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Abstract
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.
Highlights
Glomerulonephritis (GN) is a major cause of human kidney failure, with the formation of glomerular epithelial crescents being a common feature in its most severe forms
Two distinct forms of Crescentic glomerulonephritis (CRGN), nephrotoxic nephritis (NTN) and experimental autoimmune glomerulonephritis (EAG), were induced in LEW.WCrgn1,2 rats via passive transfer of heterologous nephrotoxic antibodies raised in another species or induction of autoimmunity to the glomerular basement membrane, respectively
The gene expression profiles for glomerular cytokines were significantly different in the bicongenic rat strain affected by NTN compared with the parental LEW strain
Summary
Glomerulonephritis (GN) is a major cause of human kidney failure, with the formation of glomerular epithelial crescents being a common feature in its most severe forms. NTN has been used widely as a model for studying mechanisms of crescent formation and factors leading to glomerulosclerosis and renal failure in CRGN (Aitman et al, 2006; Behmoaras et al, 2008; Behmoaras et al, 2010; Cook et al, 1999; Smith et al, 2007; Tam et al, 1999), Received 6 March 2013; Accepted 14 August 2013. Two genetic loci (Crgn and Crgn2) that are linked to CRGN susceptibility have been identified and congenic strains (strains that carry a specific genomic region from another strain; the remainder of their genome is their own) carrying Crgn and/or Crgn in either the WKY or LEW genetic background have been generated. Introgressing LEW Crgn and Crgn loci into the WKY (CRGN-susceptible) genome has been shown to reduce the incidence of disease, but the effects exerted by both WKY Crgn and Crgn in a LEW (CRGNresistant) genome have not been previously investigated
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