Crescentic 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-rs 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 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, and show development of NTN phenotypes, including glomerular crescents, in LEW.WCrgn1,2 bicongenic rats. Further, we characterise macrophage function and glomerular cytokine profiles in this new strain. Additionally, we show that LEW.WCrgn1,2 are resistant to development of glomerular crescents 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. 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.
- Received March 6, 2013.
- Accepted August 14, 2013.
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