Kim Hyunsik, Park Soo-Yeon, Lee Soo Yeon, Kwon Jae-Hwan, Byun Seunghee, Ko Byounghwi, Yoo Jung-Yoon, Kim Beom Seok, Lim Beom Jin, Yoon Ho-Geun
Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 03722, Korea.
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722, Korea.
EMBO Mol Med. 2025 Jul 1. doi: 10.1038/s44321-025-00243-1.
Chronic kidney disease (CKD) has a high prevalence worldwide and is typically accompanied by severe fibrosis. However, the exact pathogenesis of renal fibrosis and effective treatments have yet to be identified. In this study, we found that expression of the histone-acetyltransferase p300 was increased in focal segmental glomerulosclerosis patients and several distinct mouse models of renal fibrosis. Moreover, we showed that the AKT-mediated phosphorylation of Ser-1834 of p300 increased the stability of p300 upon renal fibrosis induction, and conversely, PPM1K specifically dephosphorylated p300 at Ser-1834, resulting in a significant reduction in p300 stability and renal fibrosis. Interestingly, increased p300 in proximal tubular cells (PTCs) promoted renal fibrosis development by mediating the endothelial to mesenchymal transition (EndMT) via upregulation of the mesenchymal-transition-related secreted proteins POSTN, FSTL1, and FSCN1. Both EndMT and renal fibrosis were significantly diminished by either PTC-specific deletion of p300 gene or selective inhibitors of p300. Collectively, our results demonstrate the role of p300 in the development of renal fibrosis, and suggest that p300 is a promising target for treatment of advanced CKD.
慢性肾脏病（CKD）在全球范围内具有较高的患病率，并且通常伴有严重的纤维化。然而，肾纤维化的确切发病机制以及有效的治疗方法尚未明确。在本研究中，我们发现组蛋白乙酰转移酶p300在局灶节段性肾小球硬化症患者以及几种不同的肾纤维化小鼠模型中的表达增加。此外，我们表明，AKT介导的p300丝氨酸1834位点的磷酸化在肾纤维化诱导时增加了p300的稳定性，相反，PPM1K特异性地使p300丝氨酸1834位点去磷酸化，导致p300稳定性和肾纤维化显著降低。有趣的是，近端肾小管细胞（PTCs）中p300的增加通过上调间充质转化相关分泌蛋白POSTN、FSTL1和FSCN1介导内皮向间充质转化（EndMT），从而促进肾纤维化的发展。通过PTC特异性缺失p300基因或p300的选择性抑制剂，EndMT和肾纤维化均显著减轻。总的来说，我们的结果证明了p300在肾纤维化发展中的作用，并表明p300是治疗晚期CKD的一个有前景的靶点。
