Genetic loci modulate macrophage activity and glomerular damage in experimental glomerulonephritis.
The Wistar Kyoto (WKY) rat is uniquely susceptible to experimentally induced crescentic glomerulonephritis. Two major quantitative trait loci (QTLs) on chromosomes 13 (Crgn1) and 16 (Crgn2) with logarithm of odds >8, as well as five other loci (Crgn3 through 7), largely explain this genetic susceptibility. To understand further the effects of Crgn1 and Crgn2, we generated a double-congenic strain by introgressing these loci from glomerulonephritis-resistant Lewis rats onto the WKY genetic background. Induction of nephrotoxic nephritis in the double-congenic rats (WKY.LCrgn1,2) produced markedly fewer glomerular crescents, reduced macrophage infiltration, and decreased expression of glomerular TNF-alpha and inducible nitric oxide synthase expression compared with control animals. Bone marrow and kidney transplantation studies between parental and WKY.LCrgn1,2 strains, together with in vitro experiments, demonstrated that Crgn1 and Crgn2 contribute exclusively to circulating cell-related glomerular injury by regulating macrophage infiltration and activation. The residual genetic susceptibility to crescentic glomerulonephritis in WKY.LCrgn1,2 rats associated with macrophage activity (especially with enhanced metalloelastase expression) rather than macrophage infiltration. Taken together, these results demonstrate that a genetic influence on macrophage activation, rather than number, determines glomerular damage in immune-mediated glomerulonephritis.
Behmoaras
Jacques
J
Department of Renal Medicine, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, United Kingdom. jacquesb@imperial.ac.uk
Smith
Jennifer
J
D'Souza
Zelpha
Z
Bhangal
Gurjeet
G
Chawanasuntoropoj
Ratana
R
Tam
Frederick W K
FW
Pusey
Charles D
CD
Aitman
Timothy J
TJ
Cook
H Terence
HT
D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D056426:Genetic Loci / Q000235:genetics* / Q000502:physiology*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005921:Glomerulonephritis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D016030:Kidney Transplantation; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011921:Rats, Inbred WKY; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D053508:Matrix Metalloproteinase 12