Nutrient-derived modification of mineral corticoid receptors is relevant to diabetic kidney disease progression
Nutrient-derived modification of mineral corticoid receptors is relevant to diabetic kidney disease progression
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盐皮质激素受体的营养源性修饰与糖尿病肾病进展相关
DOI：
10.1038/s41440-022-01107-8
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发表时间：
2022
影响因子：
5.4
通讯作者：
Kanasaki Keizo
中科院分区：
文献类型：
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作者：
Takeshi Matsubara;Hideki Yokoi;Hiroyuki Yamada;Motoko Yanagita;Kanasaki Keizo
2型糖尿病患者的糖尿病肾病(DKD)是终末期肾病最常见的原因，目前尚无基本的治疗方法可用于阻止其进展。此外，DKD患者的心血管风险高得令人难以置信。适合于控制主要危险因素的疗法，如那些针对血糖管理和血压控制的疗法，将是一个根本的方法。此外，直到最近，肾素血管紧张素系统(RAS)抑制剂一直是对抗DKD的唯一和最合适的治疗方法；然而，它们与显著的残余风险相关。自从后RAS抑制剂时代发现RAS抑制剂治疗DKD的临床应用以来，我们一直被蒙在鼓里，20多年来对DKD的治疗进展甚微。然而，自EMPA-Reg试验以来，我们见证了DKD治疗和钠-葡萄糖共转运体2(SGLT2)抑制剂研究的巨大进步。然而，即使使用SGLT2抑制剂治疗，DKD的残留风险仍然是一个重大负担，特别是在晚期蛋白尿患者中。因此，我们现在需要进入DKD研究的“后GLT2抑制剂时代”[1]。矿物质皮质激素受体(MR)的激活被认为是包括DKD在内的多种代谢、高血压和肾脏疾病的致病信号通路。一些临床试验已经揭示了MR拮抗剂(MRA)对糖尿病肾病患者的蛋白尿影响，但直到最近还没有确凿的证据表明肾脏结果[2]。在2020年和2021年，一种新的非类固醇MRA，非甾体酮，对糖尿病蛋白尿DKD患者的良好肾脏和心血管保护作用被报道[3]。尽管在“后SGLT2抑制剂时代”，非那瑞酮是否能改变DKD治疗的游戏规则尚未确定，但一些临床前分析已经对SGLT2抑制剂和MRA联合治疗的效果提供了令人兴奋的结果[4]。此外，分析SGLT2抑制剂或MRAs效用的临床试验表明，将这两种药物结合起来可以提供良好的器官保护。然而，DKD的MR激活机制尚未完全阐明。
Diabetic kidney disease (DKD) in type 2 diabetic patients is the most common cause of end-stage kidney disease, and no fundamental therapy is available to halt its progression. Additionally, cardiovascular risk is incredibly high among patients with DKD. Therapies appropriate for controlling major risk factors, such as those targeted to blood glucose management and blood pressure control, would be a fundamental approach. In addition, until recently, reninangiotensin system (RAS) inhibitors had been the only and most appropriate therapy to combat DKD; however, they are associated with significant residual risks. Since the discovery of the clinical utility of RAS inhibitors against DKD in the post-RAS inhibitor era, we have remained in the dark, with little progress in DKD therapy for more than 20 years. However, since the EMPA-REG trial, we have witnessed tremendous progress in DKD therapy and research on sodium-glucose cotransporter 2 (SGLT2) inhibitors. Nevertheless, even with SGLT2 inhibitor therapy, a residual risk of DKD remains a significant burden, especially in patients with advanced albuminuria. Therefore, we now need to move on to the “post-GLT2 inhibitor era” in DKD research [1]. The activation of mineral corticoid receptor (MR) has been recognized as the pathogenic signaling pathway in various metabolic, hypertensive, and kidney diseases, including DKD. Several clinical trials have revealed the proteinurialowering influence of MR antagonists (MRAs) in diabetic kidney disease patients but without hard evidence for kidney outcomes until recently [2]. In 2020 and 2021, excellent kidney and CVD protective effects of a novel nonsteroidal MRA, finerenone, on diabetic patients with albuminuricDKD were reported [3]. Although whether or not finerenone can be the game changer in DKD therapy in the “post-SGLT2 inhibitor era” has not yet been established, some preclinical analyses have provided exciting results on the effects of SGLT2 inhibitor and MRA combination therapy [4]. Additionally, clinical trials analyzing the utility of either SGLT2 inhibitors or MRAs revealed that combining these two drugs could provide excellent organ protection. However, the MR activation mechanisms in DKD have not yet been completely elucidated.