Skip to main content
SpringerLink
Log in

Glomerular endothelial cells and podocytes can express CD80 in patients with minimal change disease during relapse

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

Urinary CD80 has emerged as potential biomarker in idiopathic nephrotic syndrome (INS). However, its cellular source remains controversial. The aim of the study was to assess whether CD80 is truly expressed by glomerular cells in INS patients during relapse and in the LPS mouse model of podocyte injury.

Methods

The presence of CD80 in glomeruli was evaluated by combining immunostaining, immunogold labeling, and in situ hybridization techniques.

Results

CD80 was present along the surface of glomerular endothelial cells (GEC) and rarely in podocytes in six of nine minimal change disease (MCD) patients in relapse, two of eleven patients with focal segmental glomerulosclerosis in relapse, and absent in controls. In mice, CD80 was upregulated at mRNA and protein level in GEC and podocytes, in a similar pattern to that seen in MCD patients.

Conclusions

Glomerular endothelial cells and podocytes can express CD80 in patients with MCD during relapse. A better understanding of the role of CD80 in glomerular cells may provide further insights into the mechanisms of proteinuria in INS.

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

References

  1. Barisoni L, Schnaper HW, Kopp JB (2007) A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases. CJASN 2(3):529–542

    Article  Google Scholar 

  2. Vivarelli M, Massella L, Ruggiero B, Emma F (2017) Minimal change disease. CJASN 12(2):332–345. https://doi.org/10.2215/CJN.05000516

    Article  CAS  PubMed  Google Scholar 

  3. Colucci M, Corpetti G, Emma F, Vivarelli M (2018) Immunology of idiopathic nephrotic syndrome. Pediatr Nephrol 33(4):573–584. https://doi.org/10.1007/s00467-017-3677-5

    Article  PubMed  Google Scholar 

  4. Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, Rastaldi MP, Calvaresi N, Watanabe H, Schwarz K, Faul C, Kretzler M, Davidson A, Sugimoto H, Kalluri R, Sharpe AH, Kreidberg JA, Mundel P (2004) Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest 113(10):1390–1397

    Article  CAS  Google Scholar 

  5. Ishimoto T, Shimada M, Gabriela G, Kosugi T, Sato W, Lee PY, Lanaspa MA, Rivard C, Maruyama S, Garin EH, Johnson RJ (2013) Toll-like receptor 3 ligand, polyIC, induces proteinuria and glomerular CD80, and increases urinary CD80 in mice. Nephrol Dial Transplant 28(6):1439–1446. https://doi.org/10.1093/ndt/gfs543

    Article  CAS  PubMed  Google Scholar 

  6. Jain N, Khullar B, Oswal N, Banoth B, Joshi P, Ravindran B, Panda S, Basak S, George A, Rath S, Bal V, Sopory S (2016) TLR-mediated albuminuria needs TNFalpha-mediated cooperativity between TLRs present in hematopoietic tissues and CD80 present on non-hematopoietic tissues in mice. Dis Model Mech 9(6):707–717. https://doi.org/10.1242/dmm.023440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rivard CJ, Tanabe T, Lanaspa MA, Watanabe H, Nomura S, Andres-Hernando A, Garth K, Sekijima M, Ishimoto T, Ariyoshi Y, Garcia GE, Shah J, Lennan B, Tasaki M, Pomposelli T, Shimizu A, Sachs DH, Johnson RJ, Yamada K (2018) Upregulation of CD80 on glomerular podocytes plays an important role in development of proteinuria following pig-to-baboon xeno-renal transplantation - an experimental study. Transpl Int 31(10):1164–1177. https://doi.org/10.1111/tri.13273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shimada M, Ishimoto T, Lee PY, Lanaspa MA, Rivard CJ, Roncal-Jimenez CA, Wymer DT, Yamabe H, Mathieson PW, Saleem MA, Garin EH, Johnson RJ (2012) Toll-like receptor 3 ligands induce CD80 expression in human podocytes via an NF-kappaB-dependent pathway. Nephrol Dial Transplant 27(1):81–89. https://doi.org/10.1093/ndt/gfr271

