, the unfolded protein response and autophagy in kidney diseases. Nat Rev Nephrol. 13:681–696. 2017. View Article : Google Scholar : PubMed/NCBI
46	Szegezdi E, Fitzgerald U and Samali A: Caspase-12 and ER-stress-mediated apoptosis: The story so far. Ann N Y Acad Sci. 1010:186–194. 2003. View Article : Google Scholar : PubMed/NCBI
47	Coppolino G, Leonardi G, Andreucci M and Bolignano D: Oxidative stress and kidney function: A brief update. Curr Pharm Des. 24:4794–4799. 2018. View Article : Google Scholar : PubMed/NCBI
48	Gai Z, Wang T, Visentin M, Kullak-Ublick GA, Fu X and Wang Z: Lipid accumulation and chronic kidney disease. Nutrients. 11:7222019. View Article : Google Scholar
49	Seervi M, Rani A, Sharma AK and Santhosh Kumar TR: ROS mediated ER stress induces Bax-Bak dependent and independent apoptosis in response to Thioridazine. Biomed Pharmacother. 106:200–209. 2018. View Article : Google Scholar : PubMed/NCBI
50	Malhotra JD and Kaufman RJ: Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a double-edged sword? Antioxid Redox Signal. 9:2277–2293. 2007. View Article : Google Scholar : PubMed/NCBI
51	Cao SS and Kaufman RJ: Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal. 21:396–413. 2014. View Article : Google Scholar : PubMed/NCBI
52	Yu W, Sheng M, Xu R, Yu J, Cui K, Tong J, Shi L, Ren H and Du H: Berberine protects human renal proximal tubular cells from hypoxia/reoxygenation injury via inhibiting endoplasmic reticulum and mitochondrial stress pathways. J Transl Med. 11:242013. View Article : Google Scholar : PubMed/NCBI
53	Zhu L, Han J, Yuan R, Xue L and Pang W: Berberine ameliorates diabetic nephropathy by inhibiting TLR4/NF-κB pathway. Biol Res. 51:92018. View Article : Google Scholar : PubMed/NCBI
54	Feng X, Sureda A, Jafari S, Memariani Z, Tewari D, Annunziata G, Barrea L, Hassan STS, Šmejkal K, Malaník M, et al: Berberine in cardiovascular and metabolic diseases: From mechanisms to therapeutics. Theranostics. 9:1923–1951. 2019. View Article : Google Scholar : PubMed/NCBI