Renal Tubule-Specific Angiotensinogen Deletion Attenuates SGLT2 Expression and Ameliorates Diabetic Kidney Disease in Murine Models of Type 1 Diabetes

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2025-01-03 DOI:10.2337/db24-0553

Wen-Xia Yang, Ke Su, Min-Chun Liao, Jing Zhou, Junzheng Peng, Marie-Josée Hébert, Daniel N. Leal, Michifumi Yamashita, Kana N. Miyata, Janos G. Filep, Julie R. Ingelfinger, Shao-Ling Zhang, John S.D. Chan

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Abstract

The role of the intrarenal renin-angiotensin system (iRAS) in diabetic kidney disease (DKD) progression remains unclear. In this study, we generated mice with renal tubule-specific deletion of angiotensinogen (Agt; RT-Agt-/-) in both Akita and streptozotocin (STZ)-induced mouse model of diabetes. Both Akita RT-Agt-/- and STZ-RT-Agt-/- mice exhibited significant attenuation of glomerular hyperfiltration, urinary albumin/creatinine ratio, glomerulomegaly and tubular injury. Urinary Agt, Angiotensin II (Ang II) and oxidative stress were decreased in Akita RT-Agt-/- mice cf. Akita mice. Moreover, thickened glomerular basement membranes, podocyte foot process effacement and podocyte loss were ameliorated in Akita RT-Agt-/- mice cf. Akita mice. Mechanistically, intra-vital microscopy revealed that attenuation of glomerular hyperfiltration in Akita RT-Agt-/- mice was mediated via efferent arteriole (EA) vasodilation and afferent arteriole (AA) vasoconstriction. The AA vasoconstriction was regulated, at least partially, through tubulo-glomerular feedback by down-regulation of sodium-glucose co-transporter 2 (SGLT2) expression in renal proximal tubules. The renal protective effect of iRAS inactivation in Akita RT-Agt-/- mice was more evident than in Akita mice treated with RAS blockers. In vitro, Ang II stimulated, losartan and apocynin inhibited SGLT2 expression in immortalized human renal proximal tubular cells. These findings suggest targeting the iRAS may constitute effective treatment for DKD.

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肾小管特异性血管紧张素原缺失降低SGLT2表达并改善1型糖尿病小鼠模型中的糖尿病肾病

肾内肾素-血管紧张素系统（iRAS）在糖尿病肾病（DKD）进展中的作用尚不清楚。在这项研究中，我们产生了肾小管特异性血管紧张素原（Agt）缺失的小鼠；RT-Agt-/-)在秋田和链脲佐菌素（STZ）诱导的糖尿病小鼠模型中的表达。秋田RT-Agt-/-和STZ-RT-Agt-/-小鼠肾小球高滤过、尿白蛋白/肌酐比、肾小球肿大和肾小管损伤均明显减弱。秋田RT-Agt-/-小鼠的尿Agt、血管紧张素II （Ang II）和氧化应激均降低。此外，秋田RT-Agt-/-小鼠肾小球基底膜增厚、足细胞足突消失和足细胞损失得到改善。在机制上，活体显微镜显示秋田RT-Agt-/-小鼠肾小球高滤过的衰减是通过传出小动脉（EA）血管扩张和传入小动脉（AA）血管收缩介导的。AA血管收缩至少部分通过肾近端小管钠-葡萄糖共转运蛋白2 （SGLT2）表达下调的小管-肾小球反馈调节。iRAS失活对秋田RT-Agt-/-小鼠的肾保护作用比RAS阻滞剂处理的秋田小鼠更明显。在体外，Ang II刺激，氯沙坦和罗布麻素抑制永生化人肾近端小管细胞中SGLT2的表达。这些发现表明靶向iRAS可能是DKD的有效治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.