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

被引:3
|
作者
Su, Ke [1 ]
Zhao, Shui-Ling [1 ]
Yang, Wen-Xia [1 ]
Lo, Chao-Sheng [1 ]
Chenier, Isabelle [1 ]
Liao, Min-Chun [1 ]
Pang, Yu-Chao [1 ]
Peng, Jun-Zheng [1 ]
Miyata, Kana N. [1 ]
Cailhier, Jean-Francois [1 ]
Ethier, Jean [1 ]
Lattouf, Jean-Baptiste [1 ]
Filep, Janos G. [2 ]
Ingelfinger, Julie R. [3 ]
Zhang, Shao-Ling [1 ]
Chan, John S. D. [1 ]
机构
[1] Univ Montreal, Ctr Rech Ctr Hosp Univ Montreal CRCHUM, Dept Med, 900 St Denis St, Montreal, PQ H2X 0A9, Canada
[2] Univ Montreal, Hop Maisonneuve Rosemont, Ctr Rech, Dept Pathol & Biol Cellulaire, 5415 Boul Assompt, Montreal, PQ H1T 2M4, Canada
[3] Harvard Med Sch, Massachusetts Gen Hosp, Pediat Nephrol Unit, 15 Parkman St,WAC 709, Boston, MA 02114 USA
基金
加拿大健康研究院;
关键词
NRF2; SGLT2; CD36; BARDOXOLONE METHYL; GENE-EXPRESSION; C-FOS; NEPHROPATHY; INDUCTION; STRESS; HYPERTENSION; PROGRESSION; INHIBITION; ADIPOCYTE;
D O I
10.3390/antiox12091715
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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/dbNrf2 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/dbNrf2 KO mice were studied at 16 weeks of age. Human RPTCs (HK2) with NRF2 KO via CRISPR-Cas9 genome editing and kidneys from patients with or without T2D were examined. Compared with db/db mice, db/dbNrf2 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. NRF2 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.
引用
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页数:20
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