Sodium-Glucose Linked Cotransporter-2 Inhibition Does Not Attenuate Disease Progression in the Rat Remnant Kidney Model of Chronic Kidney Disease.
Sodium-Glucose Linked Cotransporter-2 Inhibition Does Not Attenuate Disease Progression in the Rat Remnant Kidney Model of Chronic Kidney Disease.
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DOI：
10.1371/journal.pone.0144640
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Gilbert RE
中科院分区：
文献类型：
--
作者：
Zhang Y;Thai K;Kepecs DM;Gilbert RE
近端肾小管钠-葡萄糖连接协同转运蛋白 2 (SGLT2) 的药理学抑制会导致糖尿病和非糖尿病环境中的糖尿。由于具有调节肾小管肾小球反馈的能力，SGLT2 抑制剂（如阻断肾素-血管紧张素系统的药物）可降低肾小球内压力和单一肾单位 GFR，从而可能提供肾脏保护。为了进一步研究这一点，我们对 5/6（次全）肾切除大鼠施用 SGLT2 抑制剂达格列净，这是一种进行性慢性肾病 (CKD) 模型，与人类 CKD 类似，其特征是单肾单位高滤过和肾小球内高血压，其中血管紧张素转换酶抑制剂和血管紧张素受体阻滞剂明显有益。与未治疗的大鼠相比，接受达格列净的假手术大鼠和 5/6 肾切除大鼠均出现大量糖尿。肾切除大鼠出现高血压、大量蛋白尿和肾小球滤过率下降，但服用达格列净对此没有影响。同样，SGLT2 抑制不会减弱肾小球硬化、肾小管间质纤维化或促纤维化细胞因子的过度表达，从而改变 5/6 肾切除大鼠肾脏中的生长因子-ß1 mRNA。虽然不排除对糖尿病患者的有益作用，但这些研究结果表明，SGLT2 抑制在这种经典的进行性非糖尿病 CKD 模型中不具有肾脏保护作用。
Pharmacological inhibition of the proximal tubular sodium-glucose linked cotransporter-2 (SGLT2) leads to glycosuria in both diabetic and non-diabetic settings. As a consequence of their ability to modulate tubuloglomerular feedback, SGLT2 inhibitors, like agents that block the renin-angiotensin system, reduce intraglomerular pressure and single nephron GFR, potentially affording renoprotection. To examine this further we administered the SGLT2 inhibitor, dapagliflozin, to 5/6 (subtotally) nephrectomised rats, a model of progressive chronic kidney disease (CKD) that like CKD in humans is characterised by single nephron hyperfiltration and intraglomerular hypertension and where angiotensin converting enzyme inhibitors and angiotensin receptor blockers are demonstrably beneficial. When compared with untreated rats, both sham surgery and 5/6 nephrectomised rats that had received dapagliflozin experienced substantial glycosuria. Nephrectomised rats developed hypertension, heavy proteinuria and declining GFR that was unaffected by the administration of dapagliflozin. Similarly, SGLT2 inhibition did not attenuate the extent of glomerulosclerosis, tubulointerstitial fibrosis or overexpression of the profibrotic cytokine, transforming growth factor-ß1 mRNA in the kidneys of 5/6 nephrectomised rats. While not precluding beneficial effects in the diabetic setting, these findings indicate that SGLT2 inhibition does not have renoprotective effects in this classical model of progressive non-diabetic CKD.