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.

约 40% 的糖尿病患者患有糖尿病肾病 (DKD)，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 万个细胞图谱揭示了所有肾细胞类型对 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) 对近曲小管 S1 段的早期影响表明，此类药物可诱导禁食拟态和缺氧反应。Srsf7 的体外近端小管敲除诱导促炎表型，暗示选择性剪接是 DKD 的驱动因素，并表明 SGLT2i 对近端小管选择性剪接的调节是此类药物的潜在作用机制。