Skip to main content

Advertisement

SpringerLink
Log in

Lack of Rab27a attenuates foam cell formation and macrophage inflammation in uremic apolipoprotein E knockout mice

  • Original Paper
  • Published:
Journal of Molecular Histology Aims and scope Submit manuscript

A Correction to this article was published on 14 July 2023

This article has been updated

Abstract

As the most common cardiovascular disease, atherosclerosis (AS), is a leading cause of high mortality in patients with chronic renal failure. Rab27a has been reported to regulate the progression of cardiovascular and renal diseases. Nevertheless, little studies investigated the role and mechanism of Rab27a in uremic-accelerated AS (UAAS). An animal model of UAAS was established in apolipoprotein E knockout (apoE−/−) mice using 5/6 nephrectomy (NX). We conducted in vitro and in vivo functional experiments to explore the role of Rab27a in UAAS, including the presence of oxidized low-density lipoprotein (ox-LDL). Rab27a expression was upregulated in the plaque tissues of NX apoE−/− mice. The knockout of Rab27a (Rab27a−/−) reduced AS-induced artery injury, as manifested by the reductions of plaque area, collagen deposition, inflammation and lipid droplet. Besides, cholesterol efflux was increased, while the expression of lipid metabolism-related proteins and the secretions of pro-inflammatory factors were decreased in ox-LDL-induced NX Rab27a−/− apoE−/− mice group. Further, Rab27a deletion inhibited the activation of nuclear factor κB (NF-κB) pathway. In conclusion, our study indicated that Rab27a deficiency attenuated foam cell formation and macrophage inflammation, depending on the NF-κB pathway activation, to inhibit AS progression in uremic apoE−/− mice. This finding may provide a new targeting strategy for UAAS therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

The data set used and/or analyzed in the current study can be obtained from the corresponding author upon reasonable request.

Change history

References

  • An HJ, Song DH, Koh HM, Ko GH, Lee JH, Kim DC, Yang JW, Kim MH, Seo DH, Jang SM, Lee JS (2019) RAB27A is an independent prognostic factor in clear cell renal cell carcinoma. Biomark Med 13(4):239–247

    Article  CAS  PubMed  Google Scholar 

  • Andrés-Manzano MJ, Andrés V, Dorado B (2015) Oil red O and hematoxylin and eosin staining for quantification of atherosclerosis burden in mouse aorta and aortic root. Methods Mol Biol 1339(6):85–99

    Article  PubMed  Google Scholar 

  • Aono J, Suzuki J, Iwai M, Horiuchi M, Nagai T, Nishimura K, Inoue K, Ogimoto A, Okayama H, Higaki J (2012) Deletion of the angiotensin II type 1a receptor prevents atherosclerotic plaque rupture in apolipoprotein E−/− mice. Arterioscler Thromb Vasc Biol 32(6):1453–1459

    Article  CAS  PubMed  Google Scholar 

  • Bhuin T, Roy JK (2009) Rab11 is required for embryonic nervous system development in Drosophila. Cell Tissue Res 335(2):349–356

    Article  CAS  PubMed  Google Scholar 

  • Bisgaard LS, Bosteen MH, Fink LN, Sorensen CM, Rosendahl A, Mogensen CK, Rasmussen SE, Rolin B, Nielsen LB, Pedersen TX (2016) Liraglutide reduces both atherosclerosis and kidney inflammation in moderately uremic LDLr−/− mice. PLoS ONE 11(12):e0168396

    Article  PubMed  PubMed Central  Google Scholar 

  • Chistiakov DA, Melnichenko AA, Myasoedova VA, Grechko AV, Orekhov AN (2017) Mechanisms of foam cell formation in atherosclerosis. J Mol Med 95(11):1153–1165

    Article  CAS  PubMed  Google Scholar 

  • Dai Y, Wu X, Dai D, Li J, Mehta JL (2018) MicroRNA-98 regulates foam cell formation and lipid accumulation through repression of LOX-1. Redox Biol 16:255–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ding X, Jing N, Shen A, Guo F, Zhao Y (2020) MiR-21-5p in macrophage-derived extracellular vesicles affects podocyte pyroptosis in diabetic nephropathy by regulating A20. J Endocrinol Invest 44:1175

