Profiling of kidney transcriptome at the single-cell level reveals a distinct response of proximal tubular cells to SGLT2 inhibitor and angiotensin receptor blocker treatment in diabetic mice.
Profiling of kidney transcriptome at the single-cell level reveals a distinct response of proximal tubular cells to SGLT2 inhibitor and angiotensin receptor blocker treatment in diabetic mice.
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DOI：
10.1016/j.ymthe.2021.10.013
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发表时间：
2021-10
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通讯作者：
Jinshan Wu;Zeguo Sun;Shumin Yang;Jia Fu;Ying Fan;Niansong Wang;Jinbo Hu;Linqiang Ma;Chuan Peng;Zhihong Wang;Kyung Lee;J. He;Qifu Li
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作者：
Jinshan Wu;Zeguo Sun;Shumin Yang;Jia Fu;Ying Fan;Niansong Wang;Jinbo Hu;Linqiang Ma;Chuan Peng;Zhihong Wang;Kyung Lee;J. He;Qifu Li
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（SGLT 2 i）已被用作糖尿病肾病（DKD）患者的标准治疗。然而，这两种药物如何具有相加的肾保护作用仍不清楚。在此，我们进行了单细胞RNA测序，以分析接受溶媒、ARB、SGLT 2 i或ARB + SGLT 2 i给药的db/db小鼠的肾细胞转录组，并使用db/m小鼠作为对照。我们确定了10个不同的集群肾细胞为主的近端肾小管（PT）细胞。我们发现ARB具有更强的抗炎和抗纤维化作用，而SGLT 2 i对PT中线粒体功能的影响更大。我们还确定了一个新的PT亚群，在DKD中增加，但通过治疗逆转。这一新的亚群也通过DKD对小鼠和人肾脏的免疫染色得到证实。总之，我们的研究揭示了肾细胞特异性基因特征对ARB和SGLT 2 i的反应，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。
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.