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TISSUE-SPECIFIC STEM CELLS

Inhibition of Histone Deacetylase Activates Side Population Cells in Kidney and Partially Reverses Chronic Renal Injury

^aDepartment of Clinical Renal Regeneration, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan;
^bDepartment of Internal Medicine, Division of Nephrology and Endocrinology, University of Tokyo, Bunkyo-ku, Tokyo, Japan;
^cDepartment of Urology, University of Tokyo, Bunkyo-ku, Tokyo, Japan;
^dDepartment of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan;
^eRenal Section, Evans Biomedical Research Center, Boston University Medical Center, Boston, Massachusetts, USA

Key Words. Stem cell • Side population • Transcription regulation • Chronic renal failure • Anti-glomerular basement membrane disease

Correspondence: Keiichi Hishikawa, M.D., Ph.D., Department of Internal Medicine, Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-865, Japan. Telephone: +81-3-3815-5411, ext. 35725; Fax: +81-3-5800-9738; e-mail: hishikawa-tky{at}umin.ac.jp

Received January 23, 2007; accepted for publication July 9, 2007.
First published online in STEM CELLS EXPRESS   July 19, 2007.



Bone morphogenic protein (BMP)-7 is expressed in the adult kidney and reverses chronic renal injury when given exogenously. Here, we report that a histone deacetylase inhibitor, trichostatin A (TSA), attenuates chronic renal injury, in part, by augmenting the expression of BMP-7 in kidney side population (SP) cells. We induced accelerated nephrotoxic serum nephritis (NTN) in C57BL/6 mice and treated them with TSA for 3 weeks. Compared with vehicle-treated NTN mice, treatment with TSA prevented the progression of proteinuria, glomerulosclerosis, interstitial fibrosis, and loss of kidney SP cells. Basal gene expression of renoprotective factors such as BMP-7, vascular endothelial growth factor, and hepatocyte growth factor was significantly higher in kidney SP cells as compared with non-SP cells. Treatment with TSA significantly upregulated the expression of BMP-7 in SP cells but not in non-SP cells. Moreover, initiation of treatment with TSA after 3 weeks of NTN (for 3 weeks, until 6 weeks) partially but significantly reversed renal dysfunction. Our results indicate an important role of SP cells in the kidney as one of the possible generator cells of BMP-7 and TSA as a stimulator of the cells in reversing chronic renal disease.

Disclosure of potential conflicts of interest is found at the end of this article.