Protease nexin-1, tPA, and PAI-1 are upregulated in cryoglobulinemic membranoproliferative glomerulonephritis

J Am Soc Nephrol. 2008 Feb;19(2):243-51. doi: 10.1681/ASN.2007030367. Epub 2008 Jan 16.


Thymic stromal lymphopoietin (TSLP) transgenic mice develop cryoglobulin-associated membranoproliferative glomerulonephritis, characterized by renal monocyte/macrophage infiltration, marked expansion of extracellular matrix, and variable intraluminal and mesangial deposits of cryoglobulins. A microarray approach was used to study global gene expression in glomerular RNA obtained from these mice, as well as from combined TSLP transgenic and Fcγ receptor IIb null mice (TSLP/FcIIb−/−), which develop aggravated membranoproliferative glomerulonephritis. Protease nexin-1 (PN-1) and tissue plasminogen activator (tPA), two potential regulators of fibrosis that are involved in the fibrinolytic and coagulation pathways, were dramatically upregulated in TSLP mice compared with wild-type controls. In situ hybridization revealed minimal expression of PN-1 mRNA in the glomeruli of wild-type mice, increased expression in TSLP mice, and the greatest expression in the mesangial cells of TSLP/FcIIb−/− mice. Immunohistochemistry demonstrated greater expression of PN-1, tPA, and PAI-1 in the mesangial cells of TSLP mice compared with wild-type and the greatest in TSLP/FcIIb−/− mice. In cultured mesangial cells, incubation with cryoglobulins induced an upregulation of PN-1 mRNA; increased expression of PN-1, tPA, and PAI-1 proteins; and stimulated secretion of TGF-β1. It is concluded that PN-1, tPA, PAI-1, and TGF-β1 are likely important mediators of murine cryoglobulinemic glomerulonephritis and that the cryoglobulins may directly upregulate their expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cryoglobulinemia / metabolism
  • Cryoglobulinemia / physiopathology*
  • Cryoglobulins / metabolism
  • Cryoglobulins / pharmacology
  • Female
  • Glomerulonephritis, Membranoproliferative / metabolism
  • Glomerulonephritis, Membranoproliferative / physiopathology*
  • Immunoglobulins
  • Immunohistochemistry
  • In Situ Hybridization
  • Male
  • Mesangial Cells / cytology
  • Mesangial Cells / drug effects
  • Mesangial Cells / physiology
  • Mice
  • Mice, Knockout
  • RNA, Messenger / metabolism
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / metabolism
  • Receptors, IgG / genetics
  • Receptors, IgG / metabolism
  • Serpin E2
  • Serpins / genetics
  • Serpins / metabolism*
  • Tissue Plasminogen Activator / genetics
  • Tissue Plasminogen Activator / metabolism*
  • Up-Regulation / physiology


  • Cryoglobulins
  • Fcgr2b protein, mouse
  • Immunoglobulins
  • RNA, Messenger
  • Receptors, Cytokine
  • Receptors, IgG
  • Serpin E2
  • Serpine2 protein, mouse
  • Serpins
  • Tslpr protein, mouse
  • Tissue Plasminogen Activator