Division of Nephrology, Department of Medicine, Washington University, St. Louis, MO, USA.
CVM Janssen Research & Development, Boston, MA, USA.
Cell Metab. 2022 Jul 5;34(7):1064-1078.e6. doi: 10.1016/j.cmet.2022.05.010. Epub 2022 Jun 15.
Diabetic kidney disease (DKD) occurs in ∼40% of patients with diabetes and causes kidney failure, cardiovascular disease, and premature death. We analyzed the response of a murine DKD model to five treatment regimens using single-cell RNA sequencing (scRNA-seq). Our atlas of ∼1 million cells revealed a heterogeneous response of all kidney cell types both to DKD and its treatment. Both monotherapy and combination therapies targeted differing cell types and induced distinct and non-overlapping transcriptional changes. The early effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on the S1 segment of the proximal tubule suggest that this drug class induces fasting mimicry and hypoxia responses. Diabetes downregulated the spliceosome regulator serine/arginine-rich splicing factor 7 (Srsf7) in proximal tubule that was specifically rescued by SGLT2i. In vitro proximal tubule knockdown of Srsf7 induced a pro-inflammatory phenotype, implicating alternative splicing as a driver of DKD and suggesting SGLT2i regulation of proximal tubule alternative splicing as a potential mechanism of action for this drug class.
糖尿病肾病（DKD）发生在约 40%的糖尿病患者中，可导致肾衰竭、心血管疾病和过早死亡。我们使用单细胞 RNA 测序（scRNA-seq）分析了一种小鼠 DKD 模型对五种治疗方案的反应。我们的约 100 万个细胞图谱显示，所有肾脏细胞类型对 DKD 及其治疗均有不同的反应。单药治疗和联合治疗针对不同的细胞类型，并诱导不同且不重叠的转录变化。钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2i）对近端小管 S1 段的早期作用表明，这类药物诱导禁食模拟和缺氧反应。糖尿病使近端小管中的剪接体调节因子丝氨酸/精氨酸丰富剪接因子 7（Srsf7）下调，SGLT2i 可特异性挽救这一下调。体外敲低近端小管中的 Srsf7 诱导促炎表型，表明选择性剪接是 DKD 的驱动因素，并提示 SGLT2i 对近端小管选择性剪接的调节可能是该药物类别的作用机制之一。
