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...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Chiang-Chi Huang, Chia-An Chou, Wei-Yu Chen, Jenq-Lin Yang, Wen-Chin Lee, Jin-Bor Chen, Chien-Te Lee, Lung-Chih Li
Formato: article
Lenguaje:EN
Publicado: MDPI AG 2021
Materias:
Acceso en línea:https://doaj.org/article/45d3649e3b2e4e22928ba3797f1ba245
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:45d3649e3b2e4e22928ba3797f1ba245
record_format dspace
spelling 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)
institution DOAJ
collection DOAJ
language EN
topic CD36
empagliflozin
free fatty acid
PPAR-gamma
SGLT2 inhibitor
Biology (General)
QH301-705.5
Chemistry
QD1-999
spellingShingle 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 AT chiangchihuang empagliflozinamelioratesfreefattyacidinducedlipotoxicityinrenalproximaltubularcellsviatheppargcd36pathwayinobesemice
AT chiaanchou empagliflozinamelioratesfreefattyacidinducedlipotoxicityinrenalproximaltubularcellsviatheppargcd36pathwayinobesemice
AT weiyuchen empagliflozinamelioratesfreefattyacidinducedlipotoxicityinrenalproximaltubularcellsviatheppargcd36pathwayinobesemice
AT jenqlinyang empagliflozinamelioratesfreefattyacidinducedlipotoxicityinrenalproximaltubularcellsviatheppargcd36pathwayinobesemice
AT wenchinlee empagliflozinamelioratesfreefattyacidinducedlipotoxicityinrenalproximaltubularcellsviatheppargcd36pathwayinobesemice
AT jinborchen empagliflozinamelioratesfreefattyacidinducedlipotoxicityinrenalproximaltubularcellsviatheppargcd36pathwayinobesemice
AT chientelee empagliflozinamelioratesfreefattyacidinducedlipotoxicityinrenalproximaltubularcellsviatheppargcd36pathwayinobesemice
AT lungchihli empagliflozinamelioratesfreefattyacidinducedlipotoxicityinrenalproximaltubularcellsviatheppargcd36pathwayinobesemice
_version_ 1718411798593404928