Endoplasmic reticulum stress associated apoptosis as a novel mechanism in indoxyl sulfate‑induced cardiomyocyte toxicity

Tan,Xiao; Cao,Xue‑Sen; Zhang,Pan; Xiang,Fang‑Fang; Teng,Jie; Zou,Jian‑Zhou; Ding,Xiao‑Qiang

doi:10.3892/mmr.2018.9496

Endoplasmic reticulum stress associated apoptosis as a novel mechanism in indoxyl sulfate‑induced cardiomyocyte toxicity

Authors:
- Xiao Tan
- Xue‑Sen Cao
- Pan Zhang
- Fang‑Fang Xiang
- Jie Teng
- Jian‑Zhou Zou
- Xiao‑Qiang Ding
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Affiliations: Shanghai Key Laboratory of Kidney and Blood Purification, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China, Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
Published online on: September 20, 2018 https://doi.org/10.3892/mmr.2018.9496
Pages: 5117-5122

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Abstract

Indoxyl sulfate (IS), a typical uremic toxin, is of great importance in the development of chronic kidney disease. In addition to its nephrotoxicity, previous studies have provided increasing evidence for its cardiovascular toxicity. The mechanism underlying IS‑induced cardiovascular toxicity has been elusive to date. The present study aimed to evaluate whether IS treatment could induce apoptosis of H9C2 cells, and used the endoplasmic reticulum (ER) stress‑modulator 4‑phenylbutyric acid (4‑PBA) to evaluate whether IS‑induced apoptosis is indeed associated with ERS. To evaluate whether IS induces apoptosis in H9C2 cardiomyocytes, cells were exposed to increasing concentrations of IS (500, 1,000, and 2,000 µM) for 24 h, and apoptosis was detected by flow cytometry. To determine whether IS‑induced apoptosis is associated with ERS, cells were divided into 4 groups: control group, PBA group, IS group and PBA+IS group. IS dose‑dependently induced apoptosis, and increased the expression of ER chaperones in H9C2 cells. Additionally, 4‑PBA treatment decreased IS‑induced apoptosis, and reduced ERS‑associated protein expression induced by IS. Therefore, the mechanism may be associated with the CCAAT‑enhancer‑binding protein homologous protein and c‑Jun N‑terminal kinase signaling pathways.

