Buyan Marina I, Pevzner Irina B, Buyan Andrey I, Zorova Ljubava D, Zorov Dmitry B, Andrianova Nadezda V, Plotnikov Egor Y
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia.
IUBMB Life. 2025 Jul;77(7):e70044. doi: 10.1002/iub.70044.
Undesirable tissue fibroblast activation after injury is still an unresolved problem for many organs, including the kidney. Kidney fibroblasts and tubular epithelial cells demonstrate significant differences in gene expression profiles, including metabolism-related genes. As a result, these cell types exhibit differences in the energy metabolism that could be the basis of targeted therapy for fibrosis. Among other deacetylase inhibition is considered a therapeutic approach that could simultaneously promote tissue regeneration and suppress the development of fibrosis, but their relation to bioenergetics has not been considered before. In this study, we aimed to compare the influence of the HDAC inhibitor trichostatin A (TSA) on renal tubular epithelial cells and kidney fibroblasts. We analyzed resemblance and differences in TSA effects on the proliferative activity of the cells and investigated the molecular mechanisms responsible for these effects; e.g., we focused on the activity of signaling pathways associated with cell viability (Akt/mTOR/p70). We found that TSA increased the proliferation rate of epithelial cells, while it tended to decrease the growth rate of fibroblasts. Furthermore, the amount of phosphorylated forms of kinases Akt and P70 increased in epithelial cells after incubation with TSA, indicating the activation of the Akt/mTOR/p70 signaling pathway, while decreasing its activity in fibroblast cells. Since there are differences in the bioenergetics between fibroblasts and epithelial cells, we investigated the impact of TSA on the glycolytic activity of both cell types. Indeed, we showed that TSA reduced the activity of glycolytic processes in fibroblast cells. The observed changes indicate a positive effect of TSA on regenerative versus fibrotic processes in the kidney by reducing the growth and metabolic activity of fibroblasts and activating the proliferation of epithelial cells.
损伤后不良的组织成纤维细胞激活对于包括肾脏在内的许多器官来说仍是一个未解决的问题。肾成纤维细胞和肾小管上皮细胞在基因表达谱上存在显著差异，包括与代谢相关的基因。因此，这些细胞类型在能量代谢方面表现出差异，这可能是纤维化靶向治疗的基础。其中，去乙酰化酶抑制被认为是一种可以同时促进组织再生和抑制纤维化发展的治疗方法，但它们与生物能量学的关系此前尚未被考虑。在本研究中，我们旨在比较组蛋白去乙酰化酶（HDAC）抑制剂曲古抑菌素A（TSA）对肾小管上皮细胞和肾成纤维细胞的影响。我们分析了TSA对细胞增殖活性影响的异同，并研究了造成这些影响的分子机制；例如，我们重点关注了与细胞活力相关的信号通路（Akt/mTOR/p70）的活性。我们发现TSA提高了上皮细胞的增殖率，而它倾向于降低成纤维细胞的生长速率。此外，与TSA孵育后，上皮细胞中激酶Akt和P70的磷酸化形式的量增加，表明Akt/mTOR/p70信号通路被激活，而在成纤维细胞中其活性降低。由于成纤维细胞和上皮细胞在生物能量学方面存在差异，我们研究了TSA对这两种细胞类型糖酵解活性的影响。事实上，我们发现TSA降低了成纤维细胞中糖酵解过程的活性。观察到的这些变化表明，TSA通过降低成纤维细胞的生长和代谢活性以及激活上皮细胞的增殖，对肾脏的再生与纤维化过程产生了积极影响。