    Article  PubMed  Google Scholar 

  • Feng SJ, Li H, Wang SX (2015) Lower hydrogen sulfide is associated with cardiovascular mortality, which involves cPKCβII/Akt pathway in chronic hemodialysis patients. Blood Purif 40(3):260–269

    Article  CAS  PubMed  Google Scholar 

  • Feng F, Jiang Y, Lu H, Lu X, Wang S, Wang L, Wei M, Lu W, Du Z, Ye Z, Yang G, Yuan F, Ma Y, Lei X, Lu Z (2016) Rab27A mediated by NF-κB promotes the stemness of colon cancer cells via up-regulation of cytokine secretion. Oncotarget 7(39):63342–63351

    Article  PubMed  PubMed Central  Google Scholar 

  • Feng Y, Zhong X, Tang TT, Wang C, Wang LT, Li ZL, Ni HF, Wang B, Wu M, Liu D, Liu H, Tang RN, Liu BC, Lv LL (2020) Rab27a dependent exosome releasing participated in albumin handling as a coordinated approach to lysosome in kidney disease. Cell Death Dis 11(7):513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerber PP, Cabrini M, Jancic C, Paoletti L, Banchio C, von Bilderling C, Sigaut L, Pietrasanta LI, Duette G, Freed EO, Basile Gde S, Moita CF, Moita LF, Amigorena S, Benaroch P, Geffner J, Ostrowski M (2015) Rab27a controls HIV-1 assembly by regulating plasma membrane levels of phosphatidylinositol 4,5-bisphosphate. J Cell Biol 209(3):435–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glaucylara GR, Peter L (2018) Atherosclerosis and inflammation: overview and updates. Clin Sci 132(12):1243–1252

    Article  Google Scholar 

  • Gross T, Wack G, Syhr KMJ, Tolmachova T, Seabra MC, Geisslinger G, Niederberger E, Schmidtko A, Kallenborn-Gerhardt W (2020) Rab27a contributes to the processing of inflammatory pain in mice. Cells 9(6):1488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo K, Hu L, Xi D, Zhao J, Liu J, Luo T, Ma Y, Lai W, Guo Z (2018) PSRC1 overexpression attenuates atherosclerosis progression in apoE -/ mice by modulating cholesterol transportation and inflammation. J Mol Cell Cardiol 116:69–80

    Article  CAS  PubMed  Google Scholar 

  • Jordens I, Marsman M, Kuijl C, Neefjes J (2005) Rab proteins, connecting transport and vesicle fusion. Traffic 6(12):1070–1077

    Article  CAS  PubMed  Google Scholar 

  • Kaseda R, Tsuchida Y, Yang H-C, Yancey PG, Zhong J, Tao H, Bian A, Fogo AB, Linton MRF, Fazio S (2018) Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism. BMC Nephrol 19(1):17

    Article  PubMed  PubMed Central  Google Scholar 

  • Layoun A, Samba M, Santos MM (2015) Isolation of murine peritoneal macrophages to carry out gene expression analysis upon toll-like receptors stimulation. J Vis Exp. https://doi.org/10.3791/52749

    Article  PubMed  PubMed Central  Google Scholar 

  • Li ZG, Scott MJ, Brzóska T, Sundd P, Li YH, Billiar TR, Wilson MA, Wang P, Fan J (2018) Lung epithelial cell-derived IL-25 negatively regulates LPS-induced exosome release from macrophages. Military Med Res 5(1):24

    Article  Google Scholar 

  • Li S, Jia Y, Xue M, Hu F, Zheng Z, Zhang S, Ren S, Yang Y, Si Z, Wang L, Guan M, Xue Y (2020) Inhibiting Rab27a in renal tubular epithelial cells attenuates the inflammation of diabetic kidney disease through the miR-26a-5p/CHAC1/NF-kB pathway. Life Sci 261:118347

    Article  CAS  PubMed  Google Scholar 

  • Libby P, Ridker PM, Hansson GK (2012) Inflammation in atherosclerosis. J Assoc Physicians India 32(9):2045–2051

    CAS  Google Scholar 

  • Lightbody RJ, Taylor JMW, Dempsie Y, Graham A (2020) MicroRNA sequences modulating inflammation and lipid accumulation in macrophage “foam” cells: implications for atherosclerosis. World J Cardiol 12(7):303–333

