Lysyl oxidase‑like 2 is expressed in kidney tissue and is associated with the progression of tubulointerstitial fibrosis

Choi,Sung‑Eun; Jeon,Nara; Choi,Hoon Young; Shin,Jae Il; Jeong,Hyeon Joo; Lim,Beom Jin

doi:10.3892/mmr.2017.6918

Lysyl oxidase‑like 2 is expressed in kidney tissue and is associated with the progression of tubulointerstitial fibrosis

Authors:
- Sung‑Eun Choi
- Nara Jeon
- Hoon Young Choi
- Jae Il Shin
- Hyeon Joo Jeong
- Beom Jin Lim
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Affiliations: Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea, Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
Published online on: July 4, 2017 https://doi.org/10.3892/mmr.2017.6918
Pages: 2477-2482
Copyright: © Choi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tubulointerstitial fibrosis is a common end point of chronic kidney diseases, and preventing its progression is key to avoiding renal failure. Transforming growth factor‑β (TGF‑β) and associated molecules promote tubulointerstitial fibrosis; however, effective therapies targeting these molecules have yet to be developed. Lysyl oxidase‑like 2 (LOXL2), which is involved in invasive growth and metastasis of malignant neoplasms, has recently been reported to serve a key role in hepatic and pulmonary fibrosis. However, little is currently known regarding LOXL2 expression in the kidney and its involvement in tubulointerstitial fibrosis. The present study evaluated LOXL2 expression in human and mouse kidney tissues, as well as in cultured renal cells. LOXL2 protein expression was detected in glomerular capillary loops and tubular epithelial cells in human and mouse kidneys. Glomerular LOXL2 was localized to the cytoplasm of podocytes, as determined by double immunofluorescence microscopy using a podocyte marker (synaptopodin). This result was supported by western blot analysis, which demonstrated that LOXL2 protein expression is present in cultured human podocytes and HK‑2 human proximal tubular cells. In addition, the mRNA and protein expression levels of LOXL2 were higher in a mouse model of tubulointerstitial fibrosis compared with in control mice. In addition, immunohistochemistry results demonstrated that LOXL2 is present in the fibrous interstitium and infiltrating mononuclear cells in a mouse model of tubulointerstitial fibrosis. The present study demonstrated that LOXL2 is expressed in compartments of renal tissue, where it appears to contribute to the progression of tubulointerstitial fibrosis.

