Aims

The crosstalk between sodium-glucose cotransporter 2 (SGLT2) inhibition and a membrane-associated endocytic receptor megalin function involved in renal proximal tubular protein overload in progressive diabetic nephropathy (DN) is uncertain. Here, we determined whether SGLT2 inhibition affects megalin endocytic function through suppressing its O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) and protects the diabetic kidney from protein overload.

Materials and method

We treated 8-week-old male non-obese and hypoinsulinemic KK/Ta-Ins2^Akita (KK/Ta-Akita) mice which develop progressive DN with an SGLT2 inhibitor ipragliflozin or insulin for 6 weeks, and investigated the endocytic function (proximal tubular protein reabsorption), renal expression and O-GlcNAcylation of megalin along with their effects on renal phenotypes including histology and biochemical markers.

Results

The treatment with ipragliflozin, but not insulin, suppressed megalin O-GlcNAcylation and accelerated its internalization, resulting in reduction in proximal tubular reabsorption of the highly filtered plasma proteins such as albumin and neutrophil gelatinase-associated lipocalin. These alterations following the ipragliflozin treatment contributed to amelioration of proximal tubular protein overload, mitochondrial morphological abnormality, and renal oxidative stress and tubulointerstitial fibrosis.

Conclusions

The present study provides a novel crosstalk mechanism between SGLT2 inhibition and megalin underlying the potential renal benefits of SGLT2 inhibition in DN.

中文翻译：

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钠-葡萄糖共转运蛋白2抑制通过抑制进行性糖尿病肾病中的巨蛋白O-GlcNacylation抑制肾近端小管中的蛋白质超载

目的

进行性糖尿病肾病（DN）的肾近端肾小管蛋白超负荷涉及的钠葡萄糖共转运蛋白2（SGLT2）抑制与膜相关的内吞性受体巨蛋白功能之间的串扰尚不确定。在这里，我们确定了SGLT2抑制作用是否通过抑制其O-连接的β- N-乙酰氨基葡萄糖修饰（O-GlcNAcylation）而影响了巨蛋白的内吞功能，并保护了糖尿病肾脏免受蛋白质超载。

材料与方法

我们用SGLT2抑制剂依普利氟星或胰岛素治疗8周大的雄性非肥胖和低胰岛素血症的KK / Ta- Ins2^秋田鼠（KK / Ta-Akita）小鼠进行性DN，并研究其内吞功能（近端肾小管）为6周蛋白重吸收），巨蛋白的肾脏表达和O-GlcNAcy化及其对肾脏表型的影响，包括组织学和生化标志物。

结果

用伊普拉列净而不是胰岛素进行的治疗抑制了巨蛋白O-GlcNAcy酰化并加速了其内在化，从而导致高度过滤的血浆蛋白（如白蛋白和中性白细胞明胶酶相关的脂蛋白）的近端肾小管重吸收减少。依普列净治疗后的这些改变有助于改善近端肾小管蛋白超载，线粒体形态异常，肾氧化应激和肾小管间质纤维化。

结论

本研究提供了SGLT2抑制和巨蛋白之间的新型串扰机制，潜在地DN中SGLT2抑制的潜在肾脏益处。