TY - JOUR
T1 - Sterol O-Acyltransferase Inhibition Ameliorates High-Fat Diet-Induced Renal Fibrosis and Tertiary Lymphoid Tissue Maturation after Ischemic Reperfusion Injury
AU - Ariyasu, Yuki
AU - Sato, Yuki
AU - Isobe, Yosuke
AU - Taniguchi, Keisuke
AU - Yanagita, Motoko
AU - Arita, Makoto
N1 - Funding Information:
Y.S. is employed by the TMK project. M.Y. receives research grants from Mitsubishi Tanabe, and Boehringer Ingelheim. The authors declare no other conflicts of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.
Funding Information:
This research was funded by the RIKEN Junior Research Associate Program (to Y.A.), JSPS Grant-in-Aid for Scientific Research on Innovative Areas ‘LipoQuality’ (15H05897, 15H05898 to M.A., and 18H04673 to M.Y.), JSPS KAKENHI 20H00495 (to M.A.), RIKEN Pioneering Project “Glyco-Lipidologue Initiative” (to M.A.), and JST-ERATO “ARITA Lipidome Atlas Project” grant number JPMJER2101 (to M.A.). This research was partly supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number AMED-CREST 22gm1210009 and 22zf0127003h001 (M.Y.).
Publisher Copyright:
© 2022 by the authors.
PY - 2022/12
Y1 - 2022/12
N2 - Metabolic syndrome is associated with the development of chronic kidney disease (CKD). We previously demonstrated that aged kidneys are prone to developing tertiary lymphoid tissues (TLTs) and sustain inflammation after injury, leading to CKD progression; however, the relationship between renal TLT and metabolic syndrome is unknown. In this study, we demonstrated that a high-fat diet (HFD) promoted renal TLT formation and inflammation via sterol O-acyltransferase (SOAT) 1-dependent mechanism. Mice fed a HFD prior to ischemic reperfusion injury (IRI) exhibited pronounced renal TLT formation and sustained inflammation compared to the controls. Untargeted lipidomics revealed the increased levels of cholesteryl esters (CEs) in aged kidneys with TLT formation after IRI, and, consistently, the Soat1 gene expression increased. Treatment with avasimibe, a SOAT inhibitor, attenuated TLT maturation and renal inflammation in HFD-fed mice subjected to IRI. Our findings suggest the importance of SOAT1-dependent CE accumulation in the pathophysiology of CKDs associated with TLT.
AB - Metabolic syndrome is associated with the development of chronic kidney disease (CKD). We previously demonstrated that aged kidneys are prone to developing tertiary lymphoid tissues (TLTs) and sustain inflammation after injury, leading to CKD progression; however, the relationship between renal TLT and metabolic syndrome is unknown. In this study, we demonstrated that a high-fat diet (HFD) promoted renal TLT formation and inflammation via sterol O-acyltransferase (SOAT) 1-dependent mechanism. Mice fed a HFD prior to ischemic reperfusion injury (IRI) exhibited pronounced renal TLT formation and sustained inflammation compared to the controls. Untargeted lipidomics revealed the increased levels of cholesteryl esters (CEs) in aged kidneys with TLT formation after IRI, and, consistently, the Soat1 gene expression increased. Treatment with avasimibe, a SOAT inhibitor, attenuated TLT maturation and renal inflammation in HFD-fed mice subjected to IRI. Our findings suggest the importance of SOAT1-dependent CE accumulation in the pathophysiology of CKDs associated with TLT.
KW - cholesteryl ester
KW - chronic kidney disease
KW - high-fat diet
KW - lipidomics
KW - metabolic syndrome
KW - sterol O-acyltransferase
KW - tertiary lymphoid tissue
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U2 - 10.3390/ijms232415465
DO - 10.3390/ijms232415465
M3 - Article
C2 - 36555105
AN - SCOPUS:85144542442
SN - 1661-6596
VL - 23
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 24
M1 - 15465
ER -