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1	Herzog CA, Asinger RW, Berger AK, Charytan DM, Diez J, Hart RG, Eckardt KU, Kasiske BL, McCullough PA, Passman RS, et al: Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving global outcomes (KDIGO). Kidney Int. 80:572–586. 2011. View Article : Google Scholar : PubMed/NCBI
2	Granata A, Clementi A, Virzi GM, Brocca A, de Cal M, Scarfia VR, Zanoli L, Ronco C, Corrao S and Malatino L: Cardiorenal syndrome type 4: From chronic kidney disease to cardiovascular impairment. Eur J Intern Med. 30:1–6. 2016. View Article : Google Scholar : PubMed/NCBI
3	Tan X, Cao X, Zou J, Shen B, Zhang X, Liu Z, Lv W, Teng J and Ding X: Indoxyl sulfate, a valuable biomarker in chronic kidney disease and dialysis. Hemodial Int. 21:161–167. 2017. View Article : Google Scholar : PubMed/NCBI
4	Cao XS, Chen J, Zou JZ, Zhong YH, Teng J, Ji J, Chen ZW, Liu ZH, Shen B, Nie YX, et al: Association of indoxyl sulfate with heart failure among patients on hemodialysis. Clin J Am Soc Nephrol. 10:111–119. 2015. View Article : Google Scholar : PubMed/NCBI
5	Yisireyili M, Shimizu H, Saito S, Enomoto A, Nishijima F and Niwa T: Indoxyl sulfate promotes cardiac fibrosis with enhanced oxidative stress in hypertensive rats. Life Sci. 92:1180–1185. 2013. View Article : Google Scholar : PubMed/NCBI
6	Lin CY, Hsu YJ, Hsu SC, Chen Y, Lee HS, Lin SH, Huang SM, Tsai CS and Shih CC: CB1 cannabinoid receptor antagonist attenuates left ventricular hypertrophy and Akt-mediated cardiac fibrosis in experimental uremia. J Mol Cell Cardiol. 85:249–261. 2015. View Article : Google Scholar : PubMed/NCBI
7	Rani S, Sreenivasaiah PK, Cho C and Kim DH: Salubrinal alleviates pressure overload-induced cardiac hypertrophy by inhibiting endoplasmic reticulum stress pathway. Mol Cells. 40:66–72. 2017. View Article : Google Scholar : PubMed/NCBI
8	Lu WW, Zhao L, Zhang JS, Hou YL, Yu YR, Jia MZ, Tang CS and Qi YF: Intermedin1-53 protects against cardiac hypertrophy by inhibiting endoplasmic reticulum stress via activating AMP-activated protein kinase. J Hypertens. 33:1676–1687. 2015. View Article : Google Scholar : PubMed/NCBI
9	Logue SE, Cleary P, Saveljeva S and Samali A: New directions in ER stress-induced cell death. Apoptosis. 18:537–546. 2013. View Article : Google Scholar : PubMed/NCBI
10	Yoshida H: ER stress and diseases. FEBS J. 274:630–658. 2007. View Article : Google Scholar : PubMed/NCBI
11	Gao Y, Jia P, Shu W and Jia D: The protective effect of lycopene on hypoxia/reoxygenation-induced endoplasmic reticulum stress in H9C2 cardiomyocytes. Eur J Pharmacol. 774:71–79. 2016. View Article : Google Scholar : PubMed/NCBI
12	Taddei S, Nami R, Bruno RM, Quatrini I and Nuti R: Hypertension, left ventricular hypertrophy and chronic kidney disease. Heart Fail Rev. 16:615–620. 2011. View Article : Google Scholar : PubMed/NCBI
13	Siedlecki AM, Jin X and Muslin AJ: Uremic cardiac hypertrophy is reversed by rapamycin but not by lowering of blood pressure. Kidney Int. 75:800–808. 2009. View Article : Google Scholar : PubMed/NCBI
14	Yang K, Wang C, Nie L, Zhao X, Gu J and Guan X: Klotho protects against indoxyl sulphate-induced myocardial hypertrophy. J Am Soc Nephrol. 26:2434–2446. 2015. View Article : Google Scholar : PubMed/NCBI
15	Adijiang A, Goto S, Uramoto S, Nishijima F and Niwa T: Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats. Nephrol Dial Transplant. 23:1892–1901. 2008. View Article : Google Scholar : PubMed/NCBI
16	Yang K, Xu X, Nie L, Xiao T, Guan X, He T, Yu Y, Liu L, Huang Y, Zhang J and Zhao J: Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway. Toxicol Lett. 234:110–119. 2015. View Article : Google Scholar : PubMed/NCBI
17	Lin CJ, Liu HL, Pan CF, Chuang CK, Jayakumar T, Wang TJ, Chen HH and Wu CJ: Indoxyl sulfate predicts cardiovascular disease and renal function deterioration in advanced chronic kidney disease. Arch Med Res. 43:451–456. 2012. View Article : Google Scholar : PubMed/NCBI
18	Yu M, Kim YJ and Kang DH: Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress. Clin J Am Soc Nephrol. 6:30–39. 2011. View Article : Google Scholar : PubMed/NCBI
19	Lin CJ, Pan CF, Liu HL, Chuang CK, Jayakumar T and Wang TJ: The role of protein-bound uremic toxins on peripheral artery disease and vascular access failure in patients on hemodialysis. Atherosclerosis. 225:173–179. 2012. View Article : Google Scholar : PubMed/NCBI
20	Fujii H, Nishijima F, Goto S, Sugano M, Yamato H, Kitazawa R, Kitazawa S and Fukagawa M: Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress. Nephrol Dial Transplant. 24:2089–2095. 2009. View Article : Google Scholar : PubMed/NCBI
21	Zhang K and Kaufman RJ: From endoplasmic-reticulum stress to the inflammatory response. Nature. 454:455–462. 2008. View Article : Google Scholar : PubMed/NCBI
22	Kupsco A and Schlenk D: Oxidative stress, unfolded protein response, and apoptosis in developmental toxicity. Int Rev Cell Mol Biol. 317:1–66. 2015. View Article : Google Scholar : PubMed/NCBI
23	Wang WJ, Cheng MH, Sun MF, Hsu SF and Weng CS: Indoxyl sulfate induces renin release and apoptosis of kidney mesangial cells. J Toxicol Sci. 39:637–643. 2014. View Article : Google Scholar : PubMed/NCBI
24	Ellis RJ, Small DM, Ng KL, Vesey DA, Vitetta L and Francis RS: Indoxyl sulfate induces apoptosis and hypertrophy in human kidney proximal tubular cells. Toxicol Pathol. 46:449–459. 2018. View Article : Google Scholar : PubMed/NCBI
25	Kim SH, Yu MA, Ryu ES, Jang YH and Kang DH: Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease. Lab Invest. 92:488–498. 2012. View Article : Google Scholar : PubMed/NCBI
26	Kim YH, Kwak KA, Gil HW, Song HY and Hong SY: Indoxyl sulfate promotes apoptosis in cultured osteoblast cells. BMC Pharmacol Toxicol. 14:602013. View Article : Google Scholar : PubMed/NCBI