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1	Nishioka T, Eustace A and West C: Lysyl oxidase: From basic science to future cancer treatment. Cell Struct Funct. 37:75–80. 2012. View Article : Google Scholar : PubMed/NCBI
2	Fong SF, Dietzsch E, Fong KS, Hollosi P, Asuncion L, He Q, Parker MI and Csiszar K: Lysyl oxidase-like 2 expression is increased in colon and esophageal tumors and associated with less differentiated colon tumors. Genes Chromosomes Cancer. 46:644–655. 2007. View Article : Google Scholar : PubMed/NCBI
3	Lin ZY, Chuang YH and Chuang WL: Cancer-associated fibroblasts up-regulate CCL2, CCL26, IL6 and LOXL2 genes related to promotion of cancer progression in hepatocellular carcinoma cells. Biomed Pharmacother. 66:525–529. 2012. View Article : Google Scholar : PubMed/NCBI
4	Peinado H, Moreno-Bueno G, Hardisson D, Pérez-Gómez E, Santos V, Mendiola M, de Diego JI, Nistal M, Quintanilla M, Portillo F and Cano A: Lysyl oxidase-like 2 as a new poor prognosis marker of squamous cell carcinomas. Cancer Res. 68:4541–4550. 2008. View Article : Google Scholar : PubMed/NCBI
5	Ahn SG, Dong SM, Oshima A, Kim WH, Lee HM, Lee SA, Kwon SH, Lee JH, Lee JM, Jeong J, et al: LOXL2 expression is associated with invasiveness and negatively influences survival in breast cancer patients. Breast Cancer Res Treat. 141:89–99. 2013. View Article : Google Scholar : PubMed/NCBI
6	Kasashima H, Yashiro M, Kinoshita H, Fukuoka T, Morisaki T, Masuda G, Sakurai K, Kubo N, Ohira M and Hirakawa K: Lysyl oxidase-like 2 (LOXL2) from stromal fibroblasts stimulates the progression of gastric cancer. Cancer Lett. 354:438–446. 2014. View Article : Google Scholar : PubMed/NCBI
7	Barker HE, Bird D, Lang G and Erler JT: Tumor-secreted LOXL2 activates fibroblasts through FAK signaling. Mol Cancer Res. 11:1425–1436. 2013. View Article : Google Scholar : PubMed/NCBI
8	Barker HE, Chang J, Cox TR, Lang G, Bird D, Nicolau M, Evans HR, Gartland A and Erler JT: LOXL2-mediated matrix remodeling in metastasis and mammary gland involution. Cancer Res. 71:1561–1572. 2011. View Article : Google Scholar : PubMed/NCBI
9	Vadasz Z, Kessler O, Akiri G, Gengrinovitch S, Kagan HM, Baruch Y, Izhak OB and Neufeld G: Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J Hepatol. 43:499–507. 2005. View Article : Google Scholar : PubMed/NCBI
10	Wong CC, Tse AP, Huang YP, Zhu YT, Chiu DK, Lai RK, Au SL, Kai AK, Lee JM, Wei LL, et al: Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma. Hepatology. 60:1645–1658. 2014. View Article : Google Scholar : PubMed/NCBI
11	Chien JW, Richards TJ, Gibson KF, Zhang Y, Lindell KO, Shao L, Lyman SK, Adamkewicz JI, Smith V, Kaminski N and O'Riordan T: Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression. Eur Respir J. 43:1430–1438. 2014. View Article : Google Scholar : PubMed/NCBI
12	Van Bergen T, Marshall D, Van de Veire S, Vandewalle E, Moons L, Herman J, Smith V and Stalmans I: The role of LOX and LOXL2 in scar formation after glaucoma surgery. Invest Ophthalmol Vis Sci. 54:5788–5796. 2013. View Article : Google Scholar : PubMed/NCBI
13	Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, Mikels A, Vaysberg M, Ghermazien H, Wai C, et al: Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 16:1009–1017. 2010. View Article : Google Scholar : PubMed/NCBI
14	Meissner EG, McLaughlin M, Matthews L, Gharib AM, Wood BJ, Levy E, Sinkus R, Virtaneva K, Sturdevant D, Martens C, et al: Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: Results of a 6-month open-label safety trial. Liver Int. 36:1783–1792. 2016. View Article : Google Scholar : PubMed/NCBI
15	Saleem MA, O'Hare MJ, Reiser J, Coward RJ, Inward CD, Farren T, Xing CY, Ni L, Mathieson PW and Mundel P: A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression. J Am Soc Nephrol. 13:630–638. 2002.PubMed/NCBI
16	Long DA, Woolf AS, Suda T and Yuan HT: Increased renal angiopoietin-1 expression in folic acid-induced nephrotoxicity in mice. J Am Soc Nephrol. 12:2721–2731. 2001.PubMed/NCBI
