Impact of sodium glucose linked cotransporter-2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus.
Impact of sodium glucose linked cotransporter-2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus.
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钠 - 葡萄糖协同转运蛋白2抑制剂对糖尿病啮齿动物模型肾微血管氧张力的影响
DOI：
10.14814/phy2.14890
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发表时间：
2021-06
影响因子：
2.5
通讯作者：
Gilbert RE
中科院分区：
文献类型：
--
作者：
Hare GMT;Zhang Y;Chin K;Thai K;Jacobs E;Cazorla-Bak MP;Nghiem L;Wilson DF;Vinogradov SA;Connelly KA;Mazer CD;Evans RG;Gilbert RE
钠 - 葡萄糖协同转运蛋白2（SGLT2）抑制剂在糖尿病患者中发挥肾脏保护作用的机制尚未完全明确，但据推测，这可能包括改善肾皮质内的组织氧张力。SGLT2抑制作用在肾脏内可能较为复杂且具有区域特异性。我们假设，SGLT2抑制剂对糖尿病肾脏特定区域的肾组织氧输送和消耗具有不同影响，这些区域包括含有富含SGLT2的近端小管成分的浅表皮质，以及主要含有SGLT1受体的深部皮质和外髓质。
我们测量了用SGLT2抑制剂达格列净治疗的糖尿病大鼠（链脲佐菌素诱导）的肾小球滤过率（GFR）、肾脏微血管氧张力（PkO₂）、促红细胞生成素（EPO）信使核糖核酸（mRNA）以及网织红细胞计数。利用氧的磷光猝灭原理和血管内氧敏感探针（Oxyphor PdG4），我们在糖尿病和非糖尿病大鼠体内以区域特异性方式探究了SGLT2抑制对PkO₂的影响。分别使用蓝光和红光激发来测量浅表肾皮质或深部皮质及外髓质的PkO₂。
在接受达格列净治疗的糖尿病大鼠中，浅表皮质（蓝光激发测量）的PkO₂无变化。相比之下，深部皮质和外髓质（红光激发测量）的结果显示，接受达格列净治疗的糖尿病大鼠的PkO₂显著降低（p = 0.014）。与这些发现一致的是，糖尿病大鼠在接受SGLT2抑制治疗后，GFR降低，缺氧反应性EPO mRNA水平升高，网织红细胞计数增加（所有指标p均 < 0.05）。
这些研究结果表明，浅表皮质的肾脏微血管氧张力得以维持，但深部皮质和外髓质组织中的氧张力降低，这可能是由于SGLT - 2抑制对组织代谢的区域影响所致。深部PkO₂的降低具有生物学影响，肾脏EPO mRNA水平升高和循环网织红细胞计数增加就证明了这一点。
我们的研究结果表明，肾脏微血管氧张力（PkO₂）在浅表皮质得以维持，但在深部皮质和外髓质组织中降低，这可能是由于钠 - 葡萄糖协同转运蛋白2抑制对组织代谢的区域影响所致。深部PkO₂的降低具有生物学影响，肾脏促红细胞生成素mRNA水平升高和循环网织红细胞计数增加就证明了这一点。
The mechanisms whereby inhibitors of sodium‐glucose linked cotransporter‐2 (SGLT2) exert their nephroprotective effects in patients with diabetes are incompletely understood but have been hypothesized to include improved tissue oxygen tension within the renal cortex. The impact of SGLT2 inhibition is likely complex and region specific within the kidney. We hypothesize that SGLT2 inhibitors have differential effects on renal tissue oxygen delivery and consumption in specific regions of the diabetic kidney, including the superficial cortex, containing SGLT2‐rich components of proximal tubules, versus the deeper cortex and outer medulla, containing predominantly SGLT1 receptors. We measured glomerular filtration rate (GFR), microvascular kidney oxygen tension (PkO2), erythropoietin (EPO) mRNA, and reticulocyte count in diabetic rats (streptozotocin) treated with the SGLT2 inhibitor, dapagliflozin. Utilizing phosphorescence quenching by oxygen and an intravascular oxygen sensitive probe (Oxyphor PdG4); we explored the effects of SGLT2 inhibition on PkO2 in a region‐specific manner, in vivo, in diabetic and non‐diabetic rats. Superficial renal cortical or deeper cortical and outer medullary PkO2 were measured utilizing excitations with blue and red light wavelengths, respectively. In diabetic rats treated with dapagliflozin, measurement within the superficial cortex (blue light) demonstrated no change in PkO2. By contrast, measurements in the deeper cortex and outer medulla (red light) demonstrated a significant reduction in PkO2 in dapagliflozin treated diabetic rats (p = 0.014). Consistent with these findings, GFR was decreased, hypoxia‐responsive EPO mRNA levels were elevated and reticulocyte counts were increased with SGLT2 inhibition in diabetic rats (p < 0.05 for all). These findings indicate that microvascular kidney oxygen tension is maintained in the superficial cortex but reduced in deeper cortical and outer medullary tissue, possibly due to the regional impact of SGLT‐2 inhibition on tissue metabolism. This reduction in deeper PkO2 had biological impact as demonstrated by increased renal EPO mRNA levels and circulating reticulocyte count. Our findings indicate that microvascular kidney oxygen tension (PkO2) is maintained in the superficial cortex but reduced in deeper cortical and outer medullary tissue, possibly due to the regional impact of sodium‐glucose linked cotransporter‐2 inhibition on tissue metabolism. This reduction in deeper PkO2 had biological impact as demonstrated by increased renal erythropoietin mRNA levels and circulating reticulocyte count.
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影响因子：
24
作者：
Januzzi, James L.;Butler, Javed;Davies, Michael J.
通讯作者：
Davies, Michael J.
DOI：
10.1152/ajprenal.00206.2006
发表时间：
2007-02-01
影响因子：
4.2
作者：
Johannes, Tanja;Mik, Egbert G.;Ince, Can
通讯作者：
Ince, Can
影响因子：
158.5
作者：
Perkovic, V.;Jardine, M. J.;Bentley-Lewis, Rhonda
通讯作者：
Bentley-Lewis, Rhonda
影响因子：
4.6
作者：
Kamezaki, Michitsugu;Kusaba, Tetsuro;Tamagaki, Keiichi
通讯作者：
Tamagaki, Keiichi
影响因子：
37.8
作者：
Lytvyn Y;Bjornstad P;Udell JA;Lovshin JA;Cherney DZI
通讯作者：
Cherney DZI