Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Other
    • ASN Publications
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • ASN Publications
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
Basic ResearchChronic Kidney Disease
You have accessRestricted Access

Factor H–Related Protein 1 Drives Disease Susceptibility and Prognosis in C3 Glomerulopathy

Bárbara Márquez-Tirado, Josué Gutiérrez-Tenorio, Agustín Tortajada, Laura Lucientes Continente, Fernando Caravaca-Fontán, Talat H. Malik, Raquel Roldán Montero, Sandra Elías, Ana Saiz Gonzalez, Gema Fernández-Juarez, Pilar Sánchez-Corral, Matthew C. Pickering, Manuel Praga, Santiago Rodríguez de Córdoba and Elena Goicoechea de Jorge
JASN May 2022, ASN.2021101318; DOI: https://doi.org/10.1681/ASN.2021101318
Bárbara Márquez-Tirado
1Department of Immunology, Complutense University and Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Josué Gutiérrez-Tenorio
1Department of Immunology, Complutense University and Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Agustín Tortajada
1Department of Immunology, Complutense University and Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laura Lucientes Continente
1Department of Immunology, Complutense University and Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Fernando Caravaca-Fontán
2Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Talat H. Malik
3Centre for Inflammatory Disease, Imperial College London, London, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Raquel Roldán Montero
4Instituto de Investigación Sanitaria–Fundación Jiménez Díaz, Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sandra Elías
5Nephrology Department, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ana Saiz Gonzalez
6Pathological Anatomy, Hospital Universitario Ramón y Cajal, Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ana Saiz Gonzalez
Gema Fernández-Juarez
7Nephrology Department, Hospital Universitario Fundación, Alcorcón, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pilar Sánchez-Corral
8Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew C. Pickering
3Centre for Inflammatory Disease, Imperial College London, London, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Matthew C. Pickering
Manuel Praga
2Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain
9Department of Medicine, Complutense University of Madrid, Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Santiago Rodríguez de Córdoba
10Center for Biological Research and Rare Disease Networking Biomedical Research Center, Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Santiago Rodríguez de Córdoba
Elena Goicoechea de Jorge
1Department of Immunology, Complutense University and Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Elena Goicoechea de Jorge
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

Visual Abstract

Figure
  • Download figure
  • Open in new tab
  • Download powerpoint

Significance Statement

Mutations in factor H–related protein 1 (FHR-1) that result in duplication of its dimerization domain associate with the chronic renal disease C3 glomerulopathy (C3G), which is characterized by complement dysregulation. The molecular basis for this association is only partially understood. The authors show that these FHR-1 mutations enhance FHR-1’s binding to C3-activated fragments on opsonized surfaces and promote an excessive complement activation that overcomes FH regulation. They also show that elevated levels of FHR-1 associate with poor renal prognosis for patients with C3G, whereas a genetic deficiency of FHR-1 offers protection against C3G development. These findings advance our understanding of C3G pathogenesis and suggest that inhibition of FHR-1 may have therapeutic potential in C3G.

Abstract

Background C3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H–related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear.

Methods Using in vitro and in vivo assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain. To assess the FHR-1 mutant’s association with disease susceptibility and renal prognosis, we also analyzed CFHR1 copy number variations and FHR-1 plasma levels in two Spanish C3G cohorts and in a control population.

Results Duplication of the dimerization domain conferred FHR-1 with an increased capacity to interact with C3-opsonized surfaces, which resulted in an excessive activation of the alternative pathway. This activation does not involve C3b binding competition with factor H. These findings support a scenario in which mutant FHR-1 binds to C3-activated fragments and recruits native C3 and C3b; this leads to formation of alternative pathway C3 convertases, which increases deposition of C3b molecules, overcoming FH regulation. This suggests that a balanced FHR-1/FH ratio is crucial to control complement amplification on opsonized surfaces. Consistent with this conceptual framework, we show that the genetic deficiency of FHR-1 or decreased FHR-1 in plasma confers protection against developing C3G and associates with better renal outcome.

Conclusions Our findings explain how FHR-1 mutants with duplicated dimerization domains result in predisposition to C3G. They also provide a pathogenic mechanism that may be shared by other diseases, such as IgA nephropathy or age-related macular degeneration, and identify FHR-1 as a potential novel therapeutic target in C3G.

