Angiotensin receptor blockers (ARBs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been used as the standard therapy for patients with diabetic kidney disease (DKD). However, how these two drugs possess additive renoprotective effects remains unclear. Here, we conducted single-cell RNA sequencing to profile the kidney cell transcriptome of db/db mice treated with vehicle, ARBs, SGLT2i, or ARBs plus SGLT2i, using db/m mice as control. We identified 10 distinct clusters of kidney cells with predominant proximal tubular (PT) cells. We found that ARBs had more anti-inflammatory and anti-fibrotic effects, while SGLT2i affected more mitochondrial function in PT. We also identified a new PT subcluster, was increased in DKD, but reversed by the treatments. This new subcluster was also confirmed by immunostaining of mouse and human kidneys with DKD. Together, our study reveals kidney cell-specific gene signatures in response to ARBs and SGLT2i and identifies a new PT subcluster, which provides new insight into the pathogenesis of DKD.

血管紧张素受体阻滞剂 (ARB) 和钠-葡萄糖协同转运蛋白 2 抑制剂 (SGLT2i) 已被用作糖尿病肾病 (DKD) 患者的标准疗法。然而，这两种药物如何具有相加的肾脏保护作用仍不清楚。在这里，我们进行了单细胞 RNA 测序，以分析用载体、ARB、SGLT2i 或 ARB 加 SGLT2i 处理的 db/db 小鼠的肾细胞转录组，使用 db/m 小鼠作为对照。我们确定了 10 个不同的肾细胞簇，其中近端肾小管 (PT) 细胞占主导地位。我们发现 ARB 具有更强的抗炎和抗纤维化作用，而 SGLT2i 对 PT 中线粒体功能的影响更大。我们还确定了一个新的 PT 子群，在 DKD 中增加，但被治疗逆转。这个新的亚群也通过 DKD 小鼠和人类肾脏的免疫染色得到证实。总之，我们的研究揭示了响应 ARB 和 SGLT2i 的肾细胞特异性基因特征，并确定了一个新的 PT 亚群，这为 DKD 的发病机制提供了新的见解。