C3(H2O) prevents rescue of complement-mediated C3 glomerulopathy in Cfh–/– Cfd–/– mice

Yuzhou Zhang; Adam Keenan; Dao-Fu Dai; Kristofer S May; Gabriella R Pitcher; Richard J.H Smith; Emily E Anderson; Margaret A Lindorfer; John B Henrich; Ronald P Taylor

doi:10.1172/jci.insight.135758

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C3(H2O) prevents rescue of complement-mediated C3 glomerulopathy in Cfh–/– Cfd–/– mice

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C3(H2O) prevents rescue of complement-mediated C3 glomerulopathy in Cfh–/– Cfd–/– mice

Yuzhou Zhang, Adam Keenan, Dao-Fu Dai, Kristofer S May, Gabriella R Pitcher, Richard J.H Smith, Emily E Anderson, Margaret A Lindorfer, John B Henrich and Ronald P Taylor

JCI insight, Vol.5(9), e135758

05/07/2020

DOI: 10.1172/jci.insight.135758

PMCID: PMC7253029

PMID: 32376801

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Abstract

Therapeutic complement inhibition is a major focus for novel drug development. Of upstream targets, factor D (FD) is appealing because it circulates in plasma at low concentrations and has a single function: to cleave factor B to generate C3 convertase of the alternative pathway (AP). Mice with a targeted deletion of factor H (FH; Cfh–/– mice) develop C3 glomerulopathy (C3G) due to uncontrolled AP activity. To assess the impact of FD inhibition, we studied Cfh–/– Cfd–/– mice. We show that C3G in Cfh–/– mice is not rescued by removing FD. We used serum from Cfh–/– Cfd–/– mice to demonstrate that residual AP function occurs even when both FD and FH are missing and that hemolytic activity is present due to the action of C3(H2O). We propose that uncontrolled tick-over leads to slow activation of the AP in Cfh–/– Cfd–/– mice and that a minimal threshold of FH is necessary if tissue deposition of C3 is to be prevented. The FD/FH ratio dictates serum C3 level and renal C3b deposition. In C3G patients with chronic renal disease, the FD/FH ratio correlates inversely with C3 and C5 serum levels, suggesting that continuous AP control may be difficult to achieve by targeting FD.

Nephrology

Complement

Details

Title: Subtitle: C3(H2O) prevents rescue of complement-mediated C3 glomerulopathy in Cfh–/– Cfd–/– mice
Creators: Yuzhou Zhang - Molecular Otolaryngology and Renal Research Laboratories, and
Adam Keenan - Molecular Otolaryngology and Renal Research Laboratories, and
Dao-Fu Dai - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
Kristofer S May - Molecular Otolaryngology and Renal Research Laboratories, and
Gabriella R Pitcher - Molecular Otolaryngology and Renal Research Laboratories, and
Richard J.H Smith - Molecular Otolaryngology and Renal Research Laboratories, and
Emily E Anderson - Molecular Otolaryngology and Renal Research Laboratories, and
Margaret A Lindorfer - Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
John B Henrich - Molecular Otolaryngology and Renal Research Laboratories, and
Ronald P Taylor - Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
Resource Type: Journal article
Publication Details: JCI insight, Vol.5(9), e135758
DOI: 10.1172/jci.insight.135758
PMID: 32376801
PMCID: PMC7253029
NLM abbreviation: JCI Insight
ISSN: 2379-3708
eISSN: 2379-3708
Publisher: American Society for Clinical Investigation
Grant note: R01 DK110023 / national institute of health K08 HL145138 / national institute of health
Language: English
Date published: 05/07/2020
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Radiation Oncology; Otolaryngology; Internal Medicine
Record Identifier: 9984070579302771

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