Tofogliflozin attenuates renal lipid deposition and inflammation via PPARα upregulation mediated by miR-21a impairment in diet-induced steatohepatitic mice
We previously demonstrated hepatic, cardiac, and skin inflammation in a high-fat diet-induced steatotic liver disease (SLD) model. However, the molecular mechanism in the kidneys in this model remains unclear. It has been recently reported that SGLT2 inhibitors improve chronic kidney disease (CKD)....
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
The Japan Endocrine Society
2024-11-01
|
| Series: | Endocrine Journal |
| Subjects: | |
| Online Access: | https://www.jstage.jst.go.jp/article/endocrj/71/11/71_EJ24-0087/_html/-char/en |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832591933938073600 |
|---|---|
| author | Sae Nishihara Masahiro Koseki Katsunao Tanaka Takashi Omatsu Ayami Saga Hiroshi Sawabe Hiroyasu Inui Takeshi Okada Tohru Ohama Daisuke Okuzaki Yoshihiro Kamada Masafumi Ono Makoto Nishida Mikio Watanabe Yasushi Sakata |
| author_facet | Sae Nishihara Masahiro Koseki Katsunao Tanaka Takashi Omatsu Ayami Saga Hiroshi Sawabe Hiroyasu Inui Takeshi Okada Tohru Ohama Daisuke Okuzaki Yoshihiro Kamada Masafumi Ono Makoto Nishida Mikio Watanabe Yasushi Sakata |
| author_sort | Sae Nishihara |
| collection | DOAJ |
| description | We previously demonstrated hepatic, cardiac, and skin inflammation in a high-fat diet-induced steatotic liver disease (SLD) model. However, the molecular mechanism in the kidneys in this model remains unclear. It has been recently reported that SGLT2 inhibitors improve chronic kidney disease (CKD). Therefore, we used this model to evaluate the effects of tofogliflozin on renal lipid metabolism and inflammation. Male 8–10-week-old C57Bl/6 mice were fed a high-fat/high-cholesterol/high-sucrose/bile acid (HF/HC/HS/BA) diet with 0.015% tofogliflozin (Tofo group) or an HF/HC/HS/BA diet alone (SLD group). After eight weeks, serum lipid profiles, histology, lipid content, and mRNA/microRNA and protein expression levels in the kidney were examined. The Tofo group showed significant reductions in body (26.9 ± 0.9 vs. 24.5 ± 1.0 g; p < 0.001) and kidney weight compared to those of the SLD group. Renal cholesterol (9.1 ± 1.6 vs. 7.5 ± 0.7 mg/g; p < 0.05) and non-esterified fatty acid (NEFA) (12.0 ± 3.0 vs. 8.4 ± 1.5 μEq/g; p < 0.01) were significantly decreased in the Tofo group. Transmission electron microscopy revealed the presence of fewer lipid droplets. mRNA sequencing analysis revealed that fatty acid metabolism-related genes were upregulated and NFκB signaling pathway-related genes were downregulated in the Tofo group. MicroRNA sequencing analysis indicated that miR-21a was downregulated and miR-204 was upregulated in the Tofo group. Notably, the expression of PPARα, which has been known to be negatively regulated by miR-21, was significantly increased, leading to enhancing β-oxidation genes, Acox1 and Cpt1 in the Tofo group. Tofogliflozin decreased renal cholesterol and NEFA levels and improved inflammation through the regulation of PPARα and miR-21a. |
| format | Article |
| id | doaj-art-c8547725ada84510b6ac63c3efbd6bcb |
| institution | Kabale University |
| issn | 1348-4540 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | The Japan Endocrine Society |
| record_format | Article |
| series | Endocrine Journal |
| spelling | doaj-art-c8547725ada84510b6ac63c3efbd6bcb2025-01-22T05:38:18ZengThe Japan Endocrine SocietyEndocrine Journal1348-45402024-11-0171111055106710.1507/endocrj.EJ24-0087endocrjTofogliflozin attenuates renal lipid deposition and inflammation via PPARα upregulation mediated by miR-21a impairment in diet-induced steatohepatitic miceSae Nishihara0Masahiro Koseki1Katsunao Tanaka2Takashi Omatsu3Ayami Saga4Hiroshi Sawabe5Hiroyasu Inui6Takeshi Okada7Tohru Ohama8Daisuke Okuzaki9Yoshihiro Kamada10Masafumi Ono11Makoto Nishida12Mikio Watanabe13Yasushi Sakata14Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanGenome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, JapanDepartment of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDivision of Innovative Medicine for Hepatobiliary & Pancreatology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, JapanDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, JapanWe previously demonstrated hepatic, cardiac, and skin inflammation in a high-fat diet-induced steatotic liver disease (SLD) model. However, the molecular mechanism in the kidneys in this model remains unclear. It has been recently reported that SGLT2 inhibitors improve chronic kidney disease (CKD). Therefore, we used this model