Abstract
Rare neural cell adhesion molecule (NCAM) positive cells have been previously described within the normal human adult kidney interstitium, speculating that they could increase in the interstitium with incipient interstitial renal fibrosis (IRF). In the present study, among 93 biopsy samples of various kidney diseases, NCAM+ interstitial cells were detected in 62.4% cases. An increased number of NCAM+ cells was significantly observed only in incipient IRF compared to normal renal tissues and advanced IRF stages (p<0.001), independently of underlying diseases (p = 0.657). All three major NCAM isoforms’ RT-PCR bands were visible either in normal or in kidneys with incipient IRF, albeit their mRNA expression levels measured by qRT-PCR were different. Applying qRT-PCR on pure NCAM+ cells population, obtained by laser capture microdissection, significant mRNA over-expression of NCAM140kD isoform was found in NCAM+ cells within incipient IRF (p = 0.004), while NCAM120kD and NCAM180kD isoforms were not changed significantly (p = 0.750; p = 0.704; respectively). Simultaneously, qRT-PCR also showed significant αSMA (p = 0.014) and SLUG (p = 0.004) mRNAs up-regulation within the NCAM+ cells of incipient IRF, as well as highly decreased matrix metalloproteinases (MMP) -2 and -9 mRNAs (p = 0.028; p = 0.036; respectively). However, using double immunofluorescence MMP-9 could still be detectable on the protein level in rare NCAM+ cells within the incipient IRF. Further characterization of NCAM+ cells by double immunofluorescent labeling revealed their association with molecules involved in fibrosis. Fibroblast growth factor receptor 1 (FGFR1) and α5β1 integrin were extensively expressed on NCAM+ cells within the incipient IRF areas, whereas human epididymis protein-4 (HE4) was found to be present in few NCAM+ cells of both normal and interstitium with incipient fibrosis. Heterogeneity of NCAM+ interstitial cells in normal and incipient IRF, concerning molecules related to fibrosis and variable expression of NCAM isoforms, could suggest diverse role of NCAM+ cells in homeostasis and in regulation of renal fibrosis in diseased kidneys.
Highlights
In addition to rare fibroblasts, scarce neural cell adhesion molecule (NCAM) positive cells with spindle shaped or dendritic morphology can be detected within the interstitium of the normal adult human kidney [1, 2]
Since NCAM is one of the receptors essential during kidney organogenesis [3], we would like to clarify whether the increase of NCAM+ interstitial cell lineage during kidney repair could differ from rare NCAM+ cells situated within normal renal interstitium and if they could share some of the markers involved in tissue wound healing processes, either those which contribute or those which could ameliorate fibrosis
Normal renal tissues were obtained from 10 cadaveric kidneys that were not transplanted, as well as from 10 non-tumor renal tissues obtained after nephrectomies due to renal tumors. 93 kidney biopsy specimens were included in this study after routine diagnostic: lupus nephritis (LN)—25 cases, focal-segmental glomerulosclerosis (FSGS)—18 cases, membranous glomerulonephritis (MGN)—13 cases, membrano-proliferative glomerulonephritis (MPGN) —8 cases, renal graft—9 cases, IgA nephropathy—6 cases, mesangio-proliferative glomerulonephritis (MesPGN)—5 cases, rapid-progressive glomerulonephritis (RPGN)– 5 cases, minimal change disease—4 cases
Summary
In addition to rare fibroblasts, scarce neural cell adhesion molecule (NCAM) positive cells with spindle shaped or dendritic morphology can be detected within the interstitium of the normal adult human kidney [1, 2]. These cells seemed to have arisen from metanephric mesenchymal cells expressing NCAM during kidney development, and selectively persist within the renal interstitium after birth [3]. It has been suspected that in early phases of repairing processes of a damaged kidney interstitial NCAM+ cells could increase [2, 4]. Since NCAM is one of the receptors essential during kidney organogenesis [3], we would like to clarify whether the increase of NCAM+ interstitial cell lineage during kidney repair could differ from rare NCAM+ cells situated within normal renal interstitium and if they could share some of the markers involved in tissue wound healing processes, either those which contribute or those which could ameliorate fibrosis
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