Prevalence of CD44-Positive Glomerular Parietal Epithelial Cells Reflects Podocyte Injury in Adriamycin Nephropathy

Abstract

Background/Aims: Recent study suggests that activation of parietal epithelial cells (PECs) contributes to pathogenesis of glomerulosclerosis and the activation marker CD44 increases in evolving glomerulosclerosis. Here we examined the pathogenic roles of CD44+ epithelial cells in mouse adriamycin nephropathy (ADRN), a representative rodent model for idiopathic focal segmental glomerulosclerosis (FSGS). We also evaluated whether the prevalence of CD44+ PECs reflects different levels of podocyte injuries. Methods: As a model of FSGS with different degrees of podocyte injury, ADRN models in mice of different ages were utilized. Immunohistochemistry and immunofluorescence were used to determine roles of CD44 expression. Results: By immunohistochemistry, CD44 expression became positive in claudin-1+ PECs and an increase in CD44+ PECs was associated with reduced expression of synaptopodin and podocin in diseased glomeruli. Furthermore, immunofluorescence staining demonstrated co-expression with osteopontin, a CD44 ligand that plays a significant role in the progression of glomerulosclerosis, thereby suggesting interactions between these molecules. Analysis of the number of WT-1+ podocytes and the levels of electron microscopic foot process effacement revealed a milder degree of podocyte injury in younger ADRN models compared to older ones. Comparative immunohistochemical analysis indicated that the prevalence of CD44+ PECs consistently reflects different degrees of podocyte injury within each different-aged ADRN model. Conclusion: CD44+ PECs play significant roles in progressive glomerulosclerosis and the prevalence of the cells reflects different degrees of podocyte injury in ADRN.

CD44-Positive Glomerular Parietal Epithelial Cells in a Mouse Model of Calcineurin Inhibitors-Induced Nephrotoxicity

“…The CD44-positive PECs appeared prior to glomerulosclerosis and formed a bridge from Bowman's capsule to the capillary tuft; within this bridge, there was decreased expression of podocyte markers. These results suggested that CD44-positive PECs play a significant role in FSGS formation during CNI-induced nephrotoxicity, and previous reports have shown that they contribute to other pathophysiological form of FSGS [8,10,[20][21][22].…”

“…To date, various studies have addressed the relationship between podocyte injury and PEC dynamics [8][9][10][22][23][24]. For instance, in one investigation involving patients with collapsing glomerulopathy, hyperplastic and hypertrophic epithelial cells were frequently connected to PECs and collapsed glomerular basement membranes [23].…”

Up-Regulation of CD74 Expression in Parietal Epithelial Cells in a Mouse Model of Focal Segmental Glomerulosclerosis

“…1a, upper panels) [1,7], we investigated the expression of other markers including p-ERK, CXCR4 and AT1 in renal tissues of ADR mice by immunohistochemistry (fig. 1b).…”

“…We previously reported CD44 as a useful marker to detect PEC activation, reflecting progressive podocyte loss in ADR mice [7]. In this study, we further examined IHC expression of other proteins reported as PEC markers in several studies, CXCR4, AT1 and p-ERK [23,26,27].…”

“…Previous studies, including our own, have reported that CD44-positive PECs significantly increase during the progression of glomerulosclerosis in human and experimental FSGS [6,7]. Although CD44 expression has been used to identify aPECs, its pathological role in PEC activation is not completely understood.…”