Significance of Tubuloglomerular Feedback in SGLT1 and SGLT2 Inhibition in Diabetic Kidney Disease

糖尿病肾病中 SGLT1 和 SGLT2 抑制中肾小球反馈的意义

• 批准号: 10988559
• 负责人: Jie Zhang
• 金额: $ 41.37万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10988559
• 关键词: Significance; Tubuloglomerular; Feedback; SGLT1; SGLT2

Increased glomerular filtration rate (GFR), also known as glomerular hyperfiltration, is a common observation in the early stage of diabetes and is considered a key risk factor for the later development of diabetic kidney disease (DKD). Although the pathophysiological mechanisms of glomerular hyperfiltration in diabetes have not been fully understood, the tubuloglomerular feedback (TGF) has been implicated. In particular, the “tubular hypothesis” is now widely recognized. It describes that proximal tubular reabsorption of sodium and glucose via the sodium- glucose cotransporter 2 (SGLT2) is upregulated in the diabetic kidney, thereby reducing the NaCl delivery to the macula densa, which decreases the TGF activity and increases the single-nephron GFR in an effort to normalize NaCl excretion (SGLT2-NaCl-TGF pathway). We have recently identified a new and complementing mechanism that increases GFR in the diabetic kidney: the increased tubular glucose load at the macula densa is sensed through the apical sodium-glucose cotransporter 1 (SGLT1) and enhances the neuronal nitric oxide synthase (NOS1)-derived nitric oxide (NO) generation, which blunts TGF responsiveness and likewise increases the single-nephron GFR (SGLT1-NOS1-TGF pathway). SGLT2 inhibition is currently changing the perspectives of antidiabetic therapy with significant renoprotective effects. The benefits of SGLT2 inhibition in the diabetic kidney have been proposed to be largely independent of its blood glucose-lowering effect and mainly based on the central role of this transporter in the “tubular hypothesis” of diabetic glomerular hyperfiltration and nephropathy. In accordance with the “tubular hypothesis”, inhibition of SGLT2 increases the macula densa NaCl delivery and reduces diabetic hyperfiltration and thereby protects the diabetic kidney. However, inhibition of SGLT2 also increases glucose delivery to the macula densa, which is expected to decrease the TGF responsiveness through the macula densa SGLT1-NOS1-TGF pathway, and thereby limit both the GFR-lowering effect of SGLT2 inhibition and its protective effects on kidney. Therefore, in the present proposal, we will examine the effects of SGLT2 inhibition on the tubular glucose load at the macula densa, the macula densa NOS1/NO levels, and TGF responsiveness in diabetic mice, and then determine the significance of the macula densa SGLT1-NOS1 pathway in the SGLT2 inhibition-induced alterations in TGF and GFR by using mouse models with SGLT1 knockout or macula densa-specific NOS1 knockout; moreover, we will compare the effects of dual SGLT1/SGLT2 inhibition and selective SGLT2 inhibition on TGF activity, GFR and kidney injury in diabetic mice, and further determine the significance of the TGF mechanism in these effects by using a mouse model that lacks TGF due to macula densa-specific NKCC2 knockout. Successful completion of this proposal will establish the opposing role of the macula densa SGLT1-NOS1-TGF pathway in the protective effects of SGLT2 inhibition on diabetic glomerular hyperfiltration and kidney injury, and thus provide supportive and mechanistic evidence for the use of dual SGLT1/SGLT2 inhibition in the treatment of DKD.

肾小球滤过率（GFR）增加，也称为肾小球超滤，是肾小球疾病中常见的观察结果。 糖尿病的早期阶段，被认为是糖尿病肾病后期发展的关键危险因素 （丹麦）。尽管糖尿病肾小球高滤过的病理生理机制尚未完全阐明， 了解，肾小管肾小球反馈（TGF）已被牵连。特别是，“管状假说”是 现在被广泛认可。它描述了近端肾小管通过钠-葡萄糖重吸收钠和葡萄糖， 葡萄糖协同转运蛋白2（SGLT 2）在糖尿病肾脏中上调，从而减少了NaCl向肾脏的递送。 致密斑，其降低TGF活性并增加单肾单位GFR以使其正常化 NaCl排泄（SGLT 2-NaCl-TGF途径）。我们最近确定了一个新的补充机制 增加糖尿病肾脏的GFR：感觉到致密斑处增加的肾小管葡萄糖负荷 通过顶端钠-葡萄糖协同转运蛋白1（SGLT 1），并增强神经元型一氧化氮合酶 （NOS 1）衍生的一氧化氮（NO）产生，其减弱TGF反应性，并且同样增加了 单肾单位GFR（SGLT 1-NOS 1-TGF途径）。SGLT 2抑制目前正在改变 具有显著肾保护作用的抗糖尿病治疗。SGLT 2抑制剂在糖尿病肾脏中的获益 已经提出在很大程度上不依赖于其降血糖作用，并且主要基于 这种转运蛋白在糖尿病肾小球高滤过和肾病的“肾小管假说”中的中心作用。 根据“肾小管假说”，抑制SGLT 2可增加致密斑NaCl的递送， 减少糖尿病性超滤，从而保护糖尿病性肾脏。然而，抑制SGLT 2也 增加向致密斑的葡萄糖递送，这预期通过以下途径降低TGF应答性： 致密斑SGLT 1-NOS 1-TGF途径，从而限制SGLT 2的GFR降低作用 抑制作用及对肾脏的保护作用。因此，在本建议中，我们将研究 SGLT 2对致密斑肾小管葡萄糖负荷、致密斑NOS 1/NO水平和TGF的抑制作用 糖尿病小鼠的反应性，然后确定致密斑SGLT 1-NOS 1的意义 通过使用SGLT 1小鼠模型，研究SGLT 2抑制诱导的TGF和GFR变化的途径 敲除或致密斑特异性NOS 1敲除;此外，我们将比较双重敲除的效果。 SGLT 1/SGLT 2抑制和选择性SGLT 2抑制对糖尿病小鼠TGF活性、GFR和肾损伤的影响， 并进一步确定TGF机制在这些作用中的重要性， TGF由于黄斑致密特异性NKCC 2敲除。成功完成这一提案将建立 致密斑SGLT 1-NOS 1-TGF通路在SGLT 2抑制对视网膜病变的保护作用中的相反作用 糖尿病肾小球高滤过和肾损伤，从而提供支持性和机制的证据， 双重SGLT 1/SGLT 2抑制在DKD治疗中的用途。