小柯机器人

美国华盛顿大学Benjamin D. Humphreys研究组绘制了小鼠糖尿病肾病 (DKD)对治疗反应的单细胞转录组图谱。相关论文于2022年6月15日发表在《细胞—代谢》杂志上。

他们使用单细胞 RNA 测序 (scRNA-seq) 分析了鼠 DKD 模型对五种治疗方案的反应。他们约 100 万个细胞的图谱显示所有肾细胞类型对 DKD 及其治疗的异质反应。单一疗法和联合疗法都针对不同的细胞类型并诱导不同且不重叠的转录变化。钠-葡萄糖协同转运蛋白 2 抑制剂 (SGLT2i) 对近端小管 S1 段的早期影响表明该类药物可诱导禁食模拟和缺氧反应。糖尿病下调了近端小管中的剪接体调节因子丝氨酸/精氨酸丰富的剪接因子 7 (Srsf7)，而 SGLT2i 专门拯救了该剪接体调节因子。

Srsf7 的体外近端小管敲低诱导促炎表型，暗示选择性剪接是 DKD 的驱动因素，并表明 SGLT2i 调节近端小管选择性剪接是该类药物的潜在作用机制。

据悉，DKD发生在约 40% 的糖尿病患者中，并导致肾衰竭、心血管疾病和过早死亡。

附：英文原文

Title: Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies

Author: Haojia Wu, Romer Gonzalez Villalobos, Xiang Yao, Dermot Reilly, Tao Chen, Matthew Rankin, Eugene Myshkin, Matthew D. Breyer, Benjamin D. Humphreys

Issue&Volume: 2022-06-15

Abstract: 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.

DOI: 10.1016/j.cmet.2022.05.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00192-9

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