Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function

• Published in: Genetics (Austin) 2017-06, Vol.206 (2), p.1139-1151
• Main Authors: Chen, Tai-Di, Rotival, Maxime, Chiu, Ling-Yin, Bagnati, Marta, Ko, Jeong-Hun, Srivastava, Prashant K, Petretto, Enrico, Pusey, Charles D, Lai, Ping-Chin, Aitman, Timothy J, Cook, H Terence, Behmoaras, Jacques
• Format: Article
• Language: English
• Subjects: Animals; Cell activation; Ceruloplasmin; Ceruloplasmin - biosynthesis; Ceruloplasmin - genetics; Chromosome 2; Chromosome Mapping; Chromosomes; Cloning; DNA methylation; Gene expression; Gene Expression Regulation; Gene loci; Gene mapping; Genetic Linkage; Genetic Predisposition to Disease; Genetics; Genomes; Glomerulonephritis; Glomerulonephritis - genetics; Glomerulonephritis - pathology; Homeostasis; Humans; Hypoxia; Infiltration; Inflammation; Integration; Interference; Investigations; Kidney diseases; Kinases; Liquid chromatography; Macrophages; Macrophages - metabolism; Macrophages - pathology; Mapping; Markers; Mass spectrometry; Mass spectroscopy; Polarization; Population; Proteins; Quantitative trait loci; Rats; Rats, Inbred WKY; Ribonucleic acid; RNA; RNA-mediated interference; Rodents; Studies; Transplants & implants
• ISSN: 1943-2631; 0016-6731; 1943-2631
• DOI: 10.1534/genetics.116.197376

Crescentic glomerulonephritis (Crgn) is a complex disorder where macrophage activity and infiltration are significant effector causes. In previous linkage studies using the uniquely susceptible Wistar Kyoto (WKY) rat strain, we have identified multiple crescentic glomerulonephritis QTL ( ) and positionally cloned genes underlying and , which accounted for 40% of total variance in glomerular inflammation. Here, we have generated a backcross (BC) population ( = 166) where and were genetically fixed and found significant linkage to glomerular crescents on chromosome 2 ( , LOD = 3.8). Fine mapping analysis by integration with genome-wide expression QTLs (eQTLs) from the same BC population identified ceruloplasmin ( ) as a positional eQTL in macrophages but not in serum. Liquid chromatography-tandem mass spectrometry confirmed Cp as a protein QTL in rat macrophages. WKY macrophages overexpress Cp and its downregulation by RNA interference decreases markers of glomerular proinflammatory macrophage activation. Similarly, short incubation with Cp results in a strain-dependent macrophage polarization in the rat. These results suggest that genetically determined Cp levels can alter susceptibility to Crgn through macrophage function and propose a new role for Cp in early macrophage activation.