Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice
High serum levels of free fatty acids (FFAs) could contribute to obesity-induced nephropathy. CD36, a class B scavenger receptor, is a major receptor mediating FFA uptake in renal proximal tubular cells. Empagliflozin, a new anti-diabetic agent, is a specific inhibitor of sodium-glucose co-transport...
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oai:doaj.org-article:45d3649e3b2e4e22928ba3797f1ba2452021-11-25T17:56:22ZEmpagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice10.3390/ijms2222124081422-00671661-6596https://doaj.org/article/45d3649e3b2e4e22928ba3797f1ba2452021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12408https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067High serum levels of free fatty acids (FFAs) could contribute to obesity-induced nephropathy. CD36, a class B scavenger receptor, is a major receptor mediating FFA uptake in renal proximal tubular cells. Empagliflozin, a new anti-diabetic agent, is a specific inhibitor of sodium-glucose co-transporter 2 channels presented on renal proximal tubular cells and inhibits glucose reabsorption. In addition, empagliflozin has shown renoprotective effects. However, the mechanism through which empagliflozin regulates CD36 expression and attenuates FFA-induced lipotoxicity remains unclear. Herein, we aimed to elucidate the crosstalk between empagliflozin and CD36 in FFA-induced renal injury. C57BL/6 mice fed a high-fat diet (HFD) and palmitic acid-treated HK-2 renal tubular cells were used for in vivo and in vitro assessments. Empagliflozin attenuated HFD-induced body weight gain, insulin resistance, and inflammation in mice. In HFD-fed mice, CD36 was upregulated in the tubular area of the kidney, whereas empagliflozin attenuated CD36 expression. Furthermore, empagliflozin downregulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ. Treatment with a PPARγ inhibitor (GW9662) did not further decrease PPARγ expression, whereas a PPARγ antagonist reversed this effect; this suggested that empagliflozin may, at least partly, decrease CD36 by modulating PPARγ. In conclusion, empagliflozin can ameliorate FFA-induced renal tubular injury via the PPARγ/CD36 pathway.Chiang-Chi HuangChia-An ChouWei-Yu ChenJenq-Lin YangWen-Chin LeeJin-Bor ChenChien-Te LeeLung-Chih LiMDPI AGarticleCD36empagliflozinfree fatty acidPPAR-gammaSGLT2 inhibitorBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12408, p 12408 (2021) |
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CD36 empagliflozin free fatty acid PPAR-gamma SGLT2 inhibitor Biology (General) QH301-705.5 Chemistry QD1-999 |
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CD36 empagliflozin free fatty acid PPAR-gamma SGLT2 inhibitor Biology (General) QH301-705.5 Chemistry QD1-999 Chiang-Chi Huang Chia-An Chou Wei-Yu Chen Jenq-Lin Yang Wen-Chin Lee Jin-Bor Chen Chien-Te Lee Lung-Chih Li Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice |
description |
High serum levels of free fatty acids (FFAs) could contribute to obesity-induced nephropathy. CD36, a class B scavenger receptor, is a major receptor mediating FFA uptake in renal proximal tubular cells. Empagliflozin, a new anti-diabetic agent, is a specific inhibitor of sodium-glucose co-transporter 2 channels presented on renal proximal tubular cells and inhibits glucose reabsorption. In addition, empagliflozin has shown renoprotective effects. However, the mechanism through which empagliflozin regulates CD36 expression and attenuates FFA-induced lipotoxicity remains unclear. Herein, we aimed to elucidate the crosstalk between empagliflozin and CD36 in FFA-induced renal injury. C57BL/6 mice fed a high-fat diet (HFD) and palmitic acid-treated HK-2 renal tubular cells were used for in vivo and in vitro assessments. Empagliflozin attenuated HFD-induced body weight gain, insulin resistance, and inflammation in mice. In HFD-fed mice, CD36 was upregulated in the tubular area of the kidney, whereas empagliflozin attenuated CD36 expression. Furthermore, empagliflozin downregulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ. Treatment with a PPARγ inhibitor (GW9662) did not further decrease PPARγ expression, whereas a PPARγ antagonist reversed this effect; this suggested that empagliflozin may, at least partly, decrease CD36 by modulating PPARγ. In conclusion, empagliflozin can ameliorate FFA-induced renal tubular injury via the PPARγ/CD36 pathway. |
format |
article |
author |
Chiang-Chi Huang Chia-An Chou Wei-Yu Chen Jenq-Lin Yang Wen-Chin Lee Jin-Bor Chen Chien-Te Lee Lung-Chih Li |
author_facet |
Chiang-Chi Huang Chia-An Chou Wei-Yu Chen Jenq-Lin Yang Wen-Chin Lee Jin-Bor Chen Chien-Te Lee Lung-Chih Li |
author_sort |
Chiang-Chi Huang |
title |
Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice |
title_short |
Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice |
title_full |
Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice |
title_fullStr |
Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice |
title_full_unstemmed |
Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice |
title_sort |
empagliflozin ameliorates free fatty acid induced-lipotoxicity in renal proximal tubular cells via the pparγ/cd36 pathway in obese mice |
publisher |
MDPI AG |
publishDate |
2021 |
url |
https://doaj.org/article/45d3649e3b2e4e22928ba3797f1ba245 |
work_keys_str_mv |
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