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LOX-1-Targeted Iron Oxide Nanoparticles Detect Early Diabetic Nephropathy in db/db Mice

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Abstract

Purpose

Activation of the low-density lipoprotein receptor 1 (LOX-1) contributes to pervasive inflammation in early diabetic nephropathy (DN). This study determined the feasibility of anti-LOX-1-ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) for noninvasive detection of inflammatory renal lesions in early DN.

Procedures

Anti-mouse LOX-1 antibody was conjugated to polyethyleneglycol-coated USPIOs. In vitro analysis of USPIOs uptake was performed in RAW264.7 macrophages. DN and control mice were imaged by MRI prior to and 24 h after contrast treatment.

Results

Anti-LOX-1 USPIOs were selectively taken up by macrophages, and kidney T2* MRI showed a lower signal intensity in the cortex of DN mice after 24 h administration of anti-LOX-1 USPIOs. Positive Perl’s staining in DN lesions, indicating the presence of iron oxide, was consistent with immunohistochemistry indicating the presence of LOX-1 and CD68.

Conclusions

This report shows that anti-LOX-1 USPIOs detect LOX-1-enriched inflammatory renal lesions in early DN mice. Our study provides important information for characterizing and monitoring early DN.

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References

  1. Kdoqi (2007) KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis 49:S12–S154

    Article  Google Scholar 

  2. Stenvinkel P (2010) Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease. J Intern Med 268:456–467

    Article  CAS  PubMed  Google Scholar 

  3. Zhao H, Dong Y, Tian X et al (2013) Matrix metalloproteinases contribute to kidney fibrosis in chronic kidney diseases. World J Nephrol 2:84–89

    Article  PubMed Central  PubMed  Google Scholar 

  4. Barutta F, Piscitelli F, Pinach S et al (2011) Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy. Diabetes 60:2386–2396

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Pozzi A, Zent R, Chetyrkin S et al (2009) Modification of collagen IV by glucose or methylglyoxal alters distinct mesangial cell functions. J Am Soc Nephrol 20:2119–2125

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Diabetes C, Complications Trial/Epidemiology of Diabetes I, Complications Research G et al (2009) Modern-day clinical course of type 1 diabetes mellitus after 30 years' duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005). Arch Intern Med 169:307–1316

    Google Scholar 

  7. Yan M, Mehta JL, Zhang W et al (2011) LOX-1, oxidative stress and inflammation: a novel mechanism for diabetic cardiovascular complications. Cardiovasc Drugs Ther 25:451–459

    Article  CAS  PubMed  Google Scholar 

  8. Vincent AM, Hayes JM, McLean LL et al (2009) Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1. Diabetes 58:2376–2385

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Quigg RJ (2011) If oxidized LDL immune complexes are relevant in diabetic atherosclerosis, shouldn't they also be relevant in diabetic nephropathy? Clin Immunol 139:233–234

    Article  CAS  PubMed  Google Scholar 

  10. Sawamura T, Kume N, Aoyama T et al (1997) An endothelial receptor for oxidized low-density lipoprotein. Nature 386:73–77

    Article  CAS  PubMed  Google Scholar 

  11. Honjo M, Nakamura K, Yamashiro K et al (2003) Lectin-like oxidized LDL receptor-1 is a cell-adhesion molecule involved in endotoxin-induced inflammation. Proc Natl Acad Sci U S A 100:1274–1279

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Mehta JL, Li D (2002) Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor. J Am Coll Cardiol 39:1429–1435

    Article  CAS  PubMed  Google Scholar 

  13. Mehta JL, Chen J, Hermonat PL et al (2006) Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders. Cardiovasc Res 69:36–45

    Article  CAS  PubMed  Google Scholar 

  14. Inoue K, Arai Y, Kurihara H et al (2005) Overexpression of lectin-like oxidized low-density lipoprotein receptor-1 induces intramyocardial vasculopathy in apolipoprotein E-null mice. Circ Res 97:176–184

    Article  CAS  PubMed  Google Scholar 

  15. Dominguez JH, Mehta JL, Li D et al (2008) Anti-LOX-1 therapy in rats with diabetes and dyslipidemia: ablation of renal vascular and epithelial manifestations. Am J Physiol Renal Physiol 294:F110–F119

    Article  CAS  PubMed  Google Scholar 

  16. Yuan C, Mitsumori LM, Ferguson MS et al (2001) In Vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques. Circulation 104:2051–2056

    Article  CAS  PubMed  Google Scholar 

  17. Saam T, Hatsukami TS, Takaya N et al (2007) The vulnerable, or high-risk, atherosclerotic plaque: noninvasive MR imaging for characterization and assessment. Radiology 244:64–77

    Article  PubMed  Google Scholar 

  18. Jo SK, Hu X, Kobayashi H et al (2003) Detection of inflammation following renal ischemia by magnetic resonance imaging. Kidney Int 64:43–51

    Article  PubMed  Google Scholar 

  19. Hauger O, Delalande C, Deminiere C et al (2000) Nephrotoxic nephritis and obstructive nephropathy: evaluation with MR imaging enhanced with ultrasmall superparamagnetic iron oxide-preliminary findings in a rat model. Radiology 217:819–826

    Article  CAS  PubMed  Google Scholar 

  20. Yang D, Ye Q, Williams M et al (2001) USPIO-enhanced dynamic MRI: evaluation of normal and transplanted rat kidneys. Magn Reson Med 46:1152–1163

    Article  CAS  PubMed  Google Scholar 

  21. Gao Q, Zhang J, Hong G, Ni J (2010) One-pot reaction to synthesize PEG-coated hollow magnetite nanostructures with excellent magnetic properties. J Nanosci Nanotechnol 10:6400–6406

