title: Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies.
abstract: BACKGROUND
  In recent studies performed on cultured cells and experimental nephropathies, it has been hypothesized that tubular epithelial cells (TEC), via epithelial-mesenchymal transformation (EMT), can become collagen-producing cells. According to this theory, they should proceed through several activating steps, such as proliferation and phenotype changes, to eventually synthesize extracellular matrix (ECM).
  
  
  METHODS
  To evaluate whether EMT operates in human TECs, 133 renal biopsies of different renal diseases were studied, analyzing by immunohistochemistry and in situ hybridization the possible expression of markers of proliferation (PCNA, Mib-1), cellular phenotype (vimentin, alpha-SMA, cytokeratin, ZO-1) and ECM production (prolyl 4-hydroxylase, HSP47, interstitial collagens).
  
  
  RESULTS
  Independently of histological diagnosis, variable degrees of TEC positivity for PCNA (2.7 +/- 2.4 cells/field) and Mib-1 (1.9 +/- 2.3) were present. TECs expressing vimentin (1.4 +/- 4.7) and alpha-smooth muscle actin (alpha-SMA; 0.04 +/- 0.4) also were detected. It was possible to observe loss of epithelial antigens from 8 to 10% of the tubular cross sections. Moreover, TECs were stained by prolyl 4-hydroxylase (3.6 +/- 4.3), heat shock protein-47 (HSP47; 2.9 +/- 5.4), collagen type I (0.2 +/- 2.7) and type III (0.3 +/- 2.0). Collagen types I and III mRNAs were found in 0.8 to 1.4 cells/field. The number of TEC with EMT features were associated with serum creatinine and the degree of interstitial damage (P< or = 0.03), and even considering the 45 cases with mild interstitial lesions, the tubular expression of all markers remained strictly associated with renal function (P< or = 0.01).
  
  
  CONCLUSIONS
  Our results suggest that, via transition to a mesenchymal phenotype, TEC can produce ECM proteins in human disease and directly intervene in the fibrotic processes. Moreover, the association of EMT features with serum creatinine supports the value of these markers in the assessment of disease severity.
authors.affiliation: Renal Research Association, Renal Immunopathology Centre, San Carlo Borromeo Hospital, Via Pio II, 3, 20153 Milan, Italy. mp.rastaldi@oscb.sined.net
authors.forename: Maria P
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Franco
authors.initials: F
authors.lastname: Ferrario
authors.forename: Laura
authors.initials: L
authors.lastname: Giardino
authors.forename: Giacomo
authors.initials: G
authors.lastname: Dell'Antonio
authors.forename: Carlo
authors.initials: C
authors.lastname: Grillo
authors.forename: Paolo
authors.initials: P
authors.lastname: Grillo
authors.forename: Frank
authors.initials: F
authors.lastname: Strutz
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Müller
authors.forename: Giuliano
authors.initials: G
authors.lastname: Colasanti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Amico
mesh_terms: D000199:Actins / Q000032:analysis; D001706:Biopsy; D002454:Cell Differentiation; D002455:Cell Division; D003094:Collagen / Q000096:biosynthesis; D004847:Epithelial Cells / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000032:analysis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D014746:Vimentin / Q000096:biosynthesis
chemical_list: D000199:Actins; D018809:Proliferating Cell Nuclear Antigen; D014746:Vimentin; D003094:Collagen; D011393:Procollagen-Proline Dioxygenase