Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy.
Activation of renal interstitial fibroblasts is critically involved in the development of tubulointerstitial fibrosis in chronic kidney diseases. In this study, we investigated the effect of trichostatin A (TSA), a specific histone deacetylase (HDAC) inhibitor, on the activation of renal interstitial fibroblasts in a rat renal interstitial fibroblast line (NRK-49F) and the development of renal fibrosis in a murine model of unilateral ureteral obstruction (UUO). alpha-Smooth muscle actin (alpha-SMA) and fibronectin, two hallmarks of fibroblast activation, were highly expressed in cultured NRK-49F cells, and their expression was inhibited in the presence of TSA. Similarly, administration of TSA suppressed the expression of alpha-SMA and fibronectin and attenuated the accumulation of renal interstitial fibroblasts in the kidney after the obstructive injury. Activation of renal interstitial fibroblasts was accompanied by phosphorylation of signal transducer and activator of transcription 3 (STAT3), and TSA treatment also abolished these responses. Furthermore, inhibition of the STAT3 pathway with AG490 inhibited expression of alpha-SMA and fibronectin in NRK-49F cells. Finally, TSA treatment inhibited tubular cell apoptosis and caspase-3 activation in the obstructive kidney. Collectively, we suggest that pharmacological HDAC inhibition may induce antifibrotic activity by inactivation of renal interstitial fibroblasts and inhibition of renal tubular cell death. STAT3 may mediate those actions of HDACs.
Pang
Maoyin
M
Department of Medicine, Brown Univ. School of Medicine, Rhode Island Hospital, Providence, RI 02903, USA.
Kothapally
Jagan
J
Mao
Haiping
H
Tolbert
Evelyn
E
Ponnusamy
Murugavel
M
Chin
Y Eugene
YE
Zhuang
Shougang
S
D000107:Acetylation; D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000201:enzymology* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014517:Ureteral Obstruction / Q000201:enzymology*
D000199:Actins; D053148:Caspase 3; D005353:Fibronectins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; C544013:alpha-smooth muscle actin, mouse; C498862:Acta2 protein, rat; C012589:trichostatin A