Leptin-deficient mice are protected from accelerated nephrotoxic nephritis

Abstract

Leptin is an adipose tissue-derived hormone that signals nutritional status to the hypothalamus. Recent evidence indicates that leptin modifies proinflammatory immune responses and may provide a key link between nutritional deficiency and immune dysfunction. To study the influence of leptin deficiency on immune-mediated renal disease, susceptibility to accelerated nephrotoxic nephritis was examined in leptin-deficient C57BL/6-ob/ob mice and C57BL/6 wild-type controls. The model was induced with sheep anti-mouse glomerular basement membrane antibody injected to mice preimmunized against sheep IgG, and mice were sacrificed 8 days after induction of disease. The leptin-deficient ob/ob mice were strongly protected from glomerular crescent formation, macrophage infiltration, glomerular thrombosis, and albuminuria in this model. Our findings suggest that leptin is required for the induction and maintenance of immune-mediated glomerulonephritis, and that blockade of the leptin axis might provide an attractive therapeutic possibility in human autoimmune disease.

Figure 1

Histological and functional disease in ob/ob mice and WT C57BL/6 controls at day 8 after induction of nephritis with weight-adjusted doses of NTS (experiment 3). A: Glomerular thrombosis score (n = 50 glomeruli per kidney); B: percentage of glomerular crescents; C: macrophages/glomerular cross-section; D: albuminuria (mg/12 hours); E: serum albumin (g/L); and F: serum creatinine (μmol/L). The ob/ob mice were strongly protected from glomerulonephritis.

Figure 2

A and B: Representative PAS-stained glomeruli from WT and ob/ob mice, respectively, day 8 after induction of nephritis. The WT kidneys showed glomerular hypercellularity, capillary thrombosis, and crescent formation (A), while the ob/ob kidneys were virtually normal (B). C and D: Glomerular direct immunofluorescence for mouse IgG showing deposition of greater quantities of IgG in the WT glomerulus (C) than the ob/ob glomerulus (D). E: Quantitative immunofluorescence for sheep IgG at day 8 after induction of nephritis (AFU). The mice were given weight-adjusted doses of NTS and more sheep IgG was seen on the ob/ob glomeruli than the WT glomeruli. F: Quantitative immunofluorescence for glomerular mouse IgG at day 8 confirming greater quantities in WT glomeruli than ob/ob glomeruli. G: Serum levels of mouse total IgG specific for sheep IgG at day 8 after the induction of accelerated nephrotoxic nephritis (arbitrary ELISA units).

Figure 3

Day 8 after induction of accelerated nephrotoxic nephritis with 5 mg of NTS (experiment 1). Ob/ob mice were protected from glomerular thrombosis and crescents despite an equivalent humoral immune response to WT. A: Serum levels of mouse IgG specific for sheep IgG at day 8 after induction of accelerated nephrotoxic nephritis (arbitrary ELISA units). B: Glomerular thrombosis score (n = 50 glomeruli per kidney); C: percentage of glomerular crescents; D: macrophages/glomerular cross-section.