Inhibition of histone deacetylase activates side population cells in kidney and partially reverses chronic renal injury.
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.
Imai
Naohiko
N
Department of Clinical Renal Regeneration, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Hishikawa
Keiichi
K
Marumo
Takeshi
T
Hirahashi
Junichi
J
Inowa
Toshihiko
T
Matsuzaki
Yumi
Y
Okano
Hideyuki
H
Kitamura
Tadaichi
T
Salant
David
D
Fujita
Toshiro
T
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012756:Sheep / Q000097:blood; D013047:Specific Pathogen-Free Organisms; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D014157:Transcription Factors; C117673:Msc protein, mouse; C012589:trichostatin A