Animal models of lupus nephritis: the past, present and a future outlook

Figures & data

Figure 1. A simplified cross section of the glomerulus is depicted. The glomerular assembly comprises of a fenestrated endothelium (pink), which is contiguous with the mesangium that houses the mesangial cells (green). As such, mesangial cells are constantly exposed to blood components. The fenestrated endothelium is lined by the glomerular basement membrane (cyan). The other side of the basement membrane is lined by a specialised type of epithelial cells called podocytes and their foot processes (cyan with pink blebs).

During the evolution of lupus nephritis (LN), circulating or in-situ formed immune complexes can deposit in the mesangial (orange, class I, II LN), sub-endothelial (blue, class III and IV) or sub-epithelial (red, class V) regions and induce cellular pathology and inflammation. Some of the common pathological features include (but are not restricted to) mesangial proliferation, basement membrane thickening, endocapillary proliferation, sclerosis, crescent formation with loss of podocyte foot processes.

Table 1. Summary of the discussed models and their specific advantages and disadvantages.

Mouse model	Strain development	Kidney immune cell accumulation	Major clinical observations	Sex predominance and severity	Kidney histopathology	Mortality	Pros	Cons
MLR/lpr	Crossing strains C3H/Di, LG/J, C57BL/6, and AKR/J	CD4 − veCD8 − veB220 + ve T cells	Autoantibodies against dsDNA and Sm, IC mediated renal and skin pathology, Lymphadenopathy	Predominant in both. More severe in female	Endothelial and mesangial cell proliferation	70% mortality by 14 weeks	Rapid with high incidence and severity of disease development	Independent of Type I interferons and FcγRs
BXSB	C57BL/6 and SB/Le mice (B6 X SB/Le) F1 to SB/Le	B lymphocytes	Reactivity to ribonucleoproteins (RNP)	Male	Exudative, proliferative nephritis; Severe proteinuria, IgG and C3 deposits in the glomerular mesangium	Males- 90% mortality at eight months, Females- 50% at fifteen months	Permits studies on male LN and consequence of TLR7 signalling pathway in SLE	Unlike human lupus, lower incidence in females
NZB/NZW F1	Breeding between B/W and NZW mice	B cell activation	Splenomegaly, anti-dsDNA antibodies	Female	Proteinaceous deposits in the mesangium, proliferation of glomerular cells and tubular casts	50% mortality around eight months and >90% mortality after one year	Close phenotypic approximation of human SLE and LN	Long disease induction time and variability in disease severity
Pristane- induced	Injection of Pristane in BALB/c mice	Monocyte infiltration	Development of anti-RNP, anti- DNA and anti- histone antibodies, lung haemorrhagic, capillary damage- associated pathology, TNFα-driven arthritis and capillaritis	Female	Proliferative glomerulonephritis, moderate proteinuria, mesangial and sub-endothelial deposition of IgM and IgG with mesangial C3 deposits	Strain dependent	Valuable tool to investigate type 1 IFN-induced pathology, excellent model to demonstrate how an environmental factor induces lupus like disease	Unlike in human SLE, anti-DNA antibodies are almost entirely IgM. Long disease induction time
NTN	Injection of nephrotoxic serum antibodies against GBM	Neutrophil, mononuclear phagocytes and T cell infiltration	Renal failure	Gender independent	IgG deposits in glomeruli	Dependent on mouse strain and dose of antiserum	Independent of genetics and gender. Rapid induction of IC mediated chronic GN	Variable disease severity depending upon the source of antiserum. Limited availability of antiserum