Genetic Loci Modulate Macrophage Activity and Glomerular Damage in Experimental Glomerulonephritis

被引：23

作者：

Behmoaras, Jacques ^{[1
,2
]}

Smith, Jennifer ^{[1
]}

D'Souza, Zelpha ^{[2
]}

Bhangal, Gurjeet ^{[1
]}

Chawanasuntoropoj, Ratana ^{[3
]}

Tam, Frederick W. K. ^{[1
]}

Pusey, Charles D. ^{[1
]}

Aitman, Timothy J. ^{[2
]}

Cook, H. Terence ^{[1
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, MRC Clin Sci Ctr, Dept Renal Med, London W12 0NN, England

[2] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, MRC Clin Sci Ctr, Physiol Genom & Med Grp, London W12 0NN, England

[3] Mahidol Univ, Siriraj Hosp, Fac Med, Div Renal, Bangkok 10700, Thailand

来源：

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2010年 / 21卷 / 07期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

CRESCENTIC NEPHRITIS; METALLOELASTASE; ACTIVATION; EXPRESSION; INJURY;

D O I：

10.1681/ASN.2009090968

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

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-a 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 glonnerular damage in immune-mediated glomerulonephritis.

引用

页码：1136 / 1144

页数：9

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