Abstract
Abstract The Mer receptor tyrosine kinase plays an important role in clearance of apoptotic cells and in modulation of innate immune responses. Mice with a Mer kinase domain deletion (Mer-KO) develop progressive lupus-like autoimmunity. Gas6, the ligand for Mer, has been detected in glomeruli. We had previously noted that normal kidneys express high levels of Mer in glomerular tissue and set out to determine its anatomical location and its function in renal tissue. We hypothesized that glomerular expression of Mer might modulate experimental immunopathology. We thus compared the susceptibility of WT and Mer-KO mice to nephrotoxic anti-glomerular basement membrane-induced murine nephrotoxic nephritis by infusing mice with 7.5 ml/kg nephrotoxic sera. Mer-KO but not WT B6 recipients showed increased proteinuria and blood urine nitrogen by day 3. Glomeruli were hyperplastic and later became necrotic. PAS-positive staining was evident in Mer-KO capillary spaces as well within tubules, consistent with massive protein leakage. This early pathological change was associated with a lower survival rate (40%) in Mer-KO mice compared to WT (100%) at day 15. Altogether, data suggest that Mer acts to preserve the kidney from immune-related inflammation, either through its role as a down regulator of cytokine production or by promoting phagocytosis of apoptotic cells. We are further investigating the role of Mer in nephrotoxic nephritis. Supported by NIDCR and the US Department of Veterans Affairs.
Published Version
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