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu J, Gong X, Zhu X, Xue D, Liu Y, Wang P (2017a) Rab27A overexpression promotes bladder cancer proliferation and chemoresistance through regulation of NF-κB signaling. Oncotarget 8(43):75272–75283

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu Z, Zhu H, Dai X, Wang C, Zou MH (2017b) Macrophage liver kinase B1 inhibits foam cell formation and atherosclerosis. Circ Res 121(9):1047. https://doi.org/10.1161/CIRCRESAHA.117.311546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408

    Article  CAS  PubMed  Google Scholar 

  • Luo Y, Yu MH, Yan YR, Zhou Y, Qin SL, Huang YZ, Qin J, Zhong M (2020) Rab27A promotes cellular apoptosis and ROS production by regulating the miRNA-124-3p/STAT3/RelA signalling pathway in ulcerative colitis. J Cell Mol Med 19:11330

    Article  Google Scholar 

  • Martinez-Arroyo O, Ortega A, Perez-Hernandez J, Chaves FJ, Cortes R (2020) Rab-rabphilin system in injured human podocytes stressed by glucose overload and angiotensin II. Am J Physiol Renal Physiol 319(2):F178

    Article  PubMed  PubMed Central  Google Scholar 

  • Nyandwi JB, Ko YS, Jin H, Yun SP, Park SW, Kim HJ (2021) Rosmarinic acid increases macrophage cholesterol efflux through regulation of ABCA1 and ABCG1 in different mechanisms. Int J Mol Sci 22(16):8791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patel KM, Strong A, Tohyama J, Jin X, Morales CR, Billheimer J, Millar J, Kruth H, Rader DJ (2015) Macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis. Circ Res 116(5):789–796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plotkin JD, Elias MG, Dellinger AL, Kepley CL (2017) NF-κB inhibitors that prevent foam cell formation and atherosclerotic plaque accumulation. Nanomed Nanotechnol Biol Med 13(6):2037–2048

    Article  CAS  Google Scholar 

  • Schwarz A, Bonaterra GA, Schwarzbach H, Kinscherf RJJoBS (2017) Oxidized LDL-induced JAB1 influences NF-κB independent inflammatory signaling in human macrophages during foam cell formation. J Biomed Sci 24(1):12

    Article  PubMed  PubMed Central  Google Scholar 

  • Scott RP, Quaggin SE (2015) The cell biology of renal filtration. J Cell Biol 209(2):199–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen Y, Yuan Z, Yin A, Liu Y, Xiao Y, Wu Y, Wang L, Liang X, Zhao Y, Tian Y (2011) Antiatherogenic effect of pioglitazone on uremic apolipoprotein E knockout mice by modulation of the balance of regulatory and effector T cells. Atherosclerosis 218(2):330–338

    Article  CAS  PubMed  Google Scholar 

  • Shi H, Zhang C, Pasupuleti V, Hu X, Prosdocimo DA, Wu W, Qing Y, Wu S, Mohammad H, Gerson SL (2017) CCN3 regulates macrophage foam cell formation and atherosclerosis. Am J Pathol 187(6):1230–1237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shimada-Sugawara M, Sakai E, Okamoto K, Fukuda M, Izumi T, Yoshida N, Tsukuba T (2015) Rab27A regulates transport of cell surface receptors modulating multinucleation and lysosome-related organelles in osteoclasts. Sci Rep 5:1

    Article  Google Scholar 

  • Verma K, Srivastava VK, Datta S (2020) Rab GTPases take centre stage in understanding Entamoeba histolytica biology. Small GTPases 11(5):320–333

    Article  PubMed  Google Scholar 

  • Wan X, Chen X, Liu L, Zhao Y, Huang W-J, Zhang Q, Miao G-G, Chen W, Xie H-G, Cao C-C (2013) Berberine ameliorates chronic kidney injury caused by atherosclerotic renovascular disease through the suppression of NFκB signaling pathway in rats. PLoS ONE 8(3):e59794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Q, Ni Q, Wang X, Zhu H, Wang Z, Huang JJMO (2015) High expression of RAB27A and TP53 in pancreatic cancer predicts poor survival. Med Oncol 32(1):372

    Article  PubMed  Google Scholar 

  • Wang C, Yang W, Liang X, Song W, Lin J, Sun Y, Guan X (2020) MicroRNA-761 modulates foam cell formation and inflammation through autophagy in the progression of atherosclerosis. Mol Cell Biochem 475:135

