Original Investigations
Tubular phenotypic change in progressive tubulointerstitial fibrosis in human glomerulonephritis,☆☆,

https://doi.org/10.1053/ajkd.2001.27693Get rights and content

Abstract

There is much debate over the origins of fibroblast-type cells that accumulate in interstitial fibrosis. A controversial hypothesis, supported by data from animal and cell-culture studies, is that fibroblast-type cells can derive from tubular epithelial cells by a process of epithelial-mesenchymal transdifferentiation. However, to date, no evidence supports this postulate in human glomerulonephritis. This study sought to provide evidence that tubular epithelial cells can undergo phenotypic change toward a fibroblast-like cell in human glomerulonephritis. One hundred twenty-seven open renal biopsy specimens from patients with minimal change disease (MCD), immunoglobulin A (IgA) nephropathy, and rapidly progressive glomerulonephritis (RPGN) were examined for tubular phenotypic change by two-color immunohistochemistry using the criteria of de novo expression of α-smooth muscle actin (α-SMA), a myofibroblast marker; loss of the epithelial marker cytokeratin; and collagen production. In normal human kidney and MCD, tubular epithelial cells expressed cytokeratin with no evidence of α-SMA staining. However, in 36 of 90 cases of IgA nephropathy and 9 of 18 cases of RPGN, small numbers of tubular epithelial cells in areas of fibrosis showed de novo α-SMA expression, accounting for 0.4% ± 0.2% (IgA nephropathy) and 3.8% ± 1.5% (RPGN) of cortical tubules. An intermediate stage of phenotypic change was observed in some cuboidal epithelial cells that expressed both cytokeratin and α-SMA. Tubules containing α-SMA-positive (α-SMA+) cells also stained for collagen types I and III, suggesting that tubular cells undergoing phenotypic change have an active role in the fibrotic process. There also was a marked increase in transforming growth factor-β1 (TGF-β1) tubular expression in areas with interstitial fibrosis, including tubules with phenotypic change. There was a highly significant correlation between tubular α-SMA expression and interstitial fibrosis, interstitial α-SMA+ myofibroblast accumulation, deposition of collagen types I and III, tubular TGF-β1 expression, and renal dysfunction. In conclusion, this study provides evidence that tubular epithelial cells can undergo phenotypic change toward a myofibroblast-like phenotype on the basis of de novo α-SMA expression, loss of cytokeratin, and de novo collagen staining. These data, although not conclusive, provide the first support for the hypothesis that transdifferentiation of tubular epithelial cells has a role in progressive renal fibrosis in human glomerulonephritis. © 2001 by the National Kidney Foundation, Inc.

Section snippets

Patients

Open renal biopsy specimens from 127 patients from the Department of Nephrology, Tokai University School of Medicine (Isehara, Japan), were examined on this study. The study was approved by the University Review Board. Disease category was based on histological examination of biopsy specimens. The cohort consisted of 19 cases of minimal change disease (MCD), 90 cases of immunoglobulin A (IgA) nephropathy, and 18 cases of rapidly progressive glomerulonephritis (RPGN; Table 1).Patients with IgA

Normal human kidney

Immunohistochemistry staining identified the presence of α-SMA protein in smooth muscle cells of blood vessels in normal human kidney (Fig 1A).

. Immunohistochemistry staining showing tubular phenotypic changes in human glomerulonephritis. (A) Normal human kidney showing α-SMA expression (red/brown) in vascular smooth-muscle cells of an artery, but no staining is seen in tubules or glomeruli. (B) IgA nephropathy group 1 showing a focal area of tubulointerstitial fibrosis. Note the presence

Discussion

This study has identified phenotypic change in tubular epithelial cells in areas of tubular damage and fibrosis in human glomerulonephritis. This is based on immunohistochemistry staining showing de novo expression of the mesenchymal marker α-SMA and loss of the epithelial marker cytokeratin by cuboidal tubular epithelial cells. In addition, these phenotypic changes were associated with tubular collagen production.

Although transdifferentiation of epithelial cells into mesenchymal cells has been

References (33)

  • F Strutz et al.

    Interstitial pathomechanisms underlying progressive tubulointerstitial damage

    Kidney Blood Press Res

    (1999)
  • C Badid et al.

    Role of myofibroblasts during normal tissue repair and excessive scarring: Interest of their assessment in nephropathies

    Histol Histopathol

    (2000)
  • D Goumenos et al.

    Myofibroblasts and the progression of crescentic glomerulonephritis

    Nephrol Dial Transplant

    (1998)
  • B Hogemann et al.

    Myofibroblast-like cells produce mRNA for type I and III procollagens in chronic active hepatitis

    Scand J Gastroenterol

    (1993)
  • HY Zhang et al.

    Lung fibroblast alpha-smooth muscle actin expression and contractile phenotype in bleomycin-induced pulmonary fibrosis

    Am J Pathol

    (1996)
  • CE Alpers et al.

    Human renal cortical interstitial cells with some features of smooth muscle cells participate in tubulointerstitial and crescentic glomerular injury

    J Am Soc Nephrol

    (1994)
  • Cited by (139)

    View all citing articles on Scopus

    Supported in part by Committee of Research and Conference Grants grant no. 98/33704 from The Hong Kong University.

    ☆☆

    Address reprint requests to Hui Y. Lan, MD, PhD, Associate Professor of Medicine, Department of Medicine-Nephrology, Baylor College of Medicine, One Baylor Plaza, Alkek Bldg N520, Houston, TX 77030. E-mail: [email protected]

    0272-6386/01/3804-0006$35.00/0

    View full text