Journal
KIDNEY INTERNATIONAL
Volume 93, Issue 6, Pages 1356-1366Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2018.01.005
Keywords
CD37; glomerulonephritis; IgA nephropathy; IL-6
Categories
Funding
- Dutch Kidney Foundation [IP.11.31]
- Netherlands Organization for Scientific Research (NWO-ALW VIDI Grant) [864.11.006]
- Dutch Cancer Society [KUN2014-6845]
- European Research Council (ERC Consolidator Grant) [724281]
- European Research Council (ERC) [724281] Funding Source: European Research Council (ERC)
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Immunoglobulin A (IgA) nephropathy (IgAN), the most common glomerulonephritis worldwide, is characterized by IgA depositions in the kidney. Deficiency of CD37, a leukocyte-specific tetraspanin, leads to spontaneous development of renal pathology resembling IgAN. However, the underlying molecular mechanism has not been resolved. Here we found that CD37 expression on B cells of patients with IgAN was significantly decreased compared to B cells of healthy donors. Circulating interleukin (IL)-6 levels, but not tumor necrosis factor-alpha or IL-10, were elevated in Cd37(-/-) mice compared to wild-type mice after lipopolysaccharide treatment. Cd37(-/-) mice displayed increased glomerular neutrophil influx, immune complex deposition, and worse renal function. To evaluate the role of IL-6 in the pathogenesis of accelerated renal pathology in Cd37(-/-)mice, we generated Cd37xll6 double-knockout mice. These double-knockout and ll6(-/-) mice displayed no glomerular IgA deposition and were protected from exacerbated renal failure following lipopolysaccharide treatment. Moreover, kidneys of Cd37(-/-) mice showed more mesangial proliferation, endothelial cell activation, podocyte activation, and segmental podocyte foot process effacement compared to the double-knockout mice, emphasizing that IL-6 mediates renal pathology in Cd37(-/- )mice. Thus, our study indicates that CD37 may protect against IgA nephropathy by inhibition of the IL-6 pathway.
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