    Article  CAS  PubMed  Google Scholar 

  9. Gurkan S, Cabinian A, Lopez V, Bhaumik M, Chang JM, Rabson AB, Mundel P (2013) Inhibition of type I interferon signalling prevents TLR ligand-mediated proteinuria. J Pathol 231(2):248–256

    Article  CAS  Google Scholar 

  10. Yu CC, Fornoni A, Weins A, Hakroush S, Maiguel D, Sageshima J, Chen L, Ciancio G, Faridi MH, Behr D, Campbell KN, Chang JM, Chen HC, Oh J, Faul C, Arnaout MA, Fiorina P, Gupta V, Greka A, Burke GW 3rd, Mundel P (2013) Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med 369(25):2416–2423. https://doi.org/10.1056/NEJMoa1304572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Garin EH, Diaz LN, Mu W, Wasserfall C, Araya C, Segal M, Johnson RJ (2009) Urinary CD80 excretion increases in idiopathic minimal-change disease. J Am Soc Nephrol 20(2):260–266. https://doi.org/10.1681/ASN.2007080836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Garin EH, Mu W, Arthur JM, Rivard CJ, Araya CE, Shimada M, Johnson RJ (2010) Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis. Kidney Int 78(3):296–302. https://doi.org/10.1038/ki.2010.143

    Article  CAS  PubMed  Google Scholar 

  13. Cara-Fuentes G, Wei C, Segarra A, Ishimoto T, Rivard C, Johnson RJ, Reiser J, Garin EH (2014) CD80 and suPAR in patients with minimal change disease and focal segmental glomerulosclerosis: diagnostic and pathogenic significance. Pediatr Nephrol 29(8):1363–1371. https://doi.org/10.1007/s00467-013-2679-1

    Article  PubMed  Google Scholar 

  14. Cara-Fuentes G, Wasserfall CH, Wang H, Johnson RJ, Garin EH (2014) Minimal change disease: a dysregulation of the podocyte CD80-CTLA-4 axis? Pediatr Nephrol 29(12):2333–2340. https://doi.org/10.1007/s00467-014-2874-8

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ling C, Liu X, Shen Y, Chen Z, Fan J, Jiang Y, Meng Q (2015) Urinary CD80 levels as a diagnostic biomarker of minimal change disease. Pediatr Nephrol 30(2):309–316. https://doi.org/10.1007/s00467-014-2915-3

    Article  PubMed  Google Scholar 

  16. Mishra OP, Kumar R, Narayan G, Srivastava P, Abhinay A, Prasad R, Singh A, Batra VV (2017) Toll-like receptor 3 (TLR-3), TLR-4 and CD80 expression in peripheral blood mononuclear cells and urinary CD80 levels in children with idiopathic nephrotic syndrome. Pediatr Nephrol 32(8):1355–1361. https://doi.org/10.1007/s00467-017-3613-8

    Article  PubMed  Google Scholar 

  17. Bhatia D, Sinha A, Hari P, Sopory S, Saini S, Puraswani M, Saini H, Mitra DK, Bagga A (2018) Rituximab modulates T- and B-lymphocyte subsets and urinary CD80 excretion in patients with steroid-dependent nephrotic syndrome. Pediatr Res 84(4):520–526. https://doi.org/10.1038/s41390-018-0088-7

    Article  CAS  PubMed  Google Scholar 

  18. Ling C, Liu X, Shen Y, Chen Z, Fan J, Jiang Y, Meng Q (2018) Urinary CD80 excretion is a predictor of good outcome in children with primary nephrotic syndrome. Pediatr Nephrol 33(7):1183–1187. https://doi.org/10.1007/s00467-018-3885-7

