Mechanism of tacrolimus-induced chronic renal fibrosis following transplantation is regulated by ox-LDL and its receptor, LOX-1

Deng,Shi; Jin,Tao; Zhang,Li; Bu,Hong; Zhang,Peng

doi:10.3892/mmr.2016.5735

Mechanism of tacrolimus-induced chronic renal fibrosis following transplantation is regulated by ox-LDL and its receptor, LOX-1

Authors:
- Shi Deng
- Tao Jin
- Li Zhang
- Hong Bu
- Peng Zhang
View Affiliations

Affiliations: Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
Published online on: September 13, 2016 https://doi.org/10.3892/mmr.2016.5735
Pages: 4124-4134
Copyright: © Deng 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

Chronic renal allograft dysfunction (CRAD) is the most common cause of graft failure following renal transplantation. However, the underlying mechanisms remain to be fully elucidated. Immunosuppressants and hyperlipidemia are associated with renal fibrosis following long‑term use. The present study aimed to determine the effects of tacrolimus (FK506) and lipid metabolism disorder on CRAD. In vitro and in vivo models were used for this investigation. Cells of the mouse proximal renal tubular epithelial cell strain, NRK‑52E, were cultured either with oxidized low‑density lipoprotein (ox‑LDL), FK506, ox‑LDL combined with FK506, or vehicle, respectively. Changes in cell morphology and changes in the levels of lectin‑like ox‑LDL receptor‑1 (LOX‑1), reactive oxygen species (ROS), hydrogen peroxide and fibrosis‑associated genes were evaluated at 24, 48 and 72 h. In separate experiment, total of 60 Sprague‑Dawley rats were divided randomly into four groups, which included a high‑fat group, FK506 group, high‑fat combined with FK506 group, and control group. After 2, 4 and 8 weeks, the serum lipid levels, the levels of ox‑LDL, ROS, and the expression levels of transforming growth factor (TGF)‑β1 and connective tissue growth factor were determined. The in vitro and in vivo models revealed that lipid metabolism disorder and FK506 caused oxidative stress and a fibrogenic response. In addition, decreased levels of LOX‑1 markedly reduced the levels of TGF‑β1 in the in vitro model. Taken together, FK506 and dyslipidemia were found to be associated with CRAD following transplantation.

