Variable Expression of Neural Cell Adhesion Molecule Isoforms in Renal Tissue: Possible Role in Incipient Renal Fibrosis.
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.
Institute of Pathology, Medical Faculty, University of Belgrade, Belgrade, Serbia.
Jasmina
J
Marković-Lipkovski
Institute of Pathology, Medical Faculty, University of Belgrade, Belgrade, Serbia.
Maja
M
Životić
Section for Transplantation Immunology and Immunohematology, ZMF, University Medical Clinic, Eberhard Karls University, Tübingen, Germany; Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg-August University, Göttingen, Germany.
Claudia A
CA
Müller
Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg-August University, Göttingen, Germany.
Björn
B
Tampe
Institute of Pathology, Medical Faculty, University of Belgrade, Belgrade, Serbia.
Sanja
S
Ćirović
Institute of Pathology, Medical Faculty, University of Belgrade, Belgrade, Serbia.
Jelena
J
Vještica
Institute of Pathology, Medical Faculty, University of Belgrade, Belgrade, Serbia.
Nada
N
Tomanović
Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg-August University, Göttingen, Germany.
Michael
M
Zeisberg
Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg-August University, Göttingen, Germany.
Gerhard A
GA
Müller
D005355:Fibrosis / Q000378:metabolism*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D000081102:WAP Four-Disulfide Core Domain Protein 2
D039081:Integrin alpha5beta1; D019006:Neural Cell Adhesion Molecules; D020033:Protein Isoforms; D011506:Proteins; D012333:RNA, Messenger; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9