Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules

Matsui, Sho; Yamamoto, Takeshi; Takabatake, Yoshitsugu; Takahashi, Atsushi; Namba-Hamano, Tomoko; Matsuda, Jun; Minami, Satoshi; Sakai, Shinsuke; Yonishi, Hiroaki; Nakamura, Jun; Maeda, Shihomi; Matsumoto, Ayumi; Matsui, Isao; Yanagita, Motoko; Isaka, Yoshitaka

doi:https://doi.org/10.1080/15548627.2024.2410621

Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules

Matsui, Sho; Yamamoto, Takeshi; Takabatake, Yoshitsugu et al.

Autophagy, 2024, 21(3), 583-597

アクセス数:2,658件（2025-07-06 20:27 集計）

固定URL: https://hdl.handle.net/11094/98359

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タイトル	Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules
著者	NRID 1000070974286 1000070974286 著者名 Matsui, Sho
	NRID 1000020756994 1000020756994 researchmap permalink tyamamoto-handai3857 tyamamoto-handai3857 Scopus Author ID 55628566248 55628566248 ORCID 0009-0007-3817-0557 0009-0007-3817-0557 著者名 Yamamoto, Takeshi
	NRID 1000030403075 1000030403075 著者名 Takabatake, Yoshitsugu
	NRID 1000010704786 1000010704786 researchmap permalink takahashi-handai3857 takahashi-handai3857 Scopus Author ID 55728349700 55728349700 著者名 Takahashi, Atsushi
	NRID 1000030734420 1000030734420 researchmap permalink namba-handai3857 namba-handai3857 Scopus Author ID 8577526800 8577526800 著者名 Namba-Hamano, Tomoko
	NRID 1000010778260 1000010778260 researchmap permalink jun_matsuda jun_matsuda ORCID 0000-0003-1492-6157 0000-0003-1492-6157 著者名 Matsuda, Jun
	NRID 1000000791592 1000000791592 researchmap permalink minami415 minami415 Scopus Author ID 57188809277 57188809277 ORCID 0000-0001-5043-3435 0000-0001-5043-3435 著者名 Minami, Satoshi
	NRID 1000060817360 1000060817360 著者名 Sakai, Shinsuke
	NRID 1000040822143 1000040822143 著者名 Yonishi, Hiroaki
	NRID 1000010846679 1000010846679 著者名 Nakamura, Jun
	著者名 Maeda, Shihomi
	NRID 1000040794053 1000040794053 著者名 Matsumoto, Ayumi
	NRID 1000060456986 1000060456986 ORCID 0000-0001-8378-6130 0000-0001-8378-6130 researchmap permalink matsui-handai3857 matsui-handai3857 Scopus Author ID 24488796300 24488796300 著者名 Matsui, Isao
	NRID 1000070378769 1000070378769 著者名 Yanagita, Motoko
	NRID 1000000379166 1000000379166 researchmap permalink isaka-handai3857 isaka-handai3857 Scopus Author ID 16207611100 16207611100 ORCID 0000-0002-0820-7167 0000-0002-0820-7167 著者名 Isaka, Yoshitaka
キーワード等	Albuminuria
	autophagic stagnation
	lipotoxicity
	LRP2/Megalin
	lysosome
	SLC5A2/SGLT2 inhibitors
内容	Matsui S., Yamamoto T., Takabatake Y., et al. Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules. Autophagy, (2024); https://doi.org/10.1080/15548627.2024.2410621.
抄録	The renoprotective effects of SLC5A2/SGLT2 (solute carrier 5 (sodium/glucose cotransporter), member 2) inhibitors have recently been demonstrated in non-diabetic chronic kidney disease (CKD), even without overt albuminuria. However, the mechanism underlying this renoprotection is largely unclear. We investigated the renoprotective mechanisms of the SLC5A2 inhibitor empagliflozin with a focus on ALB (albumin) reabsorption and macroautophagy/autophagy in proximal tubules using wild-type or drug-inducible lrp2/Megalin or atg5 knockout mice with high-fat diet (HFD)-induced obesity or 5/6 nephrectomy that elevated intraglomerular pressure without overt albuminuria. Empagliflozin treatment of HFD-fed mice reduced several hallmarks of lipotoxicity in the proximal tubules, such as phospholipid accumulation in the lysosome, inflammation and fibrosis. Empagliflozin, which decreases intraglomerular pressure, not only reduced the HFD-induced increase in ALB reabsorption via LRP2 in the proximal tubules (i.e. total nephron ALB filtration), as assessed by urinary ALB excretion caused by genetic ablation of Lrp2, but also ameliorated the HFD-induced imbalance in circulating ALB-bound fatty acids. Empagliflozin alleviated the HFD-induced increase in autophagic demand and successfully prevented autophagic stagnation in the proximal tubules. Similarly, empagliflozin decreased ALB exposure and autophagic demand in 5/6 nephrectomized mice. Finally, empagliflozin reduced HFD-induced vulnerability to ischemia–reperfusion injury, whereas LRP2 blockade and atg5 ablation separately diminished this effect. Our findings indicate that empagliflozin reduces ALB exposure and prevents autophagic stagnation in the proximal tubules even without overt albuminuria. Autophagy improvement may be critical for the renoprotection mediated by SLC5A2 inhibition.