17	Stallons LJ, Whitaker RM and Schnellmann RG: Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis. Toxicol Lett. 224:326–332. 2014. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Meng XM, Nikolic-Paterson DJ and Lan HY: TGF-beta: The master regulator of fibrosis. Nat Rev Nephrol. 12:325–338. 2016. View Article : Google Scholar : PubMed/NCBI
20	Marek I, Lichtneger T, Cordasic N, Hilgers KF, Volkert G, Fahlbusch F, Rascher W, Hartner A and Menendez-Castro C: Alpha8 integrin (Itga8) signalling attenuates chronic renal interstitial fibrosis by reducing fibroblast activation, not by interfering with regulation of cell turnover. PLoS One. 11:e01504712016. View Article : Google Scholar : PubMed/NCBI
21	Sumual S, Saad S, Tang O, Yong R, McGinn S, Chen XM and Pollock CA: Differential regulation of Snail by hypoxia and hyperglycemia in human proximal tubule cells. Int J Biochem Cell Biol. 42:1689–1697. 2010. View Article : Google Scholar : PubMed/NCBI
22	Meng XM, Nikolic-Paterson DJ and Lan HY: Inflammatory processes in renal fibrosis. Nat Rev Nephrol. 10:493–503. 2014. View Article : Google Scholar : PubMed/NCBI
23	Meng XM, Huang XR, Xiao J, Chen HY, Zhong X, Chung AC and Lan HY: Diverse roles of TGF-b receptor II in renal fibrosis and inflammation in vivo and in vitro. J Pathol. 227:175–188. 2012. View Article : Google Scholar : PubMed/NCBI
24	Mack M and Yanagita M: Origin of myofibroblasts and cellular events triggering fibrosis. Kidney Int. 87:297–307. 2015. View Article : Google Scholar : PubMed/NCBI
25	Xiao L, Wang M, Yang S, Liu F and Sun L: A glimpse of the pathogenetic mechanisms of Wnt/b-catenin signaling in diabetic nephropathy. Biomed Res Int. 2013:9870642013. View Article : Google Scholar : PubMed/NCBI
26	Pang M, Wang H, Rao P, Zhao Y, Xie J, Cao Q, Wang Y, Wang YM, Lee VW, Alexander SI, et al: Autophagy links beta-catenin and Smad signaling to promote epithelial-mesenchymal transition via upregulation of integrin linked kinase. Int J Biochem Cell Biol. 76:123–134. 2016. View Article : Google Scholar : PubMed/NCBI
27	Sethi A, Mao W, Wordinger RJ and Clark AF: Transforming growth factor-beta induces extracellular matrix protein cross-linking lysyl oxidase (LOX) genes in human trabecular meshwork cells. Invest Ophthalmol Vis Sci. 52:5240–5250. 2011. View Article : Google Scholar : PubMed/NCBI
28	Voloshenyuk TG, Landesman ES, Khoutorova E, Hart AD and Gardner JD: Induction of cardiac fibroblast lysyl oxidase by TGF-b1 requires PI3K/Akt, Smad3, and MAPK signaling. Cytokine. 55:90–97. 2011. View Article : Google Scholar : PubMed/NCBI
29	Neelisetty S, Alford C, Reynolds K, Woodbury L, Nlandu-Khodo S, Yang H, Fogo AB, Hao CM, Harris RC, Zent R and Gewin L: Renal fibrosis is not reduced by blocking transforming growth factor-b signaling in matrix-producing interstitial cells. Kidney Int. 88:503–514. 2015. View Article : Google Scholar : PubMed/NCBI
30	Kim MG, Kim SC, Ko YS, Lee HY, Jo SK and Cho W: The role of M2 macrophages in the progression of chronic kidney disease following acute kidney injury. PLoS One. 10:e01439612015. View Article : Google Scholar : PubMed/NCBI
31	Chang JW, Pardo V, Sageshima J, Chen L, Tsai HL, Reiser J, Wei C, Ciancio G, Burke GW III and Fornoni A: Podocyte foot process effacement in postreperfusion allograft biopsies correlates with early recurrence of proteinuria in focal segmental glomerulosclerosis. Transplantation. 93:1238–1244. 2012. View Article : Google Scholar : PubMed/NCBI
32	Alachkar N, Wei C, Arend LJ, Jackson AM, Racusen LC, Fornoni A, Burke G, Rabb H, Kakkad K, Reiser J and Estrella MM: Podocyte effacement closely links to suPAR levels at time of posttransplantation focal segmental glomerulosclerosis occurrence and improves with therapy. Transplantation. 96:649–656. 2013. View Article : Google Scholar : PubMed/NCBI
33	Wharram BL, Goyal M, Wiggins JE, Sanden SK, Hussain S, Filipiak WE, Saunders TL, Dysko RC, Kohno K, Holzman LB and Wiggins RC: Podocyte depletion causes glomerulosclerosis: Diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol. 16:2941–2952. 2005. View Article : Google Scholar : PubMed/NCBI
34	Maezawa Y, Takemoto M and Yokote K: Cell biology of diabetic nephropathy: Roles of endothelial cells, tubulointerstitial cells and podocytes. J Diabetes Investig. 6:3–15. 2015. View Article : Google Scholar : PubMed/NCBI