Corremans Raphaëlle, Neven Ellen, Maudsley Stuart, Leysen Hanne, De Broe Marc E, D'Haese Patrick C, Vervaet Benjamin A, Verhulst Anja
Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Receptor Biology Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Kidney Int. 2022 May;101(5):929-944. doi: 10.1016/j.kint.2022.01.037. Epub 2022 Mar 7.
Current treatment strategies for chronic kidney disease (CKD) mainly focus on controlling risk factors. Metformin, a first-line drug for type 2 diabetes, exerts beneficial pleiotropic actions beyond its prescribed use and incipient data have revealed protective effects against the development of kidney impairment. This study evaluated the therapeutic efficacy of metformin and canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor recently approved by the United States Food and Drug Administration to treat diabetic nephropathy, in slowing the progression of established non-diabetic CKD. Rats with adenine-induced CKD were assigned to different treatment groups to receive either 200 mg/kg metformin, four or five weeks after the start of the adenine diet (established mild-moderate CKD), or 25 mg/kg canagliflozin four weeks after the start of the diet, by daily oral gavage administered during four weeks. Each treatment group was compared to a vehicle group. Chronic adenine dosing resulted in severe CKD in vehicle-treated rats as indicated by a marked rise in serum creatinine levels, a marked decrease in creatinine clearance, and a disturbed mineral metabolism. Metformin, but not canagliflozin, halted functional kidney decline. Additionally, kidneys of metformin-treated animals showed less interstitial area and inflammation as compared to the vehicle group. Proteomic analyses revealed that metformin's kidney-protective effect was associated with the activation of the Hippo signaling pathway, a highly conserved multiprotein kinase cascade that controls tissue development, organ size, cell proliferation, and apoptosis. Thus, metformin demonstrated therapeutic efficacy by halting the progression of established CKD in a rat model.
慢性肾脏病（CKD）的当前治疗策略主要集中在控制危险因素。二甲双胍是2型糖尿病的一线药物，除了其规定用途外还具有有益的多效性作用，初步数据显示其对肾脏损害的发生具有保护作用。本研究评估了二甲双胍和卡格列净（一种最近被美国食品药品监督管理局批准用于治疗糖尿病肾病的钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂）在减缓已确诊的非糖尿病性CKD进展方面的治疗效果。将腺嘌呤诱导的CKD大鼠分配到不同的治疗组，在腺嘌呤饮食开始四或五周后（已确诊为轻度至中度CKD）给予200mg/kg二甲双胍，或在饮食开始四周后给予25mg/kg卡格列净，通过每日口服灌胃给药，持续四周。将每个治疗组与溶剂对照组进行比较。慢性给予腺嘌呤导致溶剂对照组大鼠出现严重的CKD，表现为血清肌酐水平显著升高、肌酐清除率显著降低以及矿物质代谢紊乱。二甲双胍而非卡格列净阻止了肾脏功能的下降。此外，与溶剂对照组相比，二甲双胍治疗组动物的肾脏间质面积和炎症较少。蛋白质组学分析表明，二甲双胍的肾脏保护作用与Hippo信号通路的激活有关，Hippo信号通路是一种高度保守的多蛋白激酶级联反应，可控制组织发育、器官大小、细胞增殖和细胞凋亡。因此，在大鼠模型中，二甲双胍通过阻止已确诊的CKD进展而显示出治疗效果。
