Abstract
The factor H family in humans is composed of seven distinct proteins, including factor H-related proteins (FHR) 1-5. All members contain tandemly arranged short consensus repeats (SCR) typical of the regulators of complement activation gene family. FHR-5 is unusual for this group of proteins, as it was initially identified as a component of immune deposits in glomerular diseases. During our cloning of the cDNA for rat factor H from glomerular epithelial cells (GEC), we identified an alternative 2729-bp cDNA transcript. The translated sequence encoded a protein containing 11 SCRs, most similar to SCRs 7-15 and 19-20 in native rat factor H, which is the same basic structure of human FHR-5. As such, this rat protein was termed FHR. Recombinant rat FHR produced in a eukaryotic expression system had a molecular mass of 78 kDa. In functional studies, recombinant FHR bound C3b and inhibited the complement alternative pathway in a dose-dependent fashion. Given the prominent expression of FHR-5 in human membranous nephropathy, a disease in which complement activation occurs in the vicinity of GEC, the expression of FHR in a rat model of this disease was evaluated. In both in vitro and in vivo models of complement activation on the GEC, FHR mRNA was up-regulated by a factor of 3-6-fold compared with controls in which complement could not be activated. Thus, we have identified a novel factor H family member in rats. This FHR protein is analogous to human FHR-5, both in structure and in potential involvement in glomerular immune complex diseases.
Highlights
Tor, and membrane cofactor protein, all members of the regulators of complement activation gene family located on chromosome 1q32 [2]
Cloning of Rat factor H-related proteins (FHR) cDNA—Our initial efforts were directed toward cloning rat factor H, which we had identified in liver, platelets [28], and cultured glomerular epithelial cells (GEC)
During our attempt to clone factor H from cultured rat GEC, we identified the cDNA for a related protein
Summary
Tor, and membrane cofactor protein, all members of the regulators of complement activation gene family located on chromosome 1q32 [2]. The translated sequence encoded a protein containing 11 SCRs, most similar to SCRs 7–15 and 19 –20 in native rat factor H, which is the same basic structure of human FHR-5. Given the prominent expression of FHR-5 in human membranous nephropathy, a disease in which complement activation occurs in the vicinity of GEC, the expression of FHR in a rat model of this disease was evaluated.
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