CD44 is required for the pathogenesis of experimental crescentic glomerulonephritis and collapsing focal segmental glomerulosclerosis

Abstract

A key feature of glomerular diseases such as crescentic glomerulonephritis and focal segmental glomerulosclerosis is the activation, migration and proliferation of parietal epithelial cells. CD44-positive activated parietal epithelial cells have been identified in proliferative cellular lesions in glomerular disease. However, it remains unknown whether CD44-positive parietal epithelial cells contribute to the pathogenesis of scarring glomerular diseases. Here, we evaluated this in experimental crescentic glomerulonephritis and the transgenic anti-Thy1.1 model for collapsing focal segmental glomerulosclerosis in CD44-deficient (cd44-/-) and wild type mice. For both models albuminuria was significantly lower in cd44-/- compared to wild type mice. The number of glomerular Ki67-positive proliferating cells was significantly reduced in cd44-/- compared to wild type mice, which was associated with a reduced number of glomerular lesions in crescentic glomerulonephritis. In collapsing focal segmental glomerulosclerosis, the extracapillary proliferative cellular lesions were smaller in cd44-/- mice, but the number of glomerular lesions was not different compared to wild type mice. For crescentic glomerulonephritis the influx of granulocytes and macrophages into the glomerulus was similar. In vitro, the growth of CD44-deficient murine parietal epithelial cells was reduced compared to wild type parietal epithelial cells, and human parietal epithelial cell migration could be inhibited using antibodies directed against CD44. Thus, CD44-positive proliferating glomerular cells, most likely parietal epithelial cells, are essential in the pathogenesis of scarring glomerular disease.

Albumin induces CD44 expression in glomerular parietal epithelial cells by activating extracellular signal‐regulated kinase 1/2 pathway

“…Previous studies have shown that an increase in CD44 is associated with experimental and clinical sclerotic glomerular disease (Eymael et al, ; Fatima et al, ; Froes et al, ; Kim et al, ; Okamoto et al, ; Roeder et al, ; Yamazaki et al, ). Presence of CD44 staining in PECs was significantly associated with a decline in baseline eGFR of 50% or more, and renal survival was significantly reduced in PEC CD44‐positive patients (Froes et al, ).…”

Novel parietal epithelial cell subpopulations contribute to focal segmental glomerulosclerosis and glomerular tip lesions

“…De novo expression of CD44 is an established marker for PEC activation, 4,8,9 and modulation of CD44 signaling attenuates the development of glomerulosclerotic lesions. 10,11 In FSGS, activated PECs and podocytes form cellular adhesions (synechiae) between Bowman's capsule and the glomerular tuft. 12 Via this process, they are the earliest defining lesions for subsequent development of sclerotic lesions and FSGS.…”

CD9 Is a Novel Target in Glomerular Diseases Typified by Parietal Epithelial Cell Activation

“…2,[11][12][13] Also, various signaling pathways and receptors underlie the altered PEC behavior in glomerular diseases. 5,6,4,14,15 Nevertheless, a major knowledge gap has been identifying the molecular processes driving the switch from a quiescent to an active PEC state. The study by Lazareth et al unequivocally demonstrates that CD9 is a major regulator of PEC activation.…”