to evaluate the effects of tofogliflozin on renal lipid metabolism and inflammation. Male 8–10-week-old C57Bl/6 mice were fed a high-fat/high-cholesterol/high-sucrose/bile acid (HF/HC/HS/BA) diet with 0.015% tofogliflozin (Tofo group) or an HF/HC/HS/BA diet alone (SLD group). After eight weeks, serum lipid profiles, histology, lipid content, and mRNA/microRNA and protein expression levels in the kidney were examined. The Tofo group showed significant reductions in body (26.9 ± 0.9 vs. 24.5 ± 1.0 g; p < 0.001) and kidney weight compared to those of the SLD group. Renal cholesterol (9.1 ± 1.6 vs. 7.5 ± 0.7 mg/g; p < 0.05) and non-esterified fatty acid (NEFA) (12.0 ± 3.0 vs. 8.4 ± 1.5 μEq/g; p < 0.01) were significantly decreased in the Tofo group. Transmission electron microscopy revealed the presence of fewer lipid droplets. mRNA sequencing analysis revealed that fatty acid metabolism-related genes were upregulated and NFκB signaling pathway-related genes were downregulated in the Tofo group. MicroRNA sequencing analysis indicated that miR-21a was downregulated and miR-204 was upregulated in the Tofo group. Notably, the expression of PPARα, which has been known to be negatively regulated by miR-21, was significantly increased, leading to enhancing β-oxidation genes, Acox1 and Cpt1 in the Tofo group. Tofogliflozin decreased renal cholesterol and NEFA levels and improved inflammation through the regulation of PPARα and miR-21a.https://www.jstage.jst.go.jp/article/endocrj/71/11/71_EJ24-0087/_html/-char/entofogliflozinchronic kidney disease (ckd)inflammationperoxisome proliferator activated receptor alpha (pparα)micro-rna-21(mir-21) |
| spellingShingle | Sae Nishihara Masahiro Koseki Katsunao Tanaka Takashi Omatsu Ayami Saga Hiroshi Sawabe Hiroyasu Inui Takeshi Okada Tohru Ohama Daisuke Okuzaki Yoshihiro Kamada Masafumi Ono Makoto Nishida Mikio Watanabe Yasushi Sakata Tofogliflozin attenuates renal lipid deposition and inflammation via PPARα upregulation mediated by miR-21a impairment in diet-induced steatohepatitic mice Endocrine Journal tofogliflozin chronic kidney disease (ckd) inflammation peroxisome proliferator activated receptor alpha (pparα) micro-rna-21(mir-21) |
| title | Tofogliflozin attenuates renal lipid deposition and inflammation via PPARα upregulation mediated by miR-21a impairment in diet-induced steatohepatitic mice |
| title_full | Tofogliflozin attenuates renal lipid deposition and inflammation via PPARα upregulation mediated by miR-21a impairment in diet-induced steatohepatitic mice |
| title_fullStr | Tofogliflozin attenuates renal lipid deposition and inflammation via PPARα upregulation mediated by miR-21a impairment in diet-induced steatohepatitic mice |
| title_full_unstemmed | Tofogliflozin attenuates renal lipid deposition and inflammation via PPARα upregulation mediated by miR-21a impairment in diet-induced steatohepatitic mice |
| title_short | Tofogliflozin attenuates renal lipid deposition and inflammation via PPARα upregulation mediated by miR-21a impairment in diet-induced steatohepatitic mice |
| title_sort | tofogliflozin attenuates renal lipid deposition and inflammation via pparα upregulation mediated by mir 21a impairment in diet induced steatohepatitic mice |
| topic | tofogliflozin chronic kidney disease (ckd) inflammation peroxisome proliferator activated receptor alpha (pparα) micro-rna-21(mir-21) |
| url | https://www.jstage.jst.go.jp/article/endocrj/71/11/71_EJ24-0087/_html/-char/en |
| work_keys_str_mv | AT saenishihara tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT masahirokoseki tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT katsunaotanaka tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT takashiomatsu tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT ayamisaga tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT hiroshisawabe tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT hiroyasuinui tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT takeshiokada tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT tohruohama tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT daisukeokuzaki tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT yoshihirokamada tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT masafumiono tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT makotonishida tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT mikiowatanabe tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice AT yasushisakata tofogliflozinattenuatesrenallipiddepositionandinflammationviapparaupregulationmediatedbymir21aimpairmentindietinducedsteatohepatiticmice |