Microvesicles containing miR-34a induce apoptosis of proximal tubular epithelial cells and participate in renal interstitial fibrosis

Li,Hongyan; Xu,Yuexia; Zhang,Qin; Xu,Hongfang; Xu,Yan; Ling,Kai

doi:10.3892/etm.2019.7197

Microvesicles containing miR-34a induce apoptosis of proximal tubular epithelial cells and participate in renal interstitial fibrosis

Authors:
- Hongyan Li
- Yuexia Xu
- Qin Zhang
- Hongfang Xu
- Yan Xu
- Kai Ling
View Affiliations

Affiliations: Department of Nephrology, The First People's Hospital of Wujiang, Wujiang Hospital Affiliated to Nantong University, Suzhou, Jiangsu 215200, P.R. China
Published online on: January 24, 2019 https://doi.org/10.3892/etm.2019.7197
Pages: 2310-2316
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Function and potential mechanism of microvesicles (MVs) containing microRNA34a in renal interstitial fibrosis were investigated. A rat model of renal interstitial fibrosis was established by unilateral ureteral ligation (UUO).Rat proximal tubular epithelial cell line (NRK-52E) was used to explore the effect of MVs containing microRNA-34a on tubular epithelial cells during fibrosis, which were secreted by tubulointerstitial fibroblasts. Regardless of the UUO renal interstitial fibrosis model, or the TGF-β1-treated renal tubular epithelial cells, microRNA-34a was increased in the MVs secreted by tubulointerstitial fibroblasts. miR-34a could be transmitted through the damaged tubule basement membrane to proximal tubular epithelial cells, where it induced apoptosis of renal tubular epithelial cells by inhibiting the expression of Bcl-2, further aggravating renal interstitial fibrosis. MicroRNA-34a secreted by damaged renal interstitial fibroblasts can promote renal tubular epithelial cell apoptosis and participate in renal interstitial fibrosis by inhibiting Bcl-2.

View Figures

View References

1	Liu Y: New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol. 21:212–222. 2010. View Article : Google Scholar : PubMed/NCBI
2	Zeisberg M and Neilson EG: Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol. 21:1819–1834. 2010. View Article : Google Scholar : PubMed/NCBI
3	Bohle A, Christ H, Grund KE and Mackensen S: The role of the interstitium of the renal cortex in renal disease. Contrib Nephrol. 16:109–114. 1979. View Article : Google Scholar : PubMed/NCBI
4	Johnson A and DiPietro LA: Apoptosis and angiogenesis: An evolving mechanism for fibrosis. FASEB J. 27:3893–3901. 2013. View Article : Google Scholar : PubMed/NCBI
5	Docherty NG, O'Sullivan OE, Healy DA, Fitzpatrick JM and Watson RW: Evidence that inhibition of tubular cell apoptosis protects against renal damage and development of fibrosis following ureteric obstruction. Am J Physiol Renal Physiol. 290:F4–F13. 2006. View Article : Google Scholar : PubMed/NCBI
6	Liu Y: Hepatocyte growth factor in kidney fibrosis: Therapeutic potential and mechanisms of action. Am J Physiol Renal Physiol. 287:F7–F16. 2004. View Article : Google Scholar : PubMed/NCBI
7	Zhang G, Oldroyd SD, Huang LH, Yang B, Li Y, Ye R and El Nahas AM: Role of apoptosis and Bcl-2/Bax in the development of tubulointerstitial fibrosis during experimental obstructive nephropathy. Exp Nephrol. 9:71–80. 2001. View Article : Google Scholar : PubMed/NCBI
8	Liu CF, Liu H, Fang Y, Jiang SH, Zhu JM and Ding XQ: Rapamycin reduces renal hypoxia, interstitial inflammation and fibrosis in a rat model of unilateral ureteral obstruction. Clin Invest Med. 37:E1422014. View Article : Google Scholar : PubMed/NCBI
9	Miyajima A, Chen J, Lawrence C, Ledbetter S, Soslow RA, Stern J, Jha S, Pigato J, Lemer ML, Poppas DP, et al: Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int. 58:2301–2313. 2000. View Article : Google Scholar : PubMed/NCBI
10	Gao X, Mae H, Ayabe N, Takai T, Oshima K, Hattori M, Ueki T, Fujimoto J and Tanizawa T: Hepatocyte growth factor gene therapy retards the progression of chronic obstructive nephropathy. Kidney Int. 62:1238–1248. 2002. View Article : Google Scholar : PubMed/NCBI
11	Morrissey J, Hruska K, Guo G, Wang S, Chen Q and Klahr S: Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. J Am Soc Nephrol. 13 Suppl 1:S14–S21. 2002.PubMed/NCBI
12	Fu JH, Yang S, Nan CJ, Zhou CC, Lu DQ, Li S and Mu HQ: MiR-182 affects renal cancer cell proliferation, apoptosis, and invasion by regulating PI3K/AKT/mTOR signaling pathway. Eur Rev Med Pharmacol Sci. 22:351–357. 2018.PubMed/NCBI
13	Harvey SJ, Jarad G, Cunningham J, Goldberg S, Schermer B, Harfe BD, McManus MT, Benzing T and Miner JH: Podocyte-specific deletion of dicer alters cytoskeletal dynamics and causes glomerular disease. J Am Soc Nephrol. 19:2150–2158. 2008. View Article : Google Scholar : PubMed/NCBI
14	Ho JJ and Marsden PA: Dicer cuts the kidney. J Am Soc Nephrol. 19:2043–2046. 2008. View Article : Google Scholar : PubMed/NCBI
15	Wang Y and Lee CG: MicroRNA and cancer - focus on apoptosis. J Cell Mol Med. 13:12–23. 2009. View Article : Google Scholar : PubMed/NCBI
16	Hermeking H: The miR-34 family in cancer and apoptosis. Cell Death Differ. 17:193–199. 2010. View Article : Google Scholar : PubMed/NCBI
17	Qi R, An H, Yu Y, Zhang M, Liu S, Xu H, Guo Z, Cheng T and Cao X: Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res. 63:8323–8329. 2003.PubMed/NCBI
18	Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE, Zhai Y, Giordano TJ, Qin ZS, Moore BB, et al: p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biol. 17:1298–1307. 2007. View Article : Google Scholar : PubMed/NCBI
19	Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A and Ratajczak MZ: Membrane-derived microvesicles: Important and underappreciated mediators of cell-to-cell communication. Leukemia. 20:1487–1495. 2006. View Article : Google Scholar : PubMed/NCBI
20	Graves LE, Ariztia EV, Navari JR, Matzel HJ, Stack MS and Fishman DA: Proinvasive properties of ovarian cancer ascites-derived membrane vesicles. Cancer Res. 64:7045–7049. 2004. View Article : Google Scholar : PubMed/NCBI
21	Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM and Breakefield XO: Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 10:1470–1476. 2008. View Article : Google Scholar : PubMed/NCBI
22	Taylor DD and Gercel-Taylor C: MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 110:13–21. 2008. View Article : Google Scholar : PubMed/NCBI
23	Bryant RJ, Pawlowski T, Catto JW, Marsden G, Vessella RL, Rhees B, Kuslich C, Visakorpi T and Hamdy FC: Changes in circulating microRNA levels associated with prostate cancer. Br J Cancer. 106:768–774. 2012. View Article : Google Scholar : PubMed/NCBI
24	Cole KA, Attiyeh EF, Mosse YP, Laquaglia MJ, Diskin SJ, Brodeur GM and Maris JM: A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene. Mol Cancer Res. 6:735–742. 2008. View Article : Google Scholar : PubMed/NCBI
25	Hengartner MO: The biochemistry of apoptosis. Nature. 407:770–776. 2000. View Article : Google Scholar : PubMed/NCBI
26	Chen CC and Lau LF: Deadly liaisons: Fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines. J Cell Commun Signal. 4:63–69. 2010. View Article : Google Scholar : PubMed/NCBI
27	Borges FT, Melo SA, Özdemir BC, Kato N, Revuelta I, Miller CA, Gattone VH II, LeBleu VS and Kalluri R: TGF-β1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J Am Soc Nephrol. 24:385–392. 2013. View Article : Google Scholar : PubMed/NCBI