Detection of Activated Parietal Epithelial Cells on the Glomerular Tuft Distinguishes Early Focal Segmental Glomerulosclerosis from Minimal Change Disease

Abstract

In rodents, parietal epithelial cells (PECs) migrating onto the glomerular tuft participate in the formation of focal segmental glomerulosclerosis (FSGS) lesions. We investigated whether immunohistologic detection of PEC markers in the initial biopsies of human patients with first manifestation of idiopathic nephrotic syndrome with no immune complexes can improve the sensitivity to detect sclerotic lesions compared with standard methods. Ninety-five renal biopsies were stained for claudin-1 (PEC marker), CD44 (activated PECs), and LKIV69 (PEC matrix); 38 had been diagnosed as early primary FSGS and 57 as minimal change disease. PEC markers were detected on the tuft in 87% of the biopsies of patients diagnosed as primary FSGS. PEC markers were detected in FSGS lesions from the earliest stages of disease. In minimal change disease, no PEC activation was observed by immunohistology. However, in 25% of biopsies originally diagnosed as minimal change disease the presence of small lesions indicative of a sclerosing process were detected, which were undetectable on standard periodic acid-Schiff staining, even though only a single histologic section for each PEC marker was evaluated. Staining for LKIV69 detected lesions with the highest sensitivity. Two novel PEC markers A-kinase anchor protein 12 and annexin A3 exhibited similar sensitivity. In summary, detection of PECs on the glomerular tuft by immunostaining improves the differentiation between minimal change disease and primary FSGS and may serve to guide clinical decision making.

Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74

“…19,23,55 The fifth major and novel finding of our study was that the de novo expression of CD74 in PECs during glomerulonephritides might serve as a novel sensitive marker of PEC injury and activation.…”

“…The upregulation of CD44 in resident glomerular cells and the de novo expression in PECs during glomerular diseases was previously documented by us and others. 19,29,30 We extend these data herein by quantitative analyses of CD44 mRNA expression in microdissected glomeruli showing a significant, up to eightfold, upregulation of CD44 in RPGN and IgAN (Supplemental Figure 1B).…”

“…7,9 These effects appear to require the coexpression of CD44, 8 a hyaluronic acid-binding cell surface glycoprotein that acts as a signaling coreceptor and sensitive marker of parietal epithelial cell (PEC) activation. [17][18][19] Only a single study to date has analyzed the role of CD74 in renal disease, specifically its potential involvement in diabetic nephropathy. 16 Extracapillary proliferation leading to cellular crescents, as well as mesangial cell proliferation, are well established histologic features of a number of glomerular diseases, in particular of rapidly progressive and mesangioproliferative glomerulonephritides.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…A novel paradigm showed that the inconspicuous cells lining Bowman's capsule, the parietal epithelial cells, are crucially involved in the pathogenesis of not only crescentic glomerulonephritis but also most types of glomerulosclerosis (119)(120)(121)(122)(123)(124) (Figure 2). The identification of specific molecules resulting in activation of these cells might lead to novel therapeutic options in glomerulosclerosis.…”

Effect of Heme Oxygenase-1 Deficiency on Glomerular Proteomics

“…Disruption of this interaction owing to HO-1 deficiency in nuclei of podocytes would, therefore, be expected to increase oxidative stress level and this could account for the increased lamins A and C expression observed [33] . Finally, the increase in annexin A3 expression (2.04-fold) in Hmox1 -/-glomeruli is of potential interest, as this protein was recently identified as a novel parietal glomerular epithelial cell marker indicative of a sclerosing process [34] .…”