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The CXCL12 (SDF-1)/CXCR4 Axis Is Essential for the Development of Renal Vasculature

Yoshitsugu Takabatake^*, Tatsuki Sugiyama, Hiroshi Kohara, Taiji Matsusaka^,, Hidetake Kurihara^||, Pandelakis A. Koni^¶, Yasuyuki Nagasawa^*, Takayuki Hamano^*, Isao Matsui^*, Noritaka Kawada^*, Enyu Imai^*, Takashi Nagasawa, Hiromi Rakugi^* and Yoshitaka Isaka^*,**

Departments of *Geriatric Medicine and Nephrology and
**Advanced Technology for Transplantation, Osaka University Graduate School of Medicine (B6), Suita,
Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto,
Institute of Medical Science, Tokai University School of Medicine, Kanagawa, and
^||Department of Anatomy, Juntendo University School of Medicine, Tokyo, Japan;
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee; and
^¶Immunotherapy Center and Department of Medicine, Medical College of Georgia, Augusta, Georgia

Correspondence: Dr. Yoshitsugu Takabatake, Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine (B6), 2-2, Yamada-oka, Suita, Japan. Phone: +81-6-6879-3857; Fax: +81-6-6879-3857; E-mail:takaba{at}kid.med.osaka-u.ac.jp

Received for publication June 25, 2008. Accepted for publication March 16, 2009.

CXC chemokine ligand 12 (CXCL12; stromal cell–derived factor 1) is a unique homeostatic chemokine that signals through its cognate receptor, CXCR4. CXCL12/CXCR4 signaling is essential for the formation of blood vessels in the gastrointestinal tract during development, but its contribution to renal development remains unclear. Here, we found that CXCL12-secreting stromal cells surround CXCR4-positive epithelial components of early nephrons and blood vessels in the embryonic kidney. In glomeruli, we observed CXCL12-secreting podocytes in close proximity to CXCR4-positive endothelial cells. Both CXCL12- and CXCR4-deficient kidneys exhibited identical phenotypes; there were no apparent abnormalities in early nephrogenesis or in differentiation of podocytes and tubules, but there was defective formation of blood vessels, including ballooning of the developing glomerular tuft and disorganized patterning of the renal vasculature. To clarify the relative importance of different cellular defects resulting from ablation of CXCL12 and CXCR4, we established endothelial cell–specific CXCR4-deficient mice, which recapitulated the renal phenotypes of conventional CXCR4-deficient mice. We conclude that CXCL12 secreted from stromal cells or podocytes acts on endothelial cells to regulate vascular development in the kidney. These findings suggest new potential therapeutic targets for remodeling the injured kidney.

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