    Article  Google Scholar 

  • Wayne EC, Long C, Haney MJ, Batrakova EV, Kabanov AV (2019) Targeted delivery of siRNA lipoplexes to cancer cells using macrophage transient horizontal gene transfer. Adv Sci 6:19

    Article  Google Scholar 

  • Xiong R, Lu X, Song J, Li H, Wang S (2019a) Molecular mechanisms of hydrogen sulfide against uremic accelerated atherosclerosis through cPKCβII/Akt signal pathway. BMC Nephrol 20(1):358

    Article  PubMed  PubMed Central  Google Scholar 

  • Xiong R, Lu X, Song J, Li H, Wang SJBN (2019b) Molecular mechanisms of hydrogen sulfide against uremic accelerated atherosclerosis through cPKCβII/Akt signal pathway. BMC Nephrol 20(1):1–7

    Article  Google Scholar 

  • Yu X-H, Zheng X-L, Tang C-K (2015) Nuclear factor-κB activation as a pathological mechanism of lipid metabolism and atherosclerosis. Adv Clin Chem 70:1–30

    Article  CAS  PubMed  Google Scholar 

  • Yu F, Wu W, Liang M, Huang Y, Chen C (2020) Prognostic significance of Rab27A and Rab27B expression in esophageal squamous cell cancer. Cancer Manag Res 12:6353–6361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang C, Qin J-J, Gong F-H, Tong J-J, Cheng W-L, Wang H, Zhang Y, Zhu X, She Z-G, Xia H (2018) Mindin deficiency in macrophages protects against foam cell formation and atherosclerosis by targeting LXR-β. Clin Sci 132(11):1199–1213

    Article  CAS  Google Scholar 

  • Zhong Y, Liu C, Feng J, Li JF, Fan ZC (2020) Curcumin affects ox-LDL-induced IL-6, TNF-α, MCP-1 secretion and cholesterol efflux in THP-1 cells by suppressing the TLR4/NF-κB/miR33a signaling pathway. Exp Ther Med 20(3):1856–1870

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou M, Ren P, Zhang Y, Li S, Li M, Li P, Shang J, Liu W, Liu H (2019) Shen-Yuan-Dan capsule attenuates atherosclerosis and foam cell formation by enhancing autophagy and inhibiting PI3K/Akt/mTORC1 signaling pathway. Front Pharmacol 10:603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zuo Y, Yancey P, Castro I, Khan W, Motojima M, Ichikawa I, Fogo AB, Linton MF, Fazio S, Kon V (2009) Renal dysfunction potentiates foam cell formation by repressing ABCA1. Arterioscler Thromb Vasc Biol 29(9):1277–1282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not Applicable.

Funding

This research was supported by National Natural Science Foundation of China (Grant No. 81200541), ‘PRO•Run’ Fund of the Nephrology Group of CEBM (Grant No. KYS2021-03-02-9), Key Research and Development Program of Shaanxi (Grant No. 2020KW-043), Xi’an Science and Technology Project (Grant No. 201805095YX3SF29), The Fundamental Research Funds for the Central Universities (Grant No. xjj2017047), Shaanxi Provincial Health and Family Planning Scientific Research Fund Project, China (Grant No. 2016D064) and China Scholarship Fund (Grant No. 201506285033).

Author information

Authors and Affiliations

  1. Department of Nephrology, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277, West Yanta Road, Yanta District, Shaanxi, 710061, Xi’an, China

    Yan Shen, Yajuan Gao, Jiani Fu, Cui Wang, Yali Tang & Shengnan Chen

  2. Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, China

    Yan Zhao

Authors
  1. Yan Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yajuan Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiani Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yali Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shengnan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yan Shen.

Ethics declarations

Conflict of interest

The authors declared that they had no competing interests to the research, authorship, and/or publication of this article.

Ethical approval

The study was approved by the institutional ethics committee for animal experiments of Xi’an Jiaotong University (No. 2012-600). And carried out in accordance with the guidelines of Laboratory Animal Management Regulations.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shen, Y., Gao, Y., Fu, J. et al. Lack of Rab27a attenuates foam cell formation and macrophage inflammation in uremic apolipoprotein E knockout mice. J Mol Histol 54, 183–193 (2023). https://doi.org/10.1007/s10735-023-10125-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10735-023-10125-w

Keywords

Search

Navigation