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Twist Relates to Tubular Epithelial–Mesenchymal Transition and Interstitial Fibrogenesis in the Obstructed Kidney

Yujiro Kida, Kinji Asahina, Hirobumi Teraoka, Inna Gitelman and Tetsuji Sato

Department of Anatomy II, School of Dental Medicine, Tsurumi University, Yokohama, Japan (YK,TS); Department of Nephrology, Graduate School of Medicine (YK) and Department of Pathological Biochemistry, Medical Research Institute (KA,HT), Tokyo Medical and Dental University, Tokyo, Japan; and Department of Virology and Developmental Genetics, Faculty of Medicine, Ben Gurion University of the Negev, Beer Sheva, Israel (IG)

Correspondence to: Tetsuji Sato, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, 230-8501, Japan. E-mail: sato-t{at}tsurumi-u.ac.jp

Epithelial–mesenchymal transition (EMT) is a critical step in renal fibrosis. It has been recently reported that a transcription factor, Twist, plays a pivotal role in metastasis of breast tumors by inducing EMT. In this study, we examined whether Twist relates to renal fibrogenesis including EMT of tubular epithelia, evaluating Twist expression level in the unilateral ureteral obstruction (UUO) model. Kidneys of mice subjected to UUO were harvested 1, 3, 7, and 10 days after obstruction. Compared with control kidneys, Twist mRNA-level significantly increased 3 days after UUO (UUO day 3 kidney) and further augmented until 10 days after UUO. Twist expression increased in tubular epithelia of the dilated tubules and the expanded interstitial areas of UUO kidneys, where cell-proliferating appearances were frequently found in a time-dependent manner. Although a part of tubular cells in whole nephron segment were immunopositive for Twist in UUO day 7 kidneys, tubular epithelia downstream of nephron more frequently expressed Twist than upstream of nephron. In UUO day 7 kidneys, some tubular epithelia were confirmed to coexpress Twist and fibroblast-specific protein-1, a marker for EMT, indicating that Twist is involved in tubular EMT under pathological state. Twist was expressed also in a number of -smooth muscle actin-positive myofibroblasts located in the expanded interstitial area of UUO kidneys. From these findings, the present investigation suggests that Twist is associated with tubular EMT, proliferation of myofibroblasts, and subsequent renal fibrosis in obstructed kidneys. (J Histochem Cytochem 55:661–673, 2007)

Key Words: unilateral ureteral obstruction • Twist • epithelial–mesenchymal transition • renal fibrosis • myofibroblast

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