Strain Distribution Pattern of Susceptibility to Immune-Mediated Nephritis

Abstract

The genetic basis of immune-mediated nephritis is poorly understood. Recent studies have demonstrated that the NZW mouse strain is more prone to immune-mediated nephritis compared with C57BL/6 and BALB/c strains. The present study extends these findings by challenging 12 additional inbred strains of mice with rabbit anti-mouse glomerular basement membrane (GBM) reactive sera. Compared with control sera-injected mice and anti-GBM-injected A/J, AKR/J, C3H/HeJ, DBA/2J, MRL/MpJ, NOD/LtJ, P/J, SJL/J, and SWR/J mice, the anti-GBM-injected BUB/BnJ, DBA/1J, and 129/svJ mice developed severe proteinuria and azotemia. Their kidneys exhibited pronounced glomerulonephritis, with crescent formation, as well as tubulointerstitial disease, with these phenotypes being particularly profound in 129/svJ mice. However, these strains did not appear to differ in the nature of their xenogeneic immune response to the administered rabbit sera, either quantitatively or qualitatively. Collectively, these findings allude to the presence of genetic elements in the BUB/BnJ, DBA/1J, and 129/svJ genomes that may potentially confer susceptibility to immune-mediated nephritis. Detailed studies to dissect out the immunological and genetic basis of renal disease in these three strains are clearly warranted.

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

“…We recently noted that certain strains of mice, such as NZW, DBA/1, BUB, and 129/Sv, develop severe nephritis in response to an anti-GBM antibody insult, compared with 16 other inbred strains tested (2,3). As a quick screen for mediators that may be excreted in the urine of nephritic mice, we assayed urine from 2 strains of mice with mild experimental nephritis (i.e., B6 and BALB/c), and 2 strains of mice with severe experimental nephritis (i.e., DBA/1 and 129/Sv), 14 days following the nephrotoxic insult (the peak of disease) for the presence Figure 1.…”

“…B6, 129/Sv, BALB/c, and DBA/1 mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Urine samples from the mice subjected to accelerated experimental nephritis were collected on day 1, day 7, and day 14/15 or day 21 after disease induction, as described previously (3). Female mice were used for all experiments, and 24-hour urine collection using metabolic cages was carried out for all mice.…”

“…Membranes bearing antibodies to 62 mouse cytokines/chemokines/ soluble receptors were purchased from Ray Biotech (Norcross, GA [online at http://www.raybiotech.com]) and were used to screen urine obtained from B6, BALB/c, 129/Sv, and DBA/1 mice (5 mice per strain) 14 days after induction of experimental nephritis, as detailed previously (3). The specific molecules that were assayed on the arrays were Axl, Blc, CD30 ligand (CD30L), CD30T, CD40, Crg2, cutaneous T cell-attracting chemokine (CTACK), CXCL16, eotaxin, eotaxin 2, Fas ligand, fractalkine, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interferon-␥ (IFN␥), insulin-like growth factor binding protein 3 (IGFBP-3), IGFBP-5, IGFBP-6, interleukin-1␣ (IL-1␣), IL-1␤, IL-2, IL-3, IL-3Rb, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12 p40/p70, IL-12 p70, IL-13, IL- (MIP-1␣), MIP-1␤, MIP-2, MIP-3␣, MIP-3␤, platelet factor 4 (PF-4), P-selectin, RANTES, stem cell factor (SCF), stromal cell-derived factor 1␣ (SDF-1␣), thymus and activation-regulated chemokine (TARC), T cell-attracting chemokine 3 (TCA-3), thymusexpressed chemokine (TECK), tissue inhibitor of metalloproteinases 1 (TIMP-1), TNF␣, TNFRI, TNFRII, thrombopoietin (TPO), VCAM-1, and vascular endothelial growth factor (VEGF).…”

“…Urine and blood samples were collected from all groups of mice on days 0, 7, 14, 17, and 21. Mice were killed on day 21, and the kidneys were processed, analyzed, and graded for histopathology, as detailed elsewhere (3).…”

“…Examples of the former include the C57BL/6 (B6) and BALB/c mouse strains, whereas the 129/Sv, BUB, NZW, and DBA/1 mouse strains develop severe proliferative renal disease following an anti-GBM antibody challenge (2,3). The genetic and molecular players that account for this strain difference currently remain unknown.…”