Imperial College London
Alternate

ProfessorMatthewPickering

Faculty of Medicine, Department of Immunology and Inflammation

Centre Director, Professor of Rheumatology
 
 
 
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Contact

 

matthew.pickering Website

 
 
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Assistant

 

Miss Claudia Rocchi +44 (0)20 3313 2315

 
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Location

 

9N12Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Malik:2021:10.1073/pnas.2022722118,
author = {Malik, TH and Gitterman, DP and Lavin, DP and Lomax-Browne, HJ and Hiemeyer, EC and Moran, LB and Boroviak, K and Cook, HT and Gilmore, AC and Mandwie, M and Ahmad, A and Alexander, IE and Logan, GJ and Marchbank, KJ and Bradley, A and Pickering, MC},
doi = {10.1073/pnas.2022722118},
journal = {Proceedings of the National Academy of Sciences},
pages = {1--9},
title = {Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage},
url = {http://dx.doi.org/10.1073/pnas.2022722118},
volume = {118},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Genetic variation within the factor H–related (FHR) genes is associated with the complement-mediated kidney disease, C3 glomerulopathy (C3G). There is no definitive treatment for C3G, and a significant proportion of patients develop end-stage renal disease. The prototypical example is CFHR5 nephropathy, through which an internal duplication within a single CFHR5 gene generates a mutant FHR5 protein (FHR5mut) that leads to accumulation of complement C3 within glomeruli. To elucidate how abnormal FHR proteins cause C3G, we modeled CFHR5 nephropathy in mice. Animals lacking the murine factor H (FH) and FHR proteins, but coexpressing human FH and FHR5mut (hFH-FHR5mut), developed glomerular C3 deposition, whereas mice coexpressing human FH with the normal FHR5 protein (hFH-FHR5) did not. Like in patients, the FHR5mut had a dominant gain-of-function effect, and when administered in hFH-FHR5 mice, it triggered C3 deposition. Importantly, adeno-associated virus vector-delivered homodimeric mini-FH, a molecule with superior surface C3 binding compared to FH, reduced glomerular C3 deposition in the presence of the FHR5mut. Our data demonstrate that FHR5mut causes C3G by disrupting the homeostatic regulation of complement within the kidney and is directly pathogenic in C3G. These results support the use of FH-derived molecules with enhanced C3 binding for treating C3G associated with abnormal FHR proteins. They also suggest that targeting FHR5 represents a way to treat complement-mediated kidney injury.
AU  - Malik,TH
AU  - Gitterman,DP
AU  - Lavin,DP
AU  - Lomax-Browne,HJ
AU  - Hiemeyer,EC
AU  - Moran,LB
AU  - Boroviak,K
AU  - Cook,HT
AU  - Gilmore,AC
AU  - Mandwie,M
AU  - Ahmad,A
AU  - Alexander,IE
AU  - Logan,GJ
AU  - Marchbank,KJ
AU  - Bradley,A
AU  - Pickering,MC
DO  - 10.1073/pnas.2022722118
EP  - 9
PY  - 2021///
SN  - 0027-8424
SP  - 1
TI  - Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage
T2  - Proceedings of the National Academy of Sciences
UR  - http://dx.doi.org/10.1073/pnas.2022722118
UR  - https://www.pnas.org/content/118/13/e2022722118
UR  - http://hdl.handle.net/10044/1/87711
VL  - 118
ER  -
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