Pang Maoyin, Kothapally Jagan, Mao Haiping, Tolbert Evelyn, Ponnusamy Murugavel, Chin Y Eugene, Zhuang Shougang
Department of Medicine, Brown Univ. School of Medicine, Rhode Island Hospital, Providence, RI 02903, USA.
Am J Physiol Renal Physiol. 2009 Oct;297(4):F996-F1005. doi: 10.1152/ajprenal.00282.2009. Epub 2009 Jul 29.
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.
肾间质成纤维细胞的激活在慢性肾脏病肾小管间质纤维化的发展过程中起关键作用。在本研究中，我们调查了曲古抑菌素A（TSA）（一种特异性组蛋白脱乙酰酶（HDAC）抑制剂）对大鼠肾间质成纤维细胞系（NRK-49F）中肾间质成纤维细胞激活的影响以及对单侧输尿管梗阻（UUO）小鼠模型肾纤维化发展的影响。α-平滑肌肌动蛋白（α-SMA）和纤连蛋白是成纤维细胞激活的两个标志，在培养的NRK-49F细胞中高表达，且在TSA存在的情况下其表达受到抑制。同样，给予TSA可抑制α-SMA和纤连蛋白的表达，并减轻梗阻性损伤后肾脏中肾间质成纤维细胞的积聚。肾间质成纤维细胞的激活伴随着信号转导和转录激活因子3（STAT3）的磷酸化，TSA处理也消除了这些反应。此外，用AG490抑制STAT3途径可抑制NRK-49F细胞中α-SMA和纤连蛋白的表达。最后，TSA处理可抑制梗阻性肾脏中肾小管细胞凋亡和半胱天冬酶-3的激活。总体而言，我们认为药理学上抑制HDAC可能通过使肾间质成纤维细胞失活和抑制肾小管细胞死亡来诱导抗纤维化活性。STAT3可能介导HDAC的这些作用。