出版者	Taylor and Francis Ltd.
収録物名	Autophagy
巻(号)	21(3)
ページ	583-597
刊行年月	2024-10-14
言語	英語
ハンドルURL	https://hdl.handle.net/11094/98359
PISSN	15548627
eISSN	15548635
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1080/15548627.2024.2410621
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCTERMS.bibliographicCitation	Autophagy. 2024, 21(3), p. 583-597
DC.title	Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules
DC.creator	Matsui, Sho
	Yamamoto, Takeshi
	Takabatake, Yoshitsugu
	Takahashi, Atsushi
	Namba-Hamano, Tomoko
	Matsuda, Jun
	Minami, Satoshi
	Sakai, Shinsuke
	Yonishi, Hiroaki
	Nakamura, Jun
	Maeda, Shihomi
	Matsumoto, Ayumi
	Matsui, Isao
	Yanagita, Motoko
	Isaka, Yoshitaka
DC.publisher	Taylor and Francis Ltd.
DC.language' scheme='DCTERMS.RFC1766	英語
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-10-14
DC.identifier	https://doi.org/10.1080/15548627.2024.2410621
DC.subject	Albuminuria
	autophagic stagnation
	lipotoxicity
	LRP2/Megalin
	lysosome
	SLC5A2/SGLT2 inhibitors
DC.description	Matsui S., Yamamoto T., Takabatake Y., et al. Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules. Autophagy, (2024); https://doi.org/10.1080/15548627.2024.2410621.
DCTERMS.abstract	The renoprotective effects of SLC5A2/SGLT2 (solute carrier 5 (sodium/glucose cotransporter), member 2) inhibitors have recently been demonstrated in non-diabetic chronic kidney disease (CKD), even without overt albuminuria. However, the mechanism underlying this renoprotection is largely unclear. We investigated the renoprotective mechanisms of the SLC5A2 inhibitor empagliflozin with a focus on ALB (albumin) reabsorption and macroautophagy/autophagy in proximal tubules using wild-type or drug-inducible lrp2/Megalin or atg5 knockout mice with high-fat diet (HFD)-induced obesity or 5/6 nephrectomy that elevated intraglomerular pressure without overt albuminuria. Empagliflozin treatment of HFD-fed mice reduced several hallmarks of lipotoxicity in the proximal tubules, such as phospholipid accumulation in the lysosome, inflammation and fibrosis. Empagliflozin, which decreases intraglomerular pressure, not only reduced the HFD-induced increase in ALB reabsorption via LRP2 in the proximal tubules (i.e. total nephron ALB filtration), as assessed by urinary ALB excretion caused by genetic ablation of Lrp2, but also ameliorated the HFD-induced imbalance in circulating ALB-bound fatty acids. Empagliflozin alleviated the HFD-induced increase in autophagic demand and successfully prevented autophagic stagnation in the proximal tubules. Similarly, empagliflozin decreased ALB exposure and autophagic demand in 5/6 nephrectomized mice. Finally, empagliflozin reduced HFD-induced vulnerability to ischemia–reperfusion injury, whereas LRP2 blockade and atg5 ablation separately diminished this effect. Our findings indicate that empagliflozin reduces ALB exposure and prevents autophagic stagnation in the proximal tubules even without overt albuminuria. Autophagy improvement may be critical for the renoprotection mediated by SLC5A2 inhibition.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
DC.format	98359
citation_title	Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules
citation_author	Matsui, Sho
	Yamamoto, Takeshi
	Takabatake, Yoshitsugu
	Takahashi, Atsushi
	Namba-Hamano, Tomoko
	Matsuda, Jun
	Minami, Satoshi
	Sakai, Shinsuke
	Yonishi, Hiroaki
	Nakamura, Jun
	Maeda, Shihomi
	Matsumoto, Ayumi
	Matsui, Isao
	Yanagita, Motoko
	Isaka, Yoshitaka
citation_publisher	Taylor and Francis Ltd.
citation_language	英語
citation_date	2024-10-14
citation_journal_title	Autophagy
citation_volume	21
citation_issue	3
citation_firstpage	583
citation_lastpage	597
citation_doi	https://doi.org/10.1080/15548627.2024.2410621
citation_public_url	https://hdl.handle.net/11094/98359

Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules

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