    Article  PubMed  Google Scholar 

  19. Garin EH, Reiser J, Cara-Fuentes G, Wei C, Matar D, Wang H, Alachkar N, Johnson RJ (2015) Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis. Pediatr Nephrol 30(3):469–477. https://doi.org/10.1007/s00467-014-2957-6

    Article  PubMed  Google Scholar 

  20. Isom R, Shoor S, Higgins J, Cara-Fuentes G, Johnson RJ (2019) Abatacept in steroid-dependent minimal change disease and CD80-uria. Kidney Int Rep 4(9):1349–1353. https://doi.org/10.1016/j.ekir.2019.05.1155

    Article  PubMed  PubMed Central  Google Scholar 

  21. Larsen CP, Messias NC, Walker PD (2014) B7-1 immunostaining in proteinuric kidney disease. Am J Kidney Dis 64(6):1001–1003. https://doi.org/10.1053/j.ajkd.2014.07.023

    Article  PubMed  Google Scholar 

  22. Novelli R, Gagliardini E, Ruggiero B, Benigni A, Remuzzi G (2016) Any value of podocyte B7-1 as a biomarker in human MCD and FSGS? Am J Physiol Renal Physiol 310(5):F335–F341. https://doi.org/10.1152/ajprenal.00510.2015

    Article  CAS  PubMed  Google Scholar 

  23. Lee SW, Baek SH, Paik JH, Kim S, Na KY, Chae DW, Chin HJ (2017) Tubular B7-1 expression parallels proteinuria levels, but not clinical outcomes in adult minimal change disease patients. Sci Rep 7:41859. https://doi.org/10.1038/srep41859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Alwadhi RK, Mathew JL, Rath B (2004) Clinical profile of children with nephrotic syndrome not on glucorticoid therapy, but presenting with infection. J Pediatr Child Health 40(1–2):28–32

    Article  CAS  Google Scholar 

  25. Cleuren ACA, van der Ent MA, Jiang H, Hunker KL, Yee A, Siemieniak DR, Molema G, Aird WC, Ganesh SK, Ginsburg D (2019) The in vivo endothelial cell translatome is highly heterogeneous across vascular beds. Proc Natl Acad Sci U S A 116(47):23618–23624. https://doi.org/10.1073/pnas.1912409116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Minamikawa S, Nozu K, Maeta S, Yamamura T, Nakanishi K, Fujimura J, Horinouchi T, Nagano C, Sakakibara N, Nagase H, Shima H, Noda K, Ninchoji T, Kaito H, Iijima K (2018) The utility of urinary CD80 as a diagnostic marker in patients with renal diseases. Sci Rep 8(1):17322. https://doi.org/10.1038/s41598-018-35798-227

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang P, Zhou S, Ge Y, Lu M, Liu Z, Gong R (2017) Valproate hampers podocyte acquisition of immune phenotypes via intercepting the GSK3beta facilitated NFkB activation. Oncotarget 8(51):88332–88344. https://doi.org/10.18632/oncotarget.19917

    Article  PubMed  PubMed Central  Google Scholar 

  28. Baye E, Gallazzini M, Delville M, Legendre C, Terzi F, Canaud G (2016) The costimulatory receptor B7-1 is not induced in injured podocytes. Kidney Int 90(5):1037–1044. https://doi.org/10.1016/j.kint.2016.06.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen W, Wu Y, Zhang G, Wang M, Yang H, Li Q (2018) GammadeltaT cells exacerbate podocyte injury via the CD28/B7-1-phosphor-SRC kinase pathway. Biomed Res Int:5647120. https://doi.org/10.1155/2018/5647120

  30. Khullar B, Balyan R, Oswal N, Jain N, Sharma A, Abdin MZ, Bagga A, Bhatnagar S, Wadhwa N, Natchu UCM, George A, Rath S, Bal V, Sopory S (2018) Interaction of CD80 with Neph1: a potential mechanism of podocyte injury. Clin Exp Nephrol 22(3):508–516. https://doi.org/10.1007/s10157-017-1489-3

    Article  CAS  PubMed  Google Scholar 

  31. MacDonald NE, Wolfish N, McLaine P, Phipps P, Rossier E (1986) Role of respiratory viruses in exacerbations of primary nephrotic syndrome. J Pediatr 108(3):378–382

    Article  CAS  Google Scholar 

  32. Tkaczyk M, Czupryniak A, Owczarek D, Lukamowicz J, Nowicki M (2008) Markers of endothelial dysfunction in children with idiopathic nephrotic syndrome. Am J Nephrol 28(2):197–202

    Article  CAS  Google Scholar 

  33. Sharma B, Saha A, Dubey NK, Kapoor K, Anubhuti BVV, Upadhayay AD (2014) Endothelial dysfuntion in children with idiopathic nephrotic syndrome. Atherosclerosis 233(2):704–706. https://doi.org/10.1016/j.atherosclerosis.2014.01.055

    Article  CAS  PubMed  Google Scholar 

  34. Chaves MMS, Mendes MS, Schwermann MP, Queiroz R, Coelho RF, Salmito FTS, Meneses GC, Martins AMC, Moreira ACOM, Libório AB (2018) Angiopoietin-2: a potential mediator of the glycocalyx injury in adult nephrotic patients. J Clin Med 7(11). https://doi.org/10.3390/jcm7110401

  35. Ohl K, Eberhardt C, Spink C, Zahn K, Wagner N, Eggermann T, Kemper MJ, Querfeld U, Hoppe B, Harendza S, Tenbrock K (2014) CTLA4 polymorphisms in minimal change nephrotic syndrome in children: a case-control study. Am J Kidney Dis 63(6):1074–1075. https://doi.org/10.1053/j.ajkd.2014.01.427

    Article  CAS  PubMed  Google Scholar 

  36. Benz K, Buttner M, Dittrich K, Campean V, Dotsch J, Amann K (2010) Characterisation of renal immune cell infiltrates in children with nephrotic syndrome. Pediatr Nephrol 25(7):1291–1298. https://doi.org/10.1007/s00467-010-1507-0

    Article  PubMed  Google Scholar 

  37. Uchida K, Suzuki K, Iwamoto M, Kawachi H, Ohno M, Horita S, Nitta K (2008) Decreased tyrosine phosphorylation of nephrin in rat and human nephrosis. Kidney Int 73(8):926–932. https://doi.org/10.1038/ki.2008.19

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. Eduardo H Garin for his suggestions.

Funding

This study was supported by NIH K12 HD028820-27 to GCF.

Author information

Authors and Affiliations

  1. Division of Pediatric Nephrology, Department of Pediatrics, University of Michigan, MSRB-2, Room 1574, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA

    Gabriel Cara-Fuentes

  2. Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, USA

    Madhusudan Venkatareddy, Rakesh Verma & Puneet Garg

  3. Division of Nephrology, Hospital Vall d’Hebron, Barcelona, Spain

    Alfons Segarra

  4. Life Sciences Institute, University of Michigan, Ann Arbor, USA

    Audrey C. Cleuren

  5. School of Medicine, University of Granada, Granada, Spain

    Alfonso Martínez-Ramos

  6. Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, USA

    Richard J. Johnson

Authors
  1. Gabriel Cara-Fuentes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Madhusudan Venkatareddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rakesh Verma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alfons Segarra
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Audrey C. Cleuren
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alfonso Martínez-Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Richard J. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Puneet Garg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gabriel Cara-Fuentes.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

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

Electronic supplementary material

ESM 1

(PPTX 191 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cara-Fuentes, G., Venkatareddy, M., Verma, R. et al. Glomerular endothelial cells and podocytes can express CD80 in patients with minimal change disease during relapse. Pediatr Nephrol 35, 1887–1896 (2020). https://doi.org/10.1007/s00467-020-04541-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-020-04541-3

Keywords

Search

Navigation