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NRF2缺乏通过下调血管紧张素原、SGLT2、CD36和FABP4的表达以及肾近端小管细胞中的脂质积累减轻db/db小鼠的糖尿病肾病。

NRF2 Deficiency Attenuates Diabetic Kidney Disease in Db/Db Mice via Down-Regulation of Angiotensinogen, SGLT2, CD36, and FABP4 Expression and Lipid Accumulation in Renal Proximal Tubular Cells.

作者信息

Su Ke, Zhao Shui-Ling, Yang Wen-Xia, Lo Chao-Sheng, Chenier Isabelle, Liao Min-Chun, Pang Yu-Chao, Peng Jun-Zheng, Miyata Kana N, Cailhier Jean-Francois, Ethier Jean, Lattouf Jean-Baptiste, Filep Janos G, Ingelfinger Julie R, Zhang Shao-Ling, Chan John S D

机构信息

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Département de Médecine, Université de Montréal, 900 Saint Denis Street, Montréal, QC H2X 0A9, Canada.

Centre de Recherche, Hôpital Maisonneuve-Rosemont, Département de Pathologie et Biologie Cellulaire, Université de Montréal, 5415 Boul. de l'Assomption, Montréal, QC H1T 2M4, Canada.

出版信息

Antioxidants (Basel). 2023 Sep 4;12(9):1715. doi: 10.3390/antiox12091715.

DOI:10.3390/antiox12091715
PMID:37760019
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10525648/
Abstract

The role(s) of nuclear factor erythroid 2-related factor 2 (NRF2) in diabetic kidney disease (DKD) is/are controversial. We hypothesized that Nrf2 deficiency in type 2 diabetes (T2D) db/db mice (db/db knockout (KO)) attenuates DKD progression through the down-regulation of angiotensinogen (AGT), sodium-glucose cotransporter-2 (SGLT2), scavenger receptor CD36, and fatty -acid-binding protein 4 (FABP4), and lipid accumulation in renal proximal tubular cells (RPTCs). Db/db KO mice were studied at 16 weeks of age. Human RPTCs (HK2) with KO via CRISPR-Cas9 genome editing and kidneys from patients with or without T2D were examined. Compared with db/db mice, db/db KO mice had lower systolic blood pressure, fasting blood glucose, kidney hypertrophy, glomerular filtration rate, urinary albumin/creatinine ratio, tubular lipid droplet accumulation, and decreased expression of AGT, SGLT2, CD36, and FABP4 in RPTCs. Male and female mice had similar results. KO attenuated the stimulatory effect of the Nrf2 activator, oltipraz, on AGT, SGLT2, and CD36 expression and high-glucose/free fatty acid (FFA)-stimulated lipid accumulation in HK2. Kidneys from T2D patients exhibited markedly higher levels of CD36 and FABP4 in RPTCs than kidneys from non-diabetic patients. These data suggest that NRF2 exacerbates DKD through the stimulation of AGT, SGLT2, CD36, and FABP4 expression and lipid accumulation in RPTCs of T2D.

摘要

核因子红细胞2相关因子2（NRF2）在糖尿病肾病（DKD）中的作用存在争议。我们推测，2型糖尿病（T2D）db/db小鼠（db/db基因敲除（KO））中Nrf2的缺乏通过下调血管紧张素原（AGT）、钠-葡萄糖协同转运蛋白2（SGLT2）、清道夫受体CD36和脂肪酸结合蛋白4（FABP4）以及肾近端小管细胞（RPTCs）中的脂质积累来减轻DKD的进展。在16周龄时对db/db KO小鼠进行研究。通过CRISPR-Cas9基因组编辑敲除Nrf2的人RPTCs（HK2）以及来自有或没有T2D患者的肾脏进行了检测。与db/db小鼠相比，db/db KO小鼠的收缩压、空腹血糖、肾脏肥大、肾小球滤过率、尿白蛋白/肌酐比值、肾小管脂质滴积累较低，并且RPTCs中AGT、SGLT2、CD36和FABP4的表达降低。雄性和雌性小鼠有相似的结果。Nrf2基因敲除减弱了Nrf2激活剂奥替普拉对AGT、SGLT2和CD36表达以及高糖/游离脂肪酸（FFA）刺激的HK2中脂质积累的刺激作用。T2D患者的肾脏在RPTCs中显示出比非糖尿病患者的肾脏明显更高水平的CD36和FABP4。这些数据表明，NRF2通过刺激T2D患者RPTCs中AGT、SGLT2、CD36和FABP4的表达以及脂质积累来加重DKD。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/682060fa2c49/antioxidants-12-01715-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/771e13a536d3/antioxidants-12-01715-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/dcef33e7100d/antioxidants-12-01715-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/027cefc6ee2b/antioxidants-12-01715-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/3f230e3175ba/antioxidants-12-01715-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/37a7c8232654/antioxidants-12-01715-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/a9d4091f404a/antioxidants-12-01715-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/eb5c9e167a88/antioxidants-12-01715-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/682060fa2c49/antioxidants-12-01715-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/771e13a536d3/antioxidants-12-01715-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/dcef33e7100d/antioxidants-12-01715-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/027cefc6ee2b/antioxidants-12-01715-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/3f230e3175ba/antioxidants-12-01715-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/37a7c8232654/antioxidants-12-01715-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/a9d4091f404a/antioxidants-12-01715-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/eb5c9e167a88/antioxidants-12-01715-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f58/10525648/682060fa2c49/antioxidants-12-01715-g008.jpg

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引用本文的文献

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Int J Mol Sci. 2025-8-2

[2]
Macrophages in Focus: Key Drivers and Therapeutic Opportunities in Diabetic Kidney Disease.

Int J Biol Sci. 2025-7-11

[3]
Association of Nrf2 Single Nucleotide Polymorphism rs35652124 and FABP4 Levels with Peripheral Artery Disease Among Type 2 Diabetes Mellitus Pakistani Population.

Curr Issues Mol Biol. 2025-7-9

[4]
Dapagliflozin, in addition to ramipril, ameliorates kidney disease progression in mice with Alport syndrome.

Am J Physiol Renal Physiol. 2025-7-1

[5]
The potential biomarker value of soluble CD36 in the treatment of diabetic kidney disease: evidence from GLP-1 and insulin interventions.

Front Endocrinol (Lausanne). 2025-5-27

[6]
Oxidative stress and NRF2 signaling in kidney injury.

Toxicol Res. 2024-12-22

[7]
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Biology (Basel). 2024-12-27

[8]
Renal Tubule-Specific Angiotensinogen Deletion Attenuates SGLT2 Expression and Ameliorates Diabetic Kidney Disease in Murine Models of Type 1 Diabetes.

Diabetes. 2025-4-1

[9]
Exogenous Ketones in Cardiovascular Disease and Diabetes: From Bench to Bedside.

J Clin Med. 2024-12-4

[10]
Interplay between the Redox System and Renal Tubular Transport.

Antioxidants (Basel). 2024-9-24

本文引用的文献

[1]
Bardoxolone Methyl for Alport Syndrome: Opportunities and Challenges.

Clin J Am Soc Nephrol. 2022-12

[2]
Effects of Bardoxolone Methyl in Alport Syndrome.

Clin J Am Soc Nephrol. 2022-12

[3]
Nrf2 deficiency deteriorates diabetic kidney disease in Akita model mice.

Redox Biol. 2022-12

[4]
Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice.

Int J Mol Sci. 2021-11-17

[5]
CD36 promotes NLRP3 inflammasome activation via the mtROS pathway in renal tubular epithelial cells of diabetic kidneys.

Cell Death Dis. 2021-5-21

[6]
Overexpression of Nrf2 in Renal Proximal Tubular Cells Stimulates Sodium-Glucose Cotransporter 2 Expression and Exacerbates Dysglycemia and Kidney Injury in Diabetic Mice.

Diabetes. 2021-6

[7]
Protective Role of Nrf2 in Renal Disease.

Antioxidants (Basel). 2020-12-31

[8]
Lipid deposition and metaflammation in diabetic kidney disease.

Curr Opin Pharmacol. 2020-12

[9]
Dapagliflozin in Patients with Chronic Kidney Disease.

N Engl J Med. 2020-9-24

[10]
CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis.

Nat Commun. 2020-9-21

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