Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease
Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease
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DOI：
10.1007/s00125-019-4859-4
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发表时间：
2019-07-01
期刊：
影响因子：
8.2
通讯作者：
Mayer, Gert
中科院分区：
文献类型：
--
作者：
Heerspink, Hiddo J. L.;Perco, Paul;Mayer, Gert
目的/假设钠-葡萄糖协同转运蛋白2（SGLT 2）抑制剂卡格列净可减缓2型糖尿病患者肾功能下降的进展。本研究的目的是评估SGLT 2抑制剂卡格列净对糖尿病肾病（DKD）进展生物标志物的影响。方法基于人近端肾小管细胞的体外转录组学实验和科学文献中与SGLT 2抑制剂相关的分子特征，构建卡格列净作用机制（MoA）网络模型。该模型被映射到一个已建立的DKD网络模型，该模型描述了与DKD相关的分子过程。随后使用两个网络中的重叠区域来选择随卡格列净治疗而变化的候选生物标志物。这些生物标志物的测量，在296个存储的血浆样本从以前报道的2年临床试验比较canagliflozin与glimepirid.Results四十四个蛋白质存在于canagliflozin MoA分子模型重叠的蛋白质在DKD网络模型。这些蛋白被认为是监测卡格列净对DKD病理生理学影响的候选蛋白。对于这些蛋白质中的10种，科学证据表明它们参与DKD进展。其中，与格列美脲相比，卡格列净300 mg/天可降低TNF受体1的血浆水平（TNFR1; 9.2%; p < 0.001），IL-6（26.6%; p = 0.010），基质金属蛋白酶7（MMP 7; 24.9%; p = 0.011）和纤连蛋白1（FN 1，14.9%; p = 0.055）。结论/解释观察到的TNFR 1，IL-6，MMP 7和FN 1表明卡格列净有助于逆转与炎症、细胞外基质转换和纤维化相关的分子过程。
Aims/hypothesis The sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin slows progression of kidney function decline in type 2 diabetes. The aim of this study was to assess the effect of the SGLT2 inhibitor canagliflozin on biomarkers for progression of diabetic kidney disease (DKD).Methods A canagliflozin mechanism of action (MoA) network model was constructed based on an in vitro transcriptomics experiment in human proximal tubular cells and molecular features linked to SGLT2 inhibitors from scientific literature. This model was mapped onto an established DKD network model that describes molecular processes associated with DKD. Overlapping areas in both networks were subsequently used to select candidate biomarkers that change with canagliflozin therapy. These biomarkers were measured in 296 stored plasma samples from a previously reported 2 year clinical trial comparing canagliflozin with glimepiride.Results Forty-four proteins present in the canagliflozin MoA molecular model overlapped with proteins in the DKD network model. These proteins were considered candidates for monitoring impact of canagliflozin on DKD pathophysiology. For ten of these proteins, scientific evidence was available suggesting that they are involved in DKD progression. Of these, compared with glimepiride, canagliflozin 300 mg/day decreased plasma levels of TNF receptor 1 (TNFR1; 9.2%; p < 0.001), IL-6 (26.6%; p = 0.010), matrix metalloproteinase 7 (MMP7; 24.9%; p = 0.011) and fibronectin 1 (FN1; 14.9%; p = 0.055) during 2 years of follow-up.Conclusions/interpretation The observed reduction in TNFR1, IL-6, MMP7 and FN1 suggests that canagliflozin contributes to reversing molecular processes related to inflammation, extracellular matrix turnover and fibrosis.