The long-term goal of this proposal is to elucidate the role and mechanisms of class I histone deacetylases (HDACs) in renal fibrosis. Chronic kidney disease (CKD) leading to end-stage kidney failure is associated with interstitial renal fibrosis regardless of the underlying cause. So far, there are no specific clinical treatments to target fibrosis. Renal fibrosis is characterized by aberrant activation and growth of renal interstitial fibroblasts. The activated fibroblast has been termed a myofibroblast and is defined by phenotypic changes such as the expression of -smooth muscle actin (-SMA). As myofibroblasts are able to proliferate rapidly and produce excessive matrix proteins (i.e. fibronectin) that contribute to the pathology of renal fibrosis, an approach that inhibits renal fibroblast activation and proliferation may attenuate or halt the progression of CKD. Our preliminary data demonstrate that: 1) treatment with trichostatin A (TSA), a specific inhibitor of class I/II histone deacetylases (HDACs), inhibits cell proliferation and expression of -SMA and fibronectin in cultured rat renal interstitial fibroblasts (NRK-49F) and in the fibrotic kidney induced by unilateralureteral obstruction (UUO) injury;2) Proliferation and activation of renal interstitial fibroblasts are accompanied by phosphorylation of signal transducer and activator of transcription 3 (STAT3);3) Blockade of the STAT3 pathway also inhibits activation and proliferation of NRK-49F;and 4) TSA abolishes STAT3 phosphorylation in NRK-49F and in the kidney following obstructive injury. From these data, we hypothesize that HDACs-mediated activation of STAT3 regulates activation and proliferation of renal interstitial fibroblasts and progression of renal fibrosis.
Specific Aim1 will define the role of the class I HDAC isoforms in regulating cell proliferation and activation and global protein expression and lysine acetylation in renal interstitial fibroblasts.
Specific Aim 2 will elucidate the mechanism of class I HDAC-mediated activation of STAT3 in renal interstitial fibroblasts.
Specific Aim 3 will evaluate the therapeutic effect of class I HDAC and STAT3 inhibitors on the progression of renal fibrosis following obstructive injury. Successful completion of these studies will increase our knowledge of the mechanisms of renal fibrosis and facilitate the development of HDAC inhibitors as novel treatments for CKD.
Renal tubulointerstitial fibrosis is characterized by aberrant activation and growth of the renal fibroblasts. As histone deacetylase (HDAC) inhibitors are being investigated as potential anticancer drugs, elucidation of the functional role and mechanism of HDACs in the activation and proliferation of renal interstitial fibroblasts could lead to use of HDAC inhibitors as therapeutic agents for chronic kidney disease.
|Shi, Yingfeng; Xu, Liuqing; Tang, Jinhua et al. (2017) Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury. Am J Physiol Renal Physiol 312:F502-F515|
|Xiong, Chongxiang; Zang, Xiujuan; Zhou, Xiaoxu et al. (2017) Pharmacological inhibition of Src kinase protects against acute kidney injury in a murine model of renal ischemia/reperfusion. Oncotarget 8:31238-31253|
|Tang, Jinhua; Zhuang, Shougang (2016) Upregulation of AMWAP: a novel mechanism for HDAC inhibitors to protect against cisplatin nephrotoxicity. Kidney Int 89:267-9|
|Yan, Yanli; Ma, Li; Zhou, Xiaoxu et al. (2016) Src inhibition blocks renal interstitial fibroblast activation and ameliorates renal fibrosis. Kidney Int 89:68-81|
|Liu, Na; Shi, Yingfeng; Zhuang, Shougang (2016) Autophagy in Chronic Kidney Diseases. Kidney Dis (Basel) 2:37-45|
|Wang, Li; Liu, Na; Xiong, Chongxiang et al. (2016) Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis. J Am Soc Nephrol 27:2631-44|
|Zhou, Xiaoxu; Zang, Xiujuan; Ponnusamy, Murugavel et al. (2016) Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression. J Am Soc Nephrol 27:2092-108|
|Xiong, Chongxiang; Masucci, Monica V; Zhou, Xiaoxu et al. (2016) Pharmacological targeting of BET proteins inhibits renal fibroblast activation and alleviates renal fibrosis. Oncotarget 7:69291-69308|
|Liu, Feng; Zhuang, Shougang (2016) Role of Receptor Tyrosine Kinase Signaling in Renal Fibrosis. Int J Mol Sci 17:|
|Yan, Yanli; Bai, Jianwen; Zhou, Xiaoxu et al. (2015) P2X7 receptor inhibition protects against ischemic acute kidney injury in mice. Am J Physiol Cell Physiol 308:C463-72|
Showing the most recent 10 out of 43 publications