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 . 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.

中文翻译：

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成纤维细胞/肌成纤维细胞谱系中 Brg1 的消除可减轻糖尿病肾病小鼠的肾纤维化

糖尿病肾病（DN）是糖尿病最常见的并发症之一，是慢性肾脏病（CKD）的典型形式。间质纤维化是 DN 的重要病理特征。在 DN 相关肾纤维化过程中，常驻成纤维细胞转分化为肌成纤维细胞以重塑细胞外基质，其潜在的表观遗传机制尚不完全清楚。通过单次注射链脲佐菌素 (STZ) 在 C57B6/j 小鼠中诱导糖尿病肾病。通过定量PCR和蛋白质印迹检查基因表达。通过PicroSirius Red染色评估肾纤维化。我们报告称，通过单细胞 RNA 测序评估，肾成纤维细胞中 Brg1（一种染色质重塑蛋白）的表达在 DN 发病过程中上调。高葡萄糖处理同样增强了原代肾成纤维细胞中的 Brg1 表达。重要的是，在小鼠糖尿病肾病的情况下，静止肾成纤维细胞或成熟肌成纤维细胞中的 Brg1 消除同等程度地减轻了肾纤维化。此外，使用小分子 Brg1 抑制剂 PFI-3 可以改善 DN 小鼠的肾纤维化并改善肾功能。总之，我们的数据提供了新的遗传证据，将 Brg1 与成纤维细胞-肌成纤维细胞转变联系起来，并为靶向 Brg1 干预 DN 相关肾纤维化提供了新的理论基础。