School of Sports and Health, Nanjing Sport Institute, Nanjing, China.
Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Departments of Pathophysiology and Human Anatomy, Nanjing Medical University, Nanjing, China.
Life Sci. 2024 May 1;344:122578. doi: 10.1016/j.lfs.2024.122578. Epub 2024 Mar 25.
Diabetic nephropathy (DN) is one of the most common complications of diabetes and represents a prototypical form of chronic kidney disease (CKD). Interstitial fibrosis is a key pathological feature of DN. During DN-associated renal fibrosis, resident fibroblasts trans-differentiate into myofibroblasts to remodel the extracellular matrix, the underlying epigenetic mechanism of which is not entirely clear.
Diabetic nephropathy was induced in C57B6/j mice by a single injection with streptozotocin (STZ). Gene expression was examined by quantitative PCR and Western blotting. Renal fibrosis was evaluated by PicroSirius Red staining.
We report that expression of Brg1, a chromatin remodeling protein, in renal fibroblasts was up-regulated during DN pathogenesis as assessed by single-cell RNA-seq. Treatment with high glucose similarly augmented Brg1 expression in primary renal fibroblasts in vitro. Importantly, Brg1 ablation in quiescent renal fibroblasts or in mature myofibroblasts equivalently attenuated renal fibrosis in the context of diabetic nephropathy in mice. Additionally, administration with a small-molecule Brg1 inhibitor PFI-3 ameliorated renal fibrosis and improved renal function in mice induced to develop DN.
In conclusion, our data provide novel genetic evidence that links Brg1 to fibroblast-myofibroblast transition and renewed rationale for targeting Brg1 in the intervention of DN-associated renal fibrosis.
糖尿病肾病（DN）是糖尿病最常见的并发症之一，也是慢性肾脏病（CKD）的典型形式。间质纤维化是 DN 的一个关键病理特征。在与 DN 相关的肾纤维化过程中，固有成纤维细胞转分化为肌成纤维细胞，重塑细胞外基质，其潜在的表观遗传机制尚不完全清楚。
通过单次链脲佐菌素（STZ）注射诱导 C57B6/j 小鼠发生糖尿病肾病。通过定量 PCR 和 Western blot 检测基因表达。通过苦味酸天狼猩红染色评估肾纤维化。
我们报告称，通过单细胞 RNA-seq 评估，在 DN 发病过程中，染色质重塑蛋白 Brg1 在肾成纤维细胞中的表达上调。体外高糖处理同样增加了原代肾成纤维细胞中 Brg1 的表达。重要的是，在糖尿病肾病小鼠模型中，在静止的肾成纤维细胞或成熟的肌成纤维细胞中敲除 Brg1 可等效地减轻肾纤维化。此外，小分子 Brg1 抑制剂 PFI-3 的给药可改善诱导发生 DN 的小鼠的肾纤维化和肾功能。
总之，我们的数据提供了新的遗传证据，将 Brg1 与成纤维细胞-肌成纤维细胞转化联系起来，并为靶向 Brg1 干预与 DN 相关的肾纤维化提供了新的理由。