    Article  CAS  PubMed  Google Scholar 

  22. Zhen L, Wei L, Gao MY et al (2005) One-pot reaction to synthesize biocompatible magnetite nanoparticles. Adv Mater 17:1001–1005

    Article  Google Scholar 

  23. Wen S, Liu DF, Liu Z et al (2012) OxLDL-targeted iron oxide nanoparticles for in vivo MRI detection of perivascular carotid collar induced atherosclerotic lesions in ApoE-deficient mice. J Lipid Res 53:829–838

    Article  CAS  PubMed  Google Scholar 

  24. Wen S, Liu DF, Cui Y et al (2014) In vivo MRI detection of carotid atherosclerotic lesions and kidney inflammation in ApoE-deficient mice by using LOX-1 targeted iron nanoparticles. Nanomedicine 10:639–649

    Article  CAS  PubMed  Google Scholar 

  25. Li D, Patel AR, Klibanov AL et al (2010) Molecular imaging of atherosclerotic plaques targeted to oxidized LDL receptor LOX-1 by SPECT/CT and magnetic resonance. Circ Cardiovasc Imaging 3:464–472

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Kanasaki K, Taduri G, Koya D (2013) Diabetic nephropathy: the role of inflammation in fibroblast activation and kidney fibrosis. Front Endocrinol (Lausanne) 4:7

    Google Scholar 

  27. Kenney WL, Cannon JG, Alexander LM (2013) Cutaneous microvascular dysfunction correlates with serum LDL and sLOX-1 receptor concentrations. Microvasc Res 85:112–117

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Palmieri VO, Coppola B, Grattagliano I et al (2013) Oxidized LDL receptor 1 gene polymorphism in patients with metabolic syndrome. Eur J Clin Invest 43:41–48

    Article  CAS  PubMed  Google Scholar 

  29. Dominguez J, Wu P, Packer CS et al (2007) Lipotoxic and inflammatory phenotypes in rats with uncontrolled metabolic syndrome and nephropathy. Am J Physiol Renal Physiol 293:F670–F679

    Article  CAS  PubMed  Google Scholar 

  30. Lopes-Virella MF, Hunt KJ, Baker NL et al (2011) Levels of oxidized LDL and advanced glycation end products-modified LDL in circulating immune complexes are strongly associated with increased levels of carotid intima-media thickness and its progression in type 1 diabetes. Diabetes 60:582–589

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Kume N, Mitsuoka H, Hayashida K et al (2010) Soluble lectin-like oxidized low-density lipoprotein receptor-1 predicts prognosis after acute coronary syndrome. Circ J 74:1399–1404

    Article  CAS  PubMed  Google Scholar 

  32. Wang LJ, Yu YH, Zhang LG et al (2008) Taurine rescues vascular endothelial dysfunction in streptozocin-induced diabetic rats: correlated with downregulation of LOX-1 and ICAM-1 expression on aortas. Eur J Pharmacol 597:75–80

    Article  CAS  PubMed  Google Scholar 

  33. Shiu SW, Wong Y, Tan KC (2012) Effect of Advanced Glycation End Products on Lectin-Like Oxidized Low Density Lipoprotein Receptor-1 Expression in Endothelial Cells. J Atheroscler Thromb

  34. Zhang M, Gao X, Wu J et al (2010) Oxidized high-density lipoprotein enhances inflammatory activity in rat mesangial cells. Diabetes Metab Res Rev 26:455–463

    Article  CAS  PubMed  Google Scholar 

  35. Liu DF, Wei W, Jing LL et al (2011) Effective PEGylation of iron oxide nanoparticles for high performance in vivo cancer imaging. Adv Funct Mater 21:1498–1504

    Article  CAS  Google Scholar 

  36. Briley-Saebo KC, Cho YS, Shaw PX et al (2011) Targeted iron oxide particles for in vivo magnetic resonance detection of atherosclerotic lesions with antibodies directed to oxidation-specific epitopes. J Am Coll Cardiol 57:337–347

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Zhang F, Wang C, Wang H et al (2013) Ox-LDL promotes migration and adhesion of bone marrow-derived mesenchymal stem cells via regulation of MCP-1 expression. Mediators Inflamm 2013:691023

    PubMed Central  PubMed  Google Scholar 

  38. Mima A (2013) Inflammation and oxidative stress in diabetic nephropathy: new insights on its inhibition as new therapeutic targets. J Diab Res 2013:248563

    Google Scholar 

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Sources of Funding

This work was supported by the Major State Basic Research Development Program of China (973 Program) (NOs. 2013CB733800, 2013CB733803), National Natural Science Foundation of China (NOs. 81230034, 81271739, 81271637, 81401460), and Jiangsu Provincial Special Program of Medical Science (BL2013029).

Conflict of Interest

The authors have declared that no competing interests exist.

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Author notes

    Authors and Affiliations

    1. Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing, Jiangsu, 210009, China

      Bing Luo, Song Wen, Yu-Chen Chen, Ying Cui, Yu-Yu Yao, Sheng-Hong Ju & Gao-Jun Teng

    2. Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China

      Fa-Bao Gao

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    1. Bing Luo
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    Correspondence to Gao-Jun Teng.

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    Bing Luo and Song Wen contributed equally to this work.

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    Luo, B., Wen, S., Chen, YC. et al. LOX-1-Targeted Iron Oxide Nanoparticles Detect Early Diabetic Nephropathy in db/db Mice. Mol Imaging Biol 17, 652–660 (2015). https://doi.org/10.1007/s11307-015-0829-5

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