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Deposition of platelet-derived microparticles in podocytes contributes to diabetic nephropathy

  • Nephrology - Original Paper
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Abstract

Background

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the developed world. Podocyte injury is a critical cellular event involved in the progression of DN. Our previous studies demonstrated that platelet-derived microparticles (PMPs) mediated endothelial injury in diabetic rats. This study aimed to investigate whether PMPs are deposited in podocytes and to assess their potential effects on podocyte injury in DN.

Methods

The deposition of PMPs in podocytes was assessed by immunofluorescent staining and electron microscopy. The changes in renal pathology and ultra-microstructure were assessed by periodic acid-Schiff staining and electron microscopy, respectively. The expression of inflammatory cytokines and extracellular matrix proteins was measured by immuno-histochemical staining and western blot.

Results

PMPs were widely deposited in podocytes of glomeruli in diabetic patients and animal models and closely associated with DN progression. Interestingly, aspirin treatment significantly inhibited the accumulation of PMPs in the glomeruli of diabetic rats, alleviated mesangial matrix expansion and fusion of foot processes, and decreased the protein expression of inflammatory cytokines and extracellular matrix secretion. An in vitro study further confirmed the deposition of PMPs in podocytes. Moreover, PMP stimulation induced the phenotypic transition of podocytes through decreased podocin protein expression and increased protein expression of α-SMA and fibronectin, which was correlated with increased production of inflammatory cytokines.

Conclusion

Our findings demonstrated for the first time that the deposition of PMPs in podocytes contributed to the development of DN.

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References

  1. Umanath K, Lewis JB (2018) Update on diabetic nephropathy: core curriculum 2018. Am J Kidney Dis 71(6):884–895. https://doi.org/10.1053/j.ajkd.2017.10.026

    Article  Google Scholar 

  2. Ma RCW (2018) Epidemiology of diabetes and diabetic complications in China. Diabetologia 61(6):1249–1260. https://doi.org/10.1007/s00125-018-4557-7

    Article  Google Scholar 

  3. Zhou Y, Echouffo-Tcheugui JB, Jian-jun Gu, Ruan X-N, Zhao G-M, Wang-hong Xu et al (2013) Prevalence of chronic kidney disease across levels of glycemia among adults in Pudong New Area, Shanghai China. BMC Nephrol 14:253

    Article  Google Scholar 

  4. Jia W, Gao X, Pang C, Hou X, Bao Y, Liu W et al (2009) Prevalence and risk factors of albuminuria and chronic kidney disease in Chinese population with type 2 diabetes and impaired glucose regulation: Shanghai diabetic complications study (SHDCS). Nephrol Dial Transplant 24(12):3724–3731. https://doi.org/10.1093/ndt/gfp349

    Article  CAS  Google Scholar 

  5. Lu B, Wen J, Song XY, Dong XH, Yang YH, Zhang ZY et al (2007) High prevalence of albuminuria in population-based patients diagnosed with type 2 diabetes in the Shanghai downtown. Diabetes Res Clin Pract 75(2):184–192. https://doi.org/10.1016/j.diabres.2006.06.024

    Article  CAS  Google Scholar 

  6. Tang SCW, Yiu WH (2020) Innate immunity in diabetic kidney disease. Nat Rev Nephrol 16(4):206–222. https://doi.org/10.1038/s41581-019-0234-4

    Article  CAS  Google Scholar 

  7. Hickey FB, Martin F (2018) Role of the immune system in diabetic kidney disease. Curr Diab Rep 18(4):20. https://doi.org/10.1007/s11892-018-0984-6

    Article  CAS  Google Scholar 

  8. Niewczas MA, Pavkov ME, Skupien J, Smiles A, Md Dom ZI, Wilson JM et al (2019) A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes. Nat Med 25(5):805–813. https://doi.org/10.1038/s41591-019-0415-5

