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 susce...

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Published in:	Journal of the American Society of Nephrology Vol. 21; no. 7; pp. 1136 - 1144
Main Authors:	BEHMOARAS, Jacques, SMITH, Jennifer, D'SOUZA, Zelpha, BHANGAL, Gurjeet, CHAWANASUNTOROPOJ, Ratana, TAM, Frederick W. K, PUSEY, Charles D, AITMAN, Timothy J, TERENCE COOK, H
Format:	Journal Article
Language:	English
Published:	Washington, DC American Society of Nephrology 01-07-2010
Subjects:	Animals Basic Research Biological and medical sciences Bone Marrow Transplantation Cells, Cultured Disease Models, Animal Genetic Loci - genetics Genetic Loci - physiology Genetic Predisposition to Disease - genetics Glomerular Mesangium - metabolism Glomerular Mesangium - pathology Glomerular Mesangium - physiopathology Glomerulonephritis Glomerulonephritis - genetics Glomerulonephritis - pathology Glomerulonephritis - physiopathology Kidney Transplantation Macrophages - pathology Macrophages - physiology Male Matrix Metalloproteinase 12 - metabolism Medical sciences Nephrology. Urinary tract diseases Nephropathies. Renovascular diseases. Renal failure Nitric Oxide Synthase Type II - metabolism Rats Rats, Inbred Lew Rats, Inbred WKY Tumor Necrosis Factor-alpha - metabolism Kidney disease Glomerulonephritis Nephrology Urinary system disease Experimental study Kidney Biological activity Urology Renal glomerulus Urinary system Genetics Lesion Macrophage
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Summary:	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.
ISSN:	1046-6673 1533-3450
DOI:	10.1681/ASN.2009090968