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Published ahead of print on May 11, 2005
J Am Soc Nephrol 16: 2044-2051, 2005
© 2005 American Society of Nephrology
doi: 10.1681/ASN.2004080681
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Pathophysiology of Renal Disease and Progression

Involvement of Renal Progenitor Tubular Cells in Epithelial-to-Mesenchymal Transition in Fibrotic Rat Kidneys

Shin Yamashita, Akito Maeshima and Yoshihisa Nojima

Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi, Japan

Address correspondence to: Dr. Akito Maeshima, Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, 3-39-15 Showa, Maebashi 371-8511, Japan. Phone: +81-27-220-8166; Fax: +81-27-220-8173; E-mail: amaeshima{at}ucsd.edu

Received for publication August 18, 2004. Accepted for publication March 30, 2005.

Renal progenitor tubular cells (label-retaining cells [LRC]) were recently identified in normal kidneys by in vivo bromodeoxyuridine (BrdU) labeling. This study was conducted to examine the behavior of LRC in renal fibrosis. BrdU was injected intraperitoneally into normal rats daily for 7 d. After a 2-wk chase period, unilateral ureteral obstruction (UUO) was induced in these rats. In normal and contralateral kidneys, LRC were observed scattering among tubular epithelial cells. After UUO, the number of the LRC significantly increased, and most of them were positive for proliferating cell nuclear antigen (PCNA). In contrast, PCNA+ cells lacking BrdU label were rarely observed. It is interesting that LRC were detected not only in tubules but also in the interstitium after UUO. Laminin staining showed that a number of the LRC were adjacent to the destroyed tubular basement membrane. Some tubules, including LRC, lost the expression of E-cadherin after UUO. A large number of cell populations expressed vimentin, heat shock protein 47, or {alpha}-smooth muscle actin in the UUO kidneys, and each population contained LRC. None of the LRC was positive for these fibroblastic markers in contralateral kidneys. When renal tubules from BrdU-treated rats were cultured in the gel, some cells protruded from the periphery of the tubules and migrated into the gel. Most of these cells were BrdU+. Neither the total content of BrdU in the kidneys nor the number of LRC in bone marrow significantly changed after UUO. Collectively, these results suggest that LRC is a cell population that proliferates, migrates, and transdifferentiates into fibroblast-like cells during renal fibrosis.




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