Effects of histone deacetylase inhibitors on rat mesangial cells.
Glomerular mesangial cells (MCs) proliferate and produce extracellular matrix proteins in many progressive renal diseases. Recently, histone deacetylase inhibitors (HDIs) were shown to have antiproliferative and antifibrogenic effects in some in vitro and in vivo models. Using the [(3)H]-thymidine incorporation test, we have found that the HDI trichostatin A (TSA) effectively inhibits MC growth at nontoxic nanomolar concentrations. Similarly, the HDI valproic acid also inhibited MCs proliferation. Cell-cycle analysis indicated an arrest in G(0)/G(1) phase in response to TSA, which was accompanied by elevation in synthesis of the cyclin-dependent kinase inhibitors (CDKIs) p21/Waf1 and p27/Kip1. TSA treatment suppressed alpha-smooth muscle actin, transforming growth factor-beta1, and collagen protein synthesis by MCs and induced myofibroblast-like appearance of proliferating MCs. In the in vivo model of the anti-Thy1.1-induced glomerulonephritis, TSA and valproic acid treatments significantly suppressed proteinuria. Collectively, these data suggest a therapeutic potential for HDIs in the treatment of mesangial proliferative diseases and glomerulosclerosis.
Freidkin
Ilya
I
Department of Nephrology and Hypertension, Hasharon Hospital, Rabin Medical Center, Petah Tikva, Israel.
Herman
Michal
M
Tobar
Ana
A
Chagnac
Avry
A
Ori
Yaacov
Y
Korzets
Asher
A
Gafter
Uzi
U
D000199:Actins / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005920:Glomerular Mesangium; D015432:Glomerulonephritis, Membranoproliferative / Q000150:complications / Q000276:immunology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007518:Isoantibodies / Q000276:immunology; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009130:Muscle, Smooth / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014635:Valproic Acid / Q000494:pharmacology
D000199:Actins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007518:Isoantibodies; D053773:Transforming Growth Factor beta1; C035678:anti-Thy antibody; C012589:trichostatin A; D014635:Valproic Acid; D003094:Collagen