Abstract
Tubulointerstitial fibrosis is a common feature of kidney disease. Histone deacetylase (HDAC) inhibitors have been reported to attenuate renal fibrosis progression. Here, we investigated the effect of CG200745, a novel HDAC inhibitor, on renal fibrosis development in a mouse model of unilateral ureteral obstruction (UUO). To examine the effects of CG200745 on renal fibrosis in UUO, C57BL/6 J male mice were divided into three groups: control, UUO, and CG200745 (30 mg/kg/day)-treated UUO groups. CG 200745 was administered through drinking water for 1 week. Human proximal tubular epithelial (HK-2) cells were also treated with CG200745 (10 µM) with or without TGF-β (2 ng/mL). Seven days after UUO, plasma creatinine did not differ among the groups. However, plasma neutrophil gelatinase-associated lipocalin (NGAL) levels were markedly increased in the UUO group, which were attenuated by CG200745 treatment. UUO kidneys developed marked fibrosis as indicated by collagen deposition and increased α-smooth muscle actin (SMA) and fibronectin expression. CG200745 treatment attenuated these fibrotic responses and suppressed UUO-induced production of transforming growth factor-beta1 (TGF-β) and phosphorylation of Smad-2/3. CG200745 treatment also attenuated UUO-induced inflammation as indicated by the expression of inflammatory markers. Furthermore, CG200745 attenuated phosphorylation of p38 mitogen-activated protein kinase in UUO kidneys. In HK-2 cells, TGF-β induced the expression of α-SMA and fibronectin, which were attenuated by CG200745 cotreatment. These results demonstrate that CG200745, a novel HDAC inhibitor, has a renoprotective effect by suppressing renal fibrosis and inflammation in a UUO mouse model.
Highlights
Chronic kidney disease (CKD) continues to increase worldwide, treatments are not sufficient to slow the progression of the disease[1]
We demonstrated that CG200745 attenuates renal injury in a mouse model of UUO
CG200745 inhibited the TGF-β/Smad-dependent signaling pathway that contributes to renal fibrosis induced by UUO
Summary
Chronic kidney disease (CKD) continues to increase worldwide, treatments are not sufficient to slow the progression of the disease[1]. Studies are underway to find candidate therapeutic agents that can attenuate the progression of CKD, and histone deacetylase (HDAC) inhibitors have been identified as such an agent[2]. Epigenetic modifications such as DNA methylation or histone acetylation are regarded as important steps in the development of acute kidney injury (AKI), CKD, and the progression of AKI to CKD, and they have been studied to identify epigenetic changes that occur in kidney injury and therapeutic targets[3]. CG200745 increases H3 acetylation and acetylation of non-histone proteins such as tubulin and p5313,14 This novel HDAC inhibitor has been shown to have anticancer effects against colon cancer[14], prostate cancer[13], non-small cell lung cancer[15], pancreatic cancer[16], and cholangiocarcinoma[17] cell lines. We investigated the renoprotective effects of CG200745 in mouse model of obstructive uropathy
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