    Article  CAS  Google Scholar 

  9. Zhang Y, Ma KL, Liu J, Wu Y, Hu ZB, Liu L et al (2015) Inflammatory stress exacerbates lipid accumulation and podocyte injuries in diabetic nephropathy. Acta Diabetol 52(6):1045–1056. https://doi.org/10.1007/s00592-015-0753-9

    Article  CAS  Google Scholar 

  10. Kao CY, Papoutsakis ET (2019) Extracellular vesicles: exosomes, microparticles, their parts, and their targets to enable their biomanufacturing and clinical applications. Curr Opin Biotechnol 60:89–98. https://doi.org/10.1016/j.copbio.2019.01.005

    Article  CAS  Google Scholar 

  11. Kailashiya J, Gupta V, Dash D (2019) Engineered human platelet-derived microparticles as natural vectors for targeted drug delivery. Oncotarget 10(56):5835–5846

    Article  Google Scholar 

  12. Ratajczak MZ, Ratajczak J (2020) Extracellular microvesicles/exosomes: discovery, disbelief, acceptance, and the future? Leukemia. https://doi.org/10.1038/s41375-020-01041-z

    Article  Google Scholar 

  13. Akbar N, Azzimato V, Choudhury RP, Aouadi M (2019) Extracellular vesicles in metabolic disease. Diabetologia 62(12):2179–2187. https://doi.org/10.1007/s00125-019-05014-5

    Article  Google Scholar 

  14. Melki I, Tessandier N, Zufferey A, Boilard E (2017) Platelet microvesicles in health and disease. Platelets 28(3):214–221. https://doi.org/10.1080/09537104.2016.1265924

    Article  CAS  Google Scholar 

  15. Pardo F, Villalobos-Labra R, Sobrevia B, Toledo F, Sobrevia L (2018) Extracellular vesicles in obesity and diabetes mellitus. Mol Aspects Med 60:81–91. https://doi.org/10.1016/j.mam.2017.11.010

    Article  CAS  Google Scholar 

  16. Hooten NN, Evans MK (2020) Extracellular vesicles as signaling mediators in type 2 diabetes mellitus. Am J Physiol Cell Physiol 3186(6):C1189–C1199. https://doi.org/10.1152/ajpcell.00536.2019

    Article  CAS  Google Scholar 

  17. Li S, Wei J, Zhang C, Li X, Meng W, Mo X et al (2016) Cell-derived microparticles in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Cell Physiol Biochem 39(6):2439–2450. https://doi.org/10.1159/000452512

    Article  CAS  Google Scholar 

  18. Agouni A, Andriantsitohaina R, Martinez M (2014) Microparticles as biomarkers of vascular dysfunction in metabolic syndrome and its individual components. Curr Vasc Pharmacol 12(3):483–492. https://doi.org/10.2174/1570161112666140423223148

    Article  CAS  Google Scholar 

  19. Zhang Y, Ma KL, Gong YX, Wang GH, Hu ZB, Liu L et al (2018) Platelet microparticles mediate glomerular endothelial injury in early diabetic nephropathy. J Am Soc Nephrol 29(11):2671–2695. https://doi.org/10.1681/ASN.2018040368

    Article  CAS  Google Scholar 

  20. Zhang C, Ou Q, Gu Y, Cheng G, Du R, Yuan L et al (2019) Circulating tissue factor-positive procoagulant microparticles in patients with type 1 diabetes. Diabetes Metab Syndr Obes 12:2819–2828. https://doi.org/10.2147/DMSO.S225761

    Article  CAS  Google Scholar 

  21. Gkaliagkousi E, Nikolaidou B, Gavriilaki E, Lazaridis A, Yiannaki E, Anyfanti P et al (2019) Increased erythrocyte- and platelet-derived microvesicles in newly diagnosed type 2 diabetes mellitus. Diab Vasc Dis Res 16(5):458–465. https://doi.org/10.1177/1479164119844691

    Article  CAS  Google Scholar 

  22. Stepanian A, Bourguignat L, Hennou S, Coupaye M, Hajage D, Salomon L et al (2013) Microparticle increase in severe obesity: not related to metabolic syndrome and unchanged after massive weight loss. Obesity (Silver Spring) 21(11):2236–2243. https://doi.org/10.1002/oby.20365