View Figures

View References

1	Womer KL, Vella JP and Sayegh MH: Chronic allograft dysfunction: Mechanisms and new approaches to therapy. Semin Nephrol. 20:126–147. 2000.PubMed/NCBI
2	Hernandez-Fuentes MP and Lechler RI: Chronic graft loss. Immunological and non-immunological factors. Contrib Nephrol. 146:54–64. 2005.PubMed/NCBI
3	Divakar D, Bailey RR, Frampton CM, George PM, Walmsley TA and Murphy J: Hyperlipidemia in stable renal transplant recipients. Nephron. 59:423–428. 1991. View Article : Google Scholar : PubMed/NCBI
4	Roodnat JI, Mulder PG, Zietse R, Rischen-Vos J, van Riemsdijk IC, IJzermans JN and Weimar W: Cholesterol as an independent predictor of outcome after renal transplantation. Transplantation. 69:1704–1710. 2000. View Article : Google Scholar : PubMed/NCBI
5	Serón D, Moreso F, Ramón JM, Hueso M, Condom E, Fulladosa X, Bover J, Gil-Vernet S, Castelao AM, Alsina J and Grinyó JM: Protocol renal allograft biopsies and the design of clinical trials aimed to prevent or treat chronic allograft nephropathy. Transplantation. 69:1849–1855. 2000. View Article : Google Scholar : PubMed/NCBI
6	Wissing KM, Abramowicz D, Broeders N and Vereerstraeten P: Hypercholesterolemia is associated with increased kidney graft loss caused by chronic rejection in male patients with previous acute rejection. Transplantation. 70:464–472. 2000. View Article : Google Scholar : PubMed/NCBI
7	Friemann S, Feuring E, Padberg W and Ernst W: Improvement of nephrotoxicity, hypertension, and lipid metabolism after conversion of kidney transplant recipients from cyclosporine to tacrolimus. Transplant Proc. 30:1240–1242. 1998. View Article : Google Scholar : PubMed/NCBI
8	Vela CG, Cristol JP, Descomps B and Mourad G: Prospective study of lipid disorders in FK506-versus cyclosporine-treated renal transplant patients. Transplant Proc. 32:3982000. View Article : Google Scholar : PubMed/NCBI
9	Ruan XZ, Varghese Z, Fernando R and Moorhead JF: Cytokine regulation of low-density lipoprotein receptor gene transcription in human mesangial cells. Nephrol Dial Transplant. 13:1391–1397. 1998. View Article : Google Scholar : PubMed/NCBI
10	Chen M, Masaki T and Sawamura T: LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: Implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther. 95:89–100. 2002. View Article : Google Scholar : PubMed/NCBI
11	Shihab FS, Bennett WM, Tanner AM and Andoh TF: Mechanism of fibrosis in experimental tacrolimus nephrotoxicity. Transplantation. 64:1829–1837. 1997. View Article : Google Scholar : PubMed/NCBI
12	Khanna AK and Pieper GM: NADPH oxidase subunits (NOX-1, p22phox, Rac-1) and tacrolimus-induced nephrotoxicity in a rat renal transplant model. Nephrol Dial Transplant. 22:376–385. 2007. View Article : Google Scholar : PubMed/NCBI
13	Kobashigawa JA and Kasiske BL: Hyperlipidemia in solid organ transplantation. Transplantation. 63:331–338. 1997. View Article : Google Scholar : PubMed/NCBI
14	Cheung CY, Wong KM, Chan HW, Liu YL, Chan YH, Wong HS, Chak WL, Cho KS, Chau KF and Li CS: Paired kidney analysis of tacrolimus and cyclosporine microemulsion-based therapy in Chinese cadaveric renal transplant recipients. Transpl Int. 19:657–666. 2006. View Article : Google Scholar : PubMed/NCBI
15	Ekberg H, Bernasconi C, Tedesco-Silva H, Vitko S, Hugo C, Demirbas A, Acevedo RR, Grinyó J, Frei U, Vanrenterghem Y, et al: Calcineurin inhibitor minimization in the Symphony study: Observational results 3 years after transplantation. Am J Transplant. 9:1876–1885. 2009. View Article : Google Scholar : PubMed/NCBI
16	Li HY, Li B, Wei YG, Yan LN, Wen TF, Zhao JC, Xu MQ, Wang WT, Ma YK and Yang JY: Higher tacrolimus blood concentration is related to hyperlipidemia in living donor liver transplantation recipients. Dig Dis Sci. 57:204–209. 2012. View Article : Google Scholar : PubMed/NCBI
17	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
18	Racusen LC, Halloran PF and Solez K: Banff 2003 meeting report: New diagnostic insights and standards. Am J Transplant. 4:1562–1566. 2004. View Article : Google Scholar : PubMed/NCBI
19	Mango R, Clementi F, Borgiani P, Forleo GB, Federici M, Contino G, Giardina E, Garza L, Fahdi IE, Lauro R, et al: Association of single nucleotide polymorphisms in the oxidised LDL receptor 1 (OLR1) gene in patients with acute myocardial infarction. J Med Genet. 40:933–936. 2003. View Article : Google Scholar : PubMed/NCBI
20	Dimény E, Fellström B, Larsson E, Tufveson G and Lithell H: Hyperlipoproteinemia in renal transplant recipients: Is there a linkage with chronic vascular rejection? Transplant Proc. 25:2065–2066. 1993.PubMed/NCBI
21	Dimény E, Wahlberg J, Lithell H and Fellström B: Hyperlipidaemia in renal transplantation-risk factor for long-term graft outcome. Eur J Clin Invest. 25:574–583. 1995. View Article : Google Scholar : PubMed/NCBI
22	Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, Tanaka T, Miwa S, Katsura Y, Kita T and Masaki T: An endothelial receptor for oxidized low-density lipoprotein. Nature. 386:73–77. 1997. View Article : Google Scholar : PubMed/NCBI
23	Chen M, Kakutani M, Minami M, Kataoka H, Kume N, Narumiya S, Kita T, Masaki T and Sawamura T: Increased expression of lectin-like oxidized low density lipoprotein receptor-1 in initial atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits. Arterioscler Thromb Vasc Biol. 20:1107–1115. 2000. View Article : Google Scholar : PubMed/NCBI
24	Kataoka H, Kume N, Miyamoto S, Minami M, Moriwaki H, Murase T, Sawamura T, Masaki T, Hashimoto N and Kita T: Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions. Circulation. 99:3110–3117. 1999. View Article : Google Scholar : PubMed/NCBI
25	Draude G, Hrboticky N and Lorenz RL: The expression of the lectin-like oxidized low-density lipoprotein receptor (LOX-1) on human vascular smooth muscle cells and monocytes and its down-regulation by lovastatin. Biochem Pharmacol. 57:383–386. 1999. View Article : Google Scholar : PubMed/NCBI
26	Cominacini L, Rigoni A, Pasini AF, Garbin U, Davoli A, Campagnola M, Pastorino AM, Lo Cascio V and Sawamura T: The binding of oxidized low density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide. J Biol Chem. 276:13750–13755. 2001.PubMed/NCBI
27	Apanay DC, Neylan JF, Ragab MS and Sgoutas DS: Cyclosporine increases the oxidizability of low-density lipoproteins in renal transplant recipients. Transplantation. 58:663–669. 1994. View Article : Google Scholar : PubMed/NCBI
28	Leask A: Transcriptional profiling of the scleroderma fibroblast reveals a potential role for connective tissue growth factor (CTGF) in pathological fibrosis. Keio J Med. 53:74–77. 2004. View Article : Google Scholar : PubMed/NCBI
29	Cheng O, Thuillier R, Sampson E, Schultz G, Ruiz P, Zhang X, Yuen PS and Mannon RB: Connective tissue growth factor is a biomarker and mediator of kidney allograft fibrosis. Am J Transplant. 6:2292–2306. 2006. View Article : Google Scholar : PubMed/NCBI
30	Sohn M, Tan Y, Wang B, Klein RL, Trojanowska M and Jaffa AA: Mechanisms of low-density lipoprotein-induced expression of connective tissue growth factor in human aortic endothelial cells. Am J Physiol Heart Circ Physiol. 290:H1624–H1634. 2006. View Article : Google Scholar : PubMed/NCBI
31	Jin S, Mathis AS, Rosenblatt J, Minko T, Friedman GS, Gioia K, Serur DS and Knipp GT: Insights into cyclosporine A-induced atherosclerotic risk in transplant recipients: Macrophage scavenger receptor regulation. Transplantation. 77:497–504. 2004. View Article : Google Scholar : PubMed/NCBI
32	Massy ZA: Hyperlipidemia and cardiovascular disease after organ transplantation. Transplantation. 72:S13–S15. 2001. View Article : Google Scholar : PubMed/NCBI
33	Varghese Z, Fernando RL, Turakhia G, Psimenou E, Fernando ON, Sweny P, Powis SH and Moorhead JF: Calcineurin inhibitors enhance low-density lipoprotein oxidation in transplant patients. Kidney Int Suppl. 71:S137–S140. 1999. View Article : Google Scholar : PubMed/NCBI