Interleukin-6 is essential for glomerular immunoglobulin A deposition and the development of renal pathology in Cd37-deficient mice

Kidney Int. 2018 Jun;93(6):1356-1366. doi: 10.1016/j.kint.2018.01.005. Epub 2018 Mar 16.


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-α 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 Cd37xIl6 double-knockout mice. These double-knockout and Il6-/- 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.

Keywords: CD37; IL-6; IgA nephropathy; glomerulonephritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / immunology
  • Albuminuria / metabolism
  • Albuminuria / prevention & control
  • Animals
  • Antigens, CD / genetics
  • Antigens, Neoplasm / blood
  • Antigens, Neoplasm / genetics
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Case-Control Studies
  • Cell Proliferation
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Glomerulonephritis, IGA / immunology
  • Glomerulonephritis, IGA / metabolism*
  • Glomerulonephritis, IGA / pathology
  • Glomerulonephritis, IGA / prevention & control
  • Humans
  • Immunoglobulin A / immunology
  • Immunoglobulin A / metabolism*
  • Interleukin-6 / deficiency
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / metabolism*
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / physiopathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration
  • Phenotype
  • Podocytes / immunology
  • Podocytes / metabolism
  • Podocytes / pathology
  • Tetraspanins / blood
  • Tetraspanins / deficiency*
  • Tetraspanins / genetics


  • Antigens, CD
  • Antigens, Neoplasm
  • CD37 protein, human
  • Cd37 protein, mouse
  • Immunoglobulin A
  • Interleukin-6
  • Tetraspanins
  • interleukin-6, mouse