Role of Novel Rat-specific Fc Receptor in Macrophage Activation Associated with Crescentic Glomerulonephritis

Page, Theresa H.; D’Souza, Zelpha; Nakanishi, Satoshi; Serikawa, Tadao; Pusey, Charles D.; Aitman, Timothy J.; Cook, H. Terence; Behmoaras, Jacques

doi:10.1074/jbc.m111.260695

Cited by 11 publications

(14 citation statements)

References 31 publications

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“…Fc receptor variation in other rat strains involving the presence or absence genomic sequence encoding a decoy Fc gamma receptor illustrates how genetic variation can modulate immunoreceptor signaling to affect renal disease risk 38 . These observations prompted our investigation to uncover further genetic variation in this pathway as a mechanism influencing renal injury in hypertension.…”

Section: Discussionmentioning

confidence: 99%

Hypertensive Renal Injury Is Associated With Gene Variation Affecting Immune Signaling

Braun

Herring

Gokul

et al. 2014

Circ Cardiovasc Genet

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Background The spontaneously hypertensive rat (SHR) strain exists in lines that contrast strongly in susceptibility to renal injury in hypertension. These inbred lines share common ancestry and only 13% of their genomes arise from different ancestors. Methods and Results We used next gen sequencing to detect natural allelic variation in 5 genes of the immunoreceptor signaling pathway (IgH, Dok3, Src, Syk and JunD) that arise from different ancestors in the injury-prone SHR-A3 and the resistant SHR-B2 lines. We created an intercross between these lines and in the F2 progeny we observed that the inheritance of haplotype blocks containing the SHR-A3 alleles of these 5 genes correlated with increased albuminuria and histological measures of renal injury. To test whether accumulated genetic variation in this pathway may create a therapeutic target in hypertensive renal injury, rats of both lines were treated with the immunosuppressant mycophenolate mofetil (MMF). MMF reduced proteinuria (albumin to creatinine ratio, uACR) from 6.6 to 1.2 mg/mg (p<0.001) in SHR-A3. Glomerular injury scores were reduced in MMF treated SHR-A3 from 1.6 to 1.4 (p<0.002). Tubulo-interstitial injury was reduced in MMF-treated SHR-A3 from 2.62 to 2.0 (p=0.001). MMF treatment also reduced renal fibrosis in SHR-A3, (3.9 vs. 2.0, p<0.001). Conclusions Polygenic susceptibility to renal injury in hypertension arises in association with genetic variation in genes that participate in immune responses and is dramatically improved by reduction of immune system activity.

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Section: Discussionmentioning

confidence: 99%

Hypertensive Renal Injury Is Associated With Gene Variation Affecting Immune Signaling

Braun

Herring

Gokul

et al. 2014

Circ Cardiovasc Genet

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“…Here, to illustrate the practical utility of ABBA for differential methylation analysis in disease, we generated WGBS data in an established experimental rat model of crescentic glomerulonephritis (CRGN) (Aitman et al 2006). In this model, we and others have previously shown that susceptibility to CRGN is mediated by macrophages (Behmoaras et al 2008; Page et al 2012); therefore, we assayed CpG methylation at single-nucleotide resolution by WGBS in primary macrophages derived from Wistar Kyoto (WKY) and Lewis (LEW) isogenic rats (two strains discordant for their predisposition to develop CRGN). We used ABBA to carry out genome-wide differential DNA methylation analysis in primary bone-marrow derived macrophages (BMDM) derived from the disease-prone rat strain (WKY, r = 4) and control strain (LEW, r = 4)—see Materials and Methods for additional details on WGBS data generation and processing.…”

Section: Resultsmentioning

confidence: 99%

“…Of the 1004 DMRs identified by ABBA, 427 overlapped with annotated genes (Table S3), and there was a significant enrichment for DMRs occurring within 1 kb of the gene boundaries ( P -value < 0.001), within exons ( P -value < 0.05), and within introns ( P -value < 0.05; Figure 3B). The genes that are within 1 kb of a DMR were enriched for pathways relevant to the pathophysiology of CRGN, including MAPK signaling (Ryan et al 2011), Phosphatidylinositol signaling (Wu et al 2014) and Fc gamma R-mediated phagocytosis (Page et al 2012) (Figure 3C). For comparison, the 207 DMRs identified by DSS overlapped with 45 genes (Table S4), which were enriched only for RNA degradation and metabolic pathways.…”

Section: Resultsmentioning

confidence: 99%

A Bayesian Approach for Analysis of Whole-Genome Bisulfite Sequencing Data Identifies Disease-Associated Changes in DNA Methylation

et al. 2017

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“…We have previously shown that the absence of an Fc-related sequence ( Fcgr3-rs ) causes macrophage overactivity and NTN susceptibility in the WKY strain, whereas, conversely, the LEW strain, which has Fcgr3-rs , is resistant to NTN and shows no macrophage overactivity (Aitman et al, 2006; Page et al, 2012). Consistent with this, Fc-mediated bead phagocytosis levels were higher in WKY BMDMs than in LEW BMDMs.…”

Section: Discussionmentioning

confidence: 99%

Experimental crescentic glomerulonephritis: a new bicongenic rat model

D’Souza

McAdoo

Smith

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYCrescentic glomerulonephritis (CRGN) is a major cause of human kidney failure, but the underlying mechanisms are not fully understood. Wistar Kyoto (WKY) rats are uniquely susceptible to CRGN following injection of nephrotoxic serum, whereas Lewis (LEW) rats are resistant. Our previous genetic studies of nephrotoxic nephritis (NTN), a form of CRGN induced by nephrotoxic serum, identified Fcgr3 and Jund as WKY genes underlying the two strongest quantitative trait loci for NTN phenotypes: Crgn1 and Crgn2, respectively. We also showed that introgression of WKY Crgn1 or Crgn2 individually into a LEW background did not lead to the formation of glomerular crescents. We have now generated a bicongenic strain, LEW.WCrgn1,2, in which WKY Crgn1 and Crgn2 are both introgressed into the LEW genetic background. These rats show development of NTN phenotypes, including glomerular crescents. Furthermore, we characterised macrophage function and glomerular cytokine profiles in this new strain. Additionally, we show that LEW.WCrgn1,2 rats are resistant to the development of glomerular crescents that is usually induced following immunisation with recombinant rat α3(IV)NC1, the specific Goodpasture autoantigen located in the glomerular basement membrane against which the immune response is directed in experimental autoimmune glomerulonephritis. Our results show that the new bicongenic strain responds differently to two distinct experimental triggers of CRGN. This is the first time that CRGN has been induced on a normally resistant rat genetic background and identifies the LEW.WCrgn1,2 strain as a new, potentially valuable model of macrophage-dependent glomerulonephritis.

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Role of Novel Rat-specific Fc Receptor in Macrophage Activation Associated with Crescentic Glomerulonephritis

Cited by 11 publications

References 31 publications

Hypertensive Renal Injury Is Associated With Gene Variation Affecting Immune Signaling

Hypertensive Renal Injury Is Associated With Gene Variation Affecting Immune Signaling

A Bayesian Approach for Analysis of Whole-Genome Bisulfite Sequencing Data Identifies Disease-Associated Changes in DNA Methylation

Experimental crescentic glomerulonephritis: a new bicongenic rat model

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