MO_V_L: Molecular Sciences V. Lectures
1 Lukács S. Lesinszki, Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
2 Michael Robson, Department of Inflammation Biology, King’s College, London, United Kingdom
3 Attila Mócsai, Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
Introduction: 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 Src-family kinases Hck, Fgr, and Lyn are critical for various autoantibody-induced inflammatory disease models. These kinases are indispensable for the physiological effector functions of neutrophil granulocytes.
Aims: We used Hck−/−Fgr−/−Lyn−/− triple knockout mice to test whether they participate in the development of nephrotoxic nephritis.
Methods: Mice were preimmunized with sheep IgG followed by intravenous injection of NTS or normal sheep serum. Eight days later urine was collected over a 24-hour period. After an additional day blood samples were 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 and hematuria on the eighth day. In these animals’ kidney glomerular hypercellularity, leukocyte infiltration, mesangial expansion and glomerular sclerosis 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. In contrast, NTS treated Hck−/−Fgr−/−Lyn−/− animals serum and urine parameters remained in the control range, with no detectable histological differences between the NTS treated and the control group.
Conclusion: Our results indicate that Hck, Fgr, and Lyn have a crucial role in the development of immune complex-mediated glomerulonephritis. These kinases may have the potential to become good targets to treat immune complex-mediated glomerulonephritis like the anti-glomerular basement membrane disease, which may provide better life quality to the patients.
Semmelweis University, Doctoral School of Molecular Medicine