  • C3 glomerulopathy
  • complement
  • factor H-related protein 1
  • glomerular disease
  • disease susceptibility
  • prognosis
  • genetic renal disease
  • Copyright © 2022 by the American Society of Nephrology
View Full Text

If you are:

  • an ASN member, select the "ASN Member" login button. 
  • an individual subscriber, login with you User Name and Password.
  • an Institutional user, select the Institution option where you will be presented with a list of Shibboleth federations. If you do not see your federation, contact publications@asn-online.org. 

ASN MEMBER LOGIN

ASN MEMBER LOGIN

Log in using your username and password

Forgot your user name or password?

Log in through your institution

You may be able to gain access using your login credentials for your institution. Contact your library if you do not have a username and password.

Purchase access

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$34.00

In order to get access to the article, you must have an account.  If you have an account, enter your user name and password into the boxes above. If you do not have an account, follow the instructions below to create one.  Once you have purchased the article, you will have access to it for 24 hours.  

Steps for Creating an Account:

Click the "Purchase Access" button.  The page will redisplay with the following message at the top of the screen. In the message, click to create an account. 

When you create the account, you will be asked to register a user name, email address and you will need to create a password that is at least eight characters in length.  You do not need an ASN Member number to complete the form. As you move through the registration page, you will have to verify you are a person by completing a Captcha request.   Lastly, your first and last name will be required. 

Once your information is successfully saved, the system will redisplay the home page of the journal.  From there, navigate back to the article to purchase.  Select the article and at the bottom of the page, use the credentials you just created to login. The article will be added to your shopping cart.  You can continue to navigate across JASN and CJASN adding to your cart from both journals. When you are ready to complete your purchse, select the Shopping Cart from the upper right hand corner of the page and follow the onscreen instructions. 

PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 33 (5)
Journal of the American Society of Nephrology
Vol. 33, Issue 5
May 2022
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
Factor H–Related Protein 1 Drives Disease Susceptibility and Prognosis in C3 Glomerulopathy
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Factor H–Related Protein 1 Drives Disease Susceptibility and Prognosis in C3 Glomerulopathy
Bárbara Márquez-Tirado, Josué Gutiérrez-Tenorio, Agustín Tortajada, Laura Lucientes Continente, Fernando Caravaca-Fontán, Talat H. Malik, Raquel Roldán Montero, Sandra Elías, Ana Saiz Gonzalez, Gema Fernández-Juarez, Pilar Sánchez-Corral, Matthew C. Pickering, Manuel Praga, Santiago Rodríguez de Córdoba, Elena Goicoechea de Jorge
JASN May 2022, ASN.2021101318; DOI: 10.1681/ASN.2021101318

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Factor H–Related Protein 1 Drives Disease Susceptibility and Prognosis in C3 Glomerulopathy
Bárbara Márquez-Tirado, Josué Gutiérrez-Tenorio, Agustín Tortajada, Laura Lucientes Continente, Fernando Caravaca-Fontán, Talat H. Malik, Raquel Roldán Montero, Sandra Elías, Ana Saiz Gonzalez, Gema Fernández-Juarez, Pilar Sánchez-Corral, Matthew C. Pickering, Manuel Praga, Santiago Rodríguez de Córdoba, Elena Goicoechea de Jorge
JASN May 2022, ASN.2021101318; DOI: 10.1681/ASN.2021101318
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Visual Abstract
    • Abstract
    • Methods
    • Results
    • Discussion
    • Disclosures
    • Funding
    • Acknowledgments
    • Author Contributions
    • Supplemental Material
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

Basic Research

  • Impaired Mineral Ion Metabolism in a Mouse Model of Targeted Calcium-Sensing Receptor (CaSR) Deletion from Vascular Smooth Muscle Cells
  • Tumor Lysis Syndrome and AKI: Beyond Crystal Mechanisms
Show more Basic Research

Chronic Kidney Disease

  • Brief Early Life Angiotensin-Converting Enzyme Inhibition Offers Renoprotection in Sheep with a Solitary Functioning Kidney at 8 Months of Age
  • The Association of Excess Body Weight with Risk of ESKD Is Mediated Through Insulin Resistance, Hypertension, and Hyperuricemia
Show more Chronic Kidney Disease

Cited By...

  • No citing articles found.
  • Google Scholar

Similar Articles

Related Articles

  • Google Scholar

Keywords

  • C3 glomerulopathy
  • complement
  • factor H-related protein 1
  • glomerular disease
  • disease susceptibility
  • prognosis
  • genetic renal disease

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals

© 2022 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire