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
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Published:2023-09-04
Issue:9
Volume:12
Page:1715
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ISSN:2076-3921
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Container-title:Antioxidants
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language:en
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Short-container-title:Antioxidants
Author:
Su Ke1, Zhao Shui-Ling1ORCID, Yang Wen-Xia1, Lo Chao-Sheng1ORCID, Chenier Isabelle1, Liao Min-Chun1, Pang Yu-Chao1, Peng Jun-Zheng1, Miyata Kana N.1, Cailhier Jean-Francois1, Ethier Jean1, Lattouf Jean-Baptiste1, Filep Janos G.2ORCID, Ingelfinger Julie R.3, Zhang Shao-Ling1, Chan John S. D.1ORCID
Affiliation:
1. 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 2. 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 3. Pediatric Nephrology Unit, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, WAC 709, Boston, MA 02114, USA
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/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.
Funder
Canadian Institutes of Health Research Kidney Foundation of Canada
Subject
Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology
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