Sterol-O acyltransferase inhibition ameliorates high-fat diet-induced renal fibrosis and tertiary lymphoid tissue maturation after ischemic reperfusion injury (Mice+injury analysis)

Metabolic syndrome is a growing global health problem and is strongly associated with the development of chronic kidney disease (CKD). Recently, the prevalence of CKD has been increasing worldwide, particularly among the older adults. We previously demonstrated that aged kidneys are prone to developing tertiary lymphoid tissues (TLTs) and sustain chronic inflammation after injury; however, the relationship between renal TLT formation and metabolic syndrome is unknown. In the present study, we demonstrated that high-fat diet (HFD) feeding partly promoted TLT formation and chronic inflammation in the kidneys via sterol-O acyltransferase (SOAT) 1-dependent lipid deposition. Wild-type mice fed a HFD prior to ischemic reperfusion injury (IRI) exhibited pronounced TLT formation with respect to size, number and maturity in the kidneys, and sustained chronic inflammation compared to the controls. Untargeted lipidomics revealed that the levels of a selective group of lipids, including cholesteryl esters (CEs), were significantly increased in aged kidneys associated with TLT formation after renal IRI. Consistently, the gene expression level of Soat1 was significantly increased in aged kidneys associated with TLT formