Development of renal fibrosis is a hallmark of renal aging and chronic kidney disease of all etiologies and characterized by extensive renal cell injuries and subsequent myofibroblast transdifferentiations (MTDs), which are significantly influenced by aberrant histone deacetylase (HDAC) activities. However, the key HDAC isoforms and effectors that are causally involved in the processes remain poorly understood. Here, we report that aberrant HDAC3 induction and its inhibition of Klotho, a renal epithelium-enriched aging suppressor, contribute significantly to renal fibrogenesis. HDAC3 was preferentially elevated with concomitant Klotho suppression in fibrotic kidneys incurred by unilateral ureter obstruction (UUO) and aristolochic acid nephropathy (AAN), whereas Hdac3 knockout resisted the fibrotic pathologies. The HDAC3 elevation is substantially blocked by the inhibitors of TGFβ receptor and Smad3 phosphorylation, suggesting that TGFβ/Smad signal activates Hdac3 transcription. Consistently, an HDAC3-selective inhibitor RGFP966 derepressed Klotho and mitigated the renal fibrotic injuries in both UUO and AAN mice. Further, HDAC3 overexpression or inhibition in renal epithelia inversely affected Klotho abundances and HDAC3 was inducibly associated with transcription regulators NCoR and NF-kB and bound to Klotho promoter in fibrotic kidney, supporting that aberrant HDAC3 targets and transcriptionally inhibits Klotho under renal fibrotic conditions. More importantly, the antirenal fibrosis effects of RGFP966 were largely compromised in mice with siRNA-mediated Klotho knockdown. Hence, HDAC3 aberration and the subsequent Klotho suppression constitute an important regulatory loop that promotes MTD and renal fibrosis and uses of HDAC3-selective inhibitors are potentially effective in treating renal fibrotic disorders.

肾纤维化的发展是所有病因的肾衰老和慢性肾病的标志，其特征是广泛的肾细胞损伤和随后的肌成纤维细胞转分化 (MTD)，这受到异常组蛋白脱乙酰酶 (HDAC) 活性的显着影响。然而，与这些过程有因果关系的关键 HDAC 亚型和效应器仍然知之甚少。在这里，我们报告异常的 HDAC3 诱导及其对 Klotho（一种富含肾上皮细胞的衰老抑制因子）的抑制，对肾纤维化有显着贡献。HDAC3 在单侧输尿管梗阻 (UUO) 和马兜铃酸肾病 (AAN) 引起的纤维化肾脏中伴随 Klotho 抑制优先升高，而Hdac3敲除抵抗了纤维化病理。HDAC3 升高被 TGFβ 受体和 Smad3 磷酸化抑制剂基本上阻断，表明 TGFβ/Smad 信号激活了Hdac3转录。一致地，HDAC3 选择性抑制剂 RGFP966 抑制了 Klotho 并减轻了 UUO 和 AAN 小鼠的肾纤维化损伤。此外，肾上皮细胞中的 HDAC3 过表达或抑制对 Klotho 丰度产生负面影响，并且 HDAC3 可诱导地与转录调节因子 NCoR 和 NF-kB 相关并与Klotho结合纤维化肾脏中的启动子，支持异常的 HDAC3 靶向并在肾纤维化条件下转录抑制 Klotho。更重要的是，RGFP966 的抗肾纤维化作用在 siRNA 介导的 Klotho 敲低的小鼠中受到很大影响。因此，HDAC3 畸变和随后的 Klotho 抑制构成了促进 MTD 和肾纤维化的重要调节回路，并且 HDAC3 选择性抑制剂的使用在治疗肾纤维化疾病中可能有效。