    Article  CAS  Google Scholar 

  23. Santilli F, Marchisio M, Lanuti P, Boccatonda A, Miscia S, Davi G (2016) Microparticles as new markers of cardiovascular risk in diabetes and beyond. Thromb Haemost 116(2):220–234. https://doi.org/10.1160/TH16-03-0176

    Article  Google Scholar 

  24. Wang GH, Ma KL, Zhang Y, Hu ZB, Liu L, Lu J et al (2019) Platelet microparticles contribute to aortic vascular endothelial injury in diabetes via the mTORC1 pathway. Acta Pharmacol Sin 40(4):468–476. https://doi.org/10.1038/s41401-018-0186-4

    Article  CAS  Google Scholar 

  25. Benameur T, Osman A, Parray A, Ait Hssain A, Munusamy S, Agouni A (2019) Molecular mechanisms underpinning microparticle-mediated cellular injury in cardiovascular complications associated with diabetes. Oxid Med Cell Longev 2019:6475187. https://doi.org/10.1155/2019/6475187

    Article  CAS  Google Scholar 

  26. Rodrigues KF, Pietrani NT, Fernandes AP, Bosco AA, de Sousa MCR, de Fátima OliveiraSilva I et al (2018) Circulating microparticles levels are increased in patients with diabetic kidney disease: a case-control research. Clin Chim Acta 479:48–55. https://doi.org/10.1016/j.cca.2017.12.048

    Article  CAS  Google Scholar 

  27. Cloutier N, Tan S, Boudreau LH, Cramb C, Subbaiah R, Lahey L et al (2013) The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes. EMBO Mol Med 5(2):235–249. https://doi.org/10.1002/emmm.201201846

    Article  CAS  Google Scholar 

  28. Boilard E, Nigrovic PA, Larabee K, Watts GF, Coblyn JS, Weinblatt ME et al (2010) Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327(5965):580–583. https://doi.org/10.1126/science.1181928

    Article  CAS  Google Scholar 

  29. Teoh NC, Ajamieh H, Wong HJ, Croft K, Mori T, Allison AC et al (2014) Microparticles mediate hepatic ischemia-reperfusion injury and are the targets of diannexin (ASP8597). PLoS ONE 9(9):e104376. https://doi.org/10.1371/journal.pone.0104376

    Article  CAS  Google Scholar 

  30. Barry OP, Praticò D, Savani RC, FitzGerald GA (1998) Modulation of monocyte-endothelial cell interactions by platelet microparticles. J Clin Invest 102(1):136–144. https://doi.org/10.1172/JCI2592

    Article  CAS  Google Scholar 

  31. Qu M, Zou X, Fang F, Wang S, Xu L, Zeng Q et al (2020) Platelet-derived microparticles enhance megakaryocyte differentiation and platelet generation via miR-1915–3p. Nat Commun. https://doi.org/10.1038/s41467-020-18802-0

    Article  Google Scholar 

  32. Liang C, Huang J, Luo P, Wang Z, He J, Wu S et al (2020) Platelet-derived microparticles mediate the intra-articular homing of mesenchymal stem cells in early-stage cartilage lesions. Stem Cells Dev 29(7):414–424. https://doi.org/10.1089/scd.2019.0137

    Article  CAS  Google Scholar 

  33. Plantureux L, Mege D, Crescence L, Carminita E, Robert S, Cointe S et al (2020) The interaction of platelets with colorectal cancer cells inhibits tumor growth but promotes metastasis. Cancer Res 80(2):291–303. https://doi.org/10.1158/0008-5472.CAN-19-1181

    Article  CAS  Google Scholar 

  34. Laffont B, Corduan A, Ple H, Duchez AC, Cloutier N, Boilard E et al (2013) Activated platelets can deliver mRNA regulatory Ago2*microRNA complexes to endothelial cells via microparticles. Blood 122(2):253–261. https://doi.org/10.1182/blood-2013-03-492801

    Article  CAS  Google Scholar 

  35. Michael JV, Wurtzel JGT, Mao GF, Rao AK, Kolpakov MA, Sabri A et al (2017) Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth. Blood 130(5):567–580. https://doi.org/10.1182/blood-2016-11-751099

    Article  CAS  Google Scholar 

  36. Kyselova A, Elgheznawy A, Wittig I, Heidler J, Mann AW, Ruf W et al (2020) Platelet-derived calpain cleaves the endothelial protease-activated receptor 1 to induce vascular inflammation in diabetes. Basic Res Cardiol 115(6):75. https://doi.org/10.1007/s00395-020-00833-9

    Article  CAS  Google Scholar 

  37. Olumuyiwa-Akeredolu OO, Page MJ, Soma P, Pretorius E (2019) Platelets: emerging facilitators of cellular crosstalk in rheumatoid arthritis. Nat Rev Rheumatol 15(4):237–248. https://doi.org/10.1038/s41584-019-0187-9

    Article  Google Scholar 

  38. Giacomazzi A, Degan M, Calabria S, Meneguzzi A, Minuz P (2016) Antiplatelet agents inhibit the generation of platelet-derived microparticles. Front Pharmacol 7:314. https://doi.org/10.3389/fphar.2016.00314

    Article  CAS  Google Scholar 

  39. Chen Y, Xiao Y, Lin Z, Xiao X, He C, Bihl JC et al (2015) The role of circulating platelets microparticles and platelet parameters in acute ischemic stroke patients. J Stroke Cerebrovasc Dis 24(10):2313–2320. https://doi.org/10.1016/j.jstrokecerebrovasdis.2015.06.018

    Article  Google Scholar 

  40. Cheng G, Shan XF, Wang XL, Dong WW, Li Z, Liu XH et al (2017) Endothelial damage effects of circulating microparticles from patients with stable angina are reduced by aspirin through ERK/p38 MAPKs pathways. Cardiovasc Ther 35(4):e12273. https://doi.org/10.1111/1755-5922.12273

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to all participants for their efforts.

Funding

This study was supported by the National Natural Science Foundation of China (82170736, 81970629), the Project for Jiangsu Provincial Medical Talent (ZDRCA2016077), the Fundamental Research Funds for the Central Universities (3224002110D), and the Jiangsu Province Ordinary University Graduate Research Innovation Project (SJCX20-0055).

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Authors and Affiliations

  1. Institute of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China

    Si Jia Huang, Gui Hua Wang, Jian Lu, Pei Pei Chen, Jia Xiu Zhang, Xue Qi Li, Ben Yin Yuan, Xiao Qi Liu, Ting Ting Jiang, Meng Ying Wang, Wen Tao Liu & Bi Cheng Liu

  2. Renal Department, Nanjing First Hospital, Nanjing, 210006, China

    Yang Zhang

  3. John Moorhead Research Laboratory, Department of Renal Medicine, University College London (UCL) Medical School, Royal Free Campus, London, NW3 2PF, UK

    Xiong Zhong Ruan

  4. Department of Nephrology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Kun Ling Ma

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  1. Si Jia Huang
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Contributions

KLM: designed the study. SJH, YZ, GHW, JL, PPC, JXZ, and XQL: performed the experiments and established the genetically modified mouse models. BYY, LQL, TTJ, MYW and WTL: analyzed the data. XZR and BCL: drafted and revised the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Kun Ling Ma.

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Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Zhongda Hospital, Affiliated to Southeast University (No. 2016ZDSYLL003.0).

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Huang, S.J., Zhang, Y., Wang, G.H. et al. Deposition of platelet-derived microparticles in podocytes contributes to diabetic nephropathy. Int Urol Nephrol 55, 355–366 (2023). https://doi.org/10.1007/s11255-022-03332-z

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  • DOI: https://doi.org/10.1007/s11255-022-03332-z

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