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Blockade of the mTOR signaling pathway with rapamycin ameliorates aristolochic acid nephropathy

  • Authors:
    • Minmin Wu
    • Lili Tang
    • Bicheng Chen
    • Jianjian Zheng
    • Fengquan Dong
    • Zhen Su
    • Fan Lin
  • View Affiliations / Copyright

    Affiliations: Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Clinical Laboratory, Chinese Medical Hospital of Jining, Jining, Shandong 272037, P.R. China, Department of Nephrology, Shenzhen University General Hospital, Shenzhen, Guangdong 518055, P.R. China
    Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 2887-2894
    |
    Published online on: February 25, 2020
       https://doi.org/10.3892/etm.2020.8550
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Abstract

Chronic aristolochic acid nephropathy (CAAN) is characterized by widespread apoptosis and interstitial fibrosis, which severely impairs kidney function. mTOR is crucial for cell proliferation and protein synthesis. In the present study, the therapeutic effects of blockade of mTOR activity by rapamycin on aristolochic acid nephropathy were investigated. In vitro experiments to determine cell apoptosis and cell cycle alterations caused by aristolochic acid (AA)‑induced injury were conducted on three groups of cells: Untreated control, AAI (treated with aristolochic acid I), and AAI + rapamycin (RMS). In vivo experiments were conducted in a CAAN mouse model. One group of mice was treated with AAI (the CAAN group), while another group was treated with AAI and rapamycin (the treatment group). Kidney function and pathological changes in these mice were assessed by serum creatinine and urea nitrogen analysis. Hematoxylin and eosin staining of renal tissue was performed to evaluate the treatment effects of rapamycin. Western blotting and immunohistochemical staining were used to explore the mechanisms by which rapamycin inhibited cell proliferation, apoptosis and tissue fibrosis. In the in vitro experiments, rapamycin prevented AAI‑induced cell apoptosis and G2/M checkpoint cell cycle arrest. In the in vivo experiments, the treatment group exhibited lower serum creatinine and urea nitrogen, less extensive tubular atrophy and increased amount of glomerulus. Additionally, western blotting and immunohistochemical staining showed that the treatment group exhibited decreased expression levels of fibrosis‑, proliferation‑ and apoptosis‑related proteins compared with the CAAN group. The findings suggest that rapamycin can ameliorate kidney injury induced by AAI via blockade of mTOR, and thus could be a therapeutic strategy for patients with CAAN.
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1 

Vanherweghem JL, Depierreux M, Tielemans C, Abramowicz D, Dratwa M, Jadoul M, Richard C, Vandervelde D, Verbeelen D, Vanhaelen-Fastre R, et al: Rapidly progressive interstitial renal fibrosis in young women: Association with slimming regimen including Chinese herbs. Lancet. 341:387–391. 1993.PubMed/NCBI View Article : Google Scholar

2 

Nortier JL, Martinez MC, Schmeiser HH, Arlt VM, Bieler CA, Petein M, Depierreux MF, De Pauw L, Abramowicz D, Vereerstraeten P and Vanherweghem JL: Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med. 342:1686–1692. 2000.PubMed/NCBI View Article : Google Scholar

3 

Heinrich M, Chan J, Wanke S, Neinhuis C and Simmonds MS: Local uses of Aristolochia species and content of nephrotoxic aristolochic acid 1 and 2-a global assessment based on bibliographic sources. J Ethnopharmacol. 125:108–144. 2009.PubMed/NCBI View Article : Google Scholar

4 

Hamano Y, Aoki T, Shirai R, Hatano M, Kimura R, Ogawa M, Yokosuka O and Ueda S: Low-dose darbepoetin alpha attenuates progression of a mouse model of aristolochic acid nephropathy through early tubular protection. Nephron Exp Nephrol. 114(e69-e81)2010.PubMed/NCBI View Article : Google Scholar

5 

Pozdzik AA, Salmon IJ, Husson CP, Decaestecker C, Rogier E, Bourgeade MF, Deschodt-Lanckman MM, Vanherweghem JL and Nortier JL: Patterns of interstitial inflammation during the evolution of renal injury in experimental aristolochic acid nephropathy. Nephrol Dial Transplant. 23:2480–2491. 2008.PubMed/NCBI View Article : Google Scholar

6 

Zhou L, Fu P, Huang XR, Liu F, Lai KN and Lan HY: Activation of p53 promotes renal injury in acute aristolochic acid nephropathy. J Am Soc Nephrol. 21:31–41. 2010.PubMed/NCBI View Article : Google Scholar

7 

Arlt VM, Stiborova M and Schmeiser HH: Aristolochic acid as a probable human cancer hazard in herbal remedies: A review. Mutagenesis. 17:265–277. 2002.PubMed/NCBI View Article : Google Scholar

8 

Li Y, Wang Z, Wang S, Zhao J, Zhang J and Huang Y: Gremlin-mediated decrease in bone morphogenetic protein signaling promotes aristolochic acid-induced epithelial-to-mesenchymal transition (EMT) in HK-2 cells. Toxicology. 297:68–75. 2012.PubMed/NCBI View Article : Google Scholar

9 

Rui HL, Wang YY, Cheng H and Chen YP: JNK-dependent AP-1 activation is required for aristolochic acid-induced TGF-β1 synthesis in human renal proximal epithelial cells. Am J Physiol Renal Physiol. 302(F1569-F1575)2012.PubMed/NCBI View Article : Google Scholar

10 

Wu CJ, Chou YC, Cheng YW, Hsiao CJ, Wang CH, Wang HY, Sheu JR and Hsiao G: Aristolochic acid downregulates monocytic matrix metalloproteinase-9 by inhibiting nuclear factor-κ activation. Chem Biol Interact. 192:209–219. 2011.PubMed/NCBI View Article : Google Scholar

11 

Hartford CM and Ratain MJ: Rapamycin: Something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther. 82:381–388. 2007.PubMed/NCBI View Article : Google Scholar

12 

Hay N and Sonenberg N: Upstream and downstream of mTOR. Genes Dev. 18:1926–1945. 2004.PubMed/NCBI View Article : Google Scholar

13 

Wang X and Proud CG: mTORC1 signaling: What we still don't know. J Mol Cell Biol. 3:206–220. 2011.PubMed/NCBI View Article : Google Scholar

14 

Laplante M and Sabatini DM: mTOR signaling in growth control and disease. Cell. 149:274–293. 2012.PubMed/NCBI View Article : Google Scholar

15 

Burnett PE, Barrow RK, Cohen NA, Snyder SH and Sabatini DM: RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA. 95:1432–1437. 1998.PubMed/NCBI View Article : Google Scholar

16 

Brown EJ, Beal PA, Keith CT, Chen J, Shin TB and Schreiber SL: Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature. 377:441–446. 1995.PubMed/NCBI View Article : Google Scholar

17 

Li J, Zhang M, Mao Y, Li Y, Zhang X, Peng X and Yu F: The potential role of aquaporin 1 on aristolochic acid I induced epithelial mesenchymal transition on HK-2 cells. J Cell Physiol. 233:4919–4925. 2018.PubMed/NCBI View Article : Google Scholar

18 

Kan WC, Hwang JY, Chuang LY, Guh JY, Ye YL, Yang YL and Huang JS: Effect of osthole on advanced glycation end products-induced renal tubular hypertrophy and role of klotho in its mechanism of action. Phytomedicine. 53:205–212. 2019.PubMed/NCBI View Article : Google Scholar

19 

Zhou Q, Du J, Hu Z, Walsh K and Wang XH: Evidence for adipose-muscle cross talk: Opposing regulation of muscle proteolysis by adiponectin and Fatty acids. Endocrinology. 148:5696–5705. 2007.PubMed/NCBI View Article : Google Scholar

20 

Dickman KG, Sweet DH, Bonala R, Ray T and Wu A: Physiological and molecular characterization of aristolochic acid transport by the kidney. J Pharmacol Exp Ther. 338:588–597. 2011.PubMed/NCBI View Article : Google Scholar

21 

Ma DH, Zheng FL, Su Y, Li MX and Guo MH: Influence and analysis of low-dosage steroid therapy in severe aristolochic acid nephropathy patients. Nephrology (Carlton). 21:835–840. 2016.PubMed/NCBI View Article : Google Scholar

22 

Luciano RL and Perazella MA: Aristolochic acid nephropathy: Epidemiology, clinical presentation, and treatment. Drug Saf. 38:55–64. 2015.PubMed/NCBI View Article : Google Scholar

23 

Stark GR and Taylor WR: Analyzing the G2/M checkpoint. Methods Mol Biol. 280:51–82. 2004.PubMed/NCBI View Article : Google Scholar

24 

Yang L, Besschetnova TY, Brooks CR, Shah JV and Bonventre JV: Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med. 16:535–543. 2010.PubMed/NCBI View Article : Google Scholar

25 

Buisson R, Niraj J, Rodrigue A, Ho CK, Kreuzer J, Foo TK, Hardy EJ, Dellaire G, Haas W, Xia B, et al: Coupling of homologous recombination and the checkpoint by ATR. Mol Cell. 65:336–346. 2017.PubMed/NCBI View Article : Google Scholar

26 

Visconti R, Della Monica R and Grieco D: Cell cycle checkpoint in cancer: A therapeutically targetable double-edged sword. J Exp Clin Cancer Res. 35(153)2016.PubMed/NCBI View Article : Google Scholar

27 

Wu MJ, Wen MC, Chiu YT, Chiou YY, Shu KH and Tang MJ: Rapamycin attenuates unilateral ureteral obstruction-induced renal fibrosis. Kidney Int. 69:2029–2036. 2006.PubMed/NCBI View Article : Google Scholar

28 

Tian J, Wang Y, Liu X, Zhou X and Li R: Rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms. Exp Biol Med (Maywood). 240:936–945. 2015.PubMed/NCBI View Article : Google Scholar

29 

Velagapudi C, Bhandari BS, Abboud-Werner S, Simone S, Abboud HE and Habib SL: The tuberin/mTOR pathway promotes apoptosis of tubular epithelial cells in diabetes. J Am Soc Nephrol. 22:262–273. 2011.PubMed/NCBI View Article : Google Scholar

30 

Liu DD, Han CC, Wan HF, He F, Xu HY, Wei SH, Du XH and Xu F: Effects of inhibiting PI3K-Akt-mTOR pathway on lipid metabolism homeostasis in goose primary hepatocytes. Animal. 10:1319–1327. 2016.PubMed/NCBI View Article : Google Scholar

31 

Zeng R, Xiong Y, Zhu F, Ma Z, Liao W, He Y, He J, Li W, Yang J, Lu Q, et al: Fenofibrate attenuated glucose-induced mesangial cells proliferation and extracellular matrix synthesis via PI3K/AKT and ERK1/2. PLoS One. 8(e76836)2013.PubMed/NCBI View Article : Google Scholar

32 

Johnson A and DiPietro LA: Apoptosis and angiogenesis: An evolving mechanism for fibrosis. FASEB J. 27:3893–3901. 2013.PubMed/NCBI View Article : Google Scholar

33 

Calastretti A, Bevilacqua A, Ceriani C, Viganò S, Zancai P, Capaccioli S and Nicolin A: Damaged microtubules can inactivate BCL-2 by means of the mTOR kinase. Oncogene. 20:6172–6180. 2001.PubMed/NCBI View Article : Google Scholar

34 

Cory S and Adams JM: The Bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer. 2:647–656. 2002.PubMed/NCBI View Article : Google Scholar

35 

Shen YL, Sun L, Hu YJ, Liu HJ, Kuang XY, Niu XL and Huang WY: P53 inhibitor pifithrin-alpha prevents the renal tubular epithelial cells against injury. Am J Transl Res. 8:4040–4053. 2016.PubMed/NCBI

36 

Bonventre JV: Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure. J Am Soc Nephrol. 14 (Suppl 1)(S55-S61)2003.PubMed/NCBI View Article : Google Scholar

37 

Gniadecki R, Hansen M and Wulf HC: Two pathways for induction of apoptosis by ultraviolet radiation in cultured human keratinocytes. J Invest Dermatol. 109:163–169. 1997.PubMed/NCBI View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Wu M, Tang L, Chen B, Zheng J, Dong F, Su Z and Lin F: Blockade of the mTOR signaling pathway with rapamycin ameliorates aristolochic acid nephropathy. Exp Ther Med 19: 2887-2894, 2020.
APA
Wu, M., Tang, L., Chen, B., Zheng, J., Dong, F., Su, Z., & Lin, F. (2020). Blockade of the mTOR signaling pathway with rapamycin ameliorates aristolochic acid nephropathy. Experimental and Therapeutic Medicine, 19, 2887-2894. https://doi.org/10.3892/etm.2020.8550
MLA
Wu, M., Tang, L., Chen, B., Zheng, J., Dong, F., Su, Z., Lin, F."Blockade of the mTOR signaling pathway with rapamycin ameliorates aristolochic acid nephropathy". Experimental and Therapeutic Medicine 19.4 (2020): 2887-2894.
Chicago
Wu, M., Tang, L., Chen, B., Zheng, J., Dong, F., Su, Z., Lin, F."Blockade of the mTOR signaling pathway with rapamycin ameliorates aristolochic acid nephropathy". Experimental and Therapeutic Medicine 19, no. 4 (2020): 2887-2894. https://doi.org/10.3892/etm.2020.8550
Copy and paste a formatted citation
x
Spandidos Publications style
Wu M, Tang L, Chen B, Zheng J, Dong F, Su Z and Lin F: Blockade of the mTOR signaling pathway with rapamycin ameliorates aristolochic acid nephropathy. Exp Ther Med 19: 2887-2894, 2020.
APA
Wu, M., Tang, L., Chen, B., Zheng, J., Dong, F., Su, Z., & Lin, F. (2020). Blockade of the mTOR signaling pathway with rapamycin ameliorates aristolochic acid nephropathy. Experimental and Therapeutic Medicine, 19, 2887-2894. https://doi.org/10.3892/etm.2020.8550
MLA
Wu, M., Tang, L., Chen, B., Zheng, J., Dong, F., Su, Z., Lin, F."Blockade of the mTOR signaling pathway with rapamycin ameliorates aristolochic acid nephropathy". Experimental and Therapeutic Medicine 19.4 (2020): 2887-2894.
Chicago
Wu, M., Tang, L., Chen, B., Zheng, J., Dong, F., Su, Z., Lin, F."Blockade of the mTOR signaling pathway with rapamycin ameliorates aristolochic acid nephropathy". Experimental and Therapeutic Medicine 19, no. 4 (2020): 2887-2894. https://doi.org/10.3892/etm.2020.8550
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