Background and Aims

Murine nephrotoxic nephritis is a widely used model of immune complex-mediated glomerulonephritis. In this model, mice are immunized with normal sheep IgG, followed by administration of a sheep antiserum against mouse glomerular preparation (nephrotoxic serum; NTS). This leads to linear glomerular antibody deposition, severe glomerular inflammation and concomitant albuminuria and increased serum creatinine levels. The three Src-family kinases, Hck, Fgr, and Lyn are critical for various autoantibody-induced inflammatory disease models.

We used Hck^−/−Fgr^−/−Lyn^−/− triple knockout mice to test whether these genes participate in the development of nephrotoxic nephritis.

Methods

Mice were preimmunized with sheep IgG followed by intravenous injection of NTS or normal sheep serum. Seven days later urine was collected over a 24-hour period. After an additional day blood was collected, the kidneys were removed, and the leukocyte infiltration and the glomerular injury was tested by flow cytometry and light microscopy.

Results

Wild type NTS treated mice developed severe albuminuria on the seventh day. In these animals’ kidney leukocyte infiltration, mesangial expansion, glomerular sclerosis and crescents could be also detected by light microscopy in several glomeruli. Serum creatinine levels were higher than in the control group, while serum albumin concentrations decreased due to the disease induction. In contrast, NTS treated Hck^−/−Fgr^−/−Lyn^−/− animals serum parameters remained in the control range, with no substantial histological differences between the NTS treated and the control group.

Conclusions

Our results indicate that Hck, Fgr, and Lyn have a crucial role in the development of immune complex-mediated glomerulonephritis.