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Trps1 Functions Downstream of Bmp7 in Kidney Development

Zhibo Gai^*, Gengyin Zhou, Shunji Itoh^*, Yoshifumi Morimoto^*, Hiroyuki Tanishima^*, Ikuji Hatamura^*, Kohsaku Uetani^*, Masataka Ito and Yasuteru Muragaki^*

*First Department of Pathology, Wakayama Medical University School of Medicine, Wakayama, Japan;
Department of Pathology, School of Medicine, Shandong University, Jinan, People's Republic of China; and
Department of Developmental Anatomy and Regenerative Biology, National Defense Medical College, Tokorozawa, Japan

Correspondence: Dr. Yasuteru Muragaki, First Department of Pathology, Wakayama Medical University Medical School, 811-1 Kimiidera, Wakayama 641-0012, Japan. Phone: +81-73-441-0634; Fax: +81-73-446-3781; E-mail: ymuragak{at}wakayama-med.ac.jp

Received for publication September 28, 2008. Accepted for publication July 31, 2009.

During embryonic development, the mesenchyme of the lungs, gut, kidneys, and other tissues expresses Trps1, an atypical member of the GATA-type family of transcription factors. Our previous work suggested the possibility that Trps1 acts downstream of bone morphogenic protein 7 (Bmp7), which is essential for normal renal development. To examine the role of Trps1 during early renal development, we generated Trps1-deficient mice and examined their renal histology. Compared with wild-type mice, Trps1-deficient newborn mice had fewer tubules and glomeruli, an expanded renal interstitium, and numerous uninduced metanephric mesenchymal cells, which resulted in fewer nephrons. In wild-type kidneys, Trps1 expression was present in ureteric buds, cap mesenchyme, and renal vesicles, whereas Trps1 was virtually absent in Bmp7-deficient kidneys. Furthermore, Trps1-deficient kidneys had low levels of Pax2 and Wt1, which are markers of condensed mesenchymal cells, suggesting that a lack of Trps1 affects the differentiation of cap mesenchyme to renal vesicles. In cultured metanephric mesenchymal cells, Bmp7 induced Trps1 and E-cadherin and downregulated vimentin. Knockdown of Trps1 with small interference RNA inhibited this Bmp7-induced mesenchymal-to-epithelial transition. Last, whole-mount in situ hybridization of Wnt9b and Wnt4 demonstrated prolonged branching of ureteric buds and sparse cap mesenchyme in the kidneys of Trps1-deficient mice. Taken together, these findings suggest that normal formation of nephrons requires Trps1, which mediates mesenchymal-to-epithelial transition and ureteric bud branching during early renal development.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673