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

¹ Department of Clinical Renal Regeneration, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan
² Department of Clinical Renal Regeneration, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Internal Medicine, Division of Nephrology and Endocrinology, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan
³ Department of Clinical Renal Regeneration, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Urology, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan
⁴ Department of Physiology, Keio University School of Medicine, Shionanomachi 35, Shinjuku-ku, Tokyo 160, Japan
⁵ Department of Urology, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan
⁶ Renal Section, Evans Biomedical Research Center, Boston University Medical Center, Boston, Massachusetts, USA

^* To whom correspondence should be addressed. E-mail: hishikawa-tky{at}umin.ac.jp.

	Abstract

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 to non-SP cells. Treatment with TSA significantly up-regulated the expression of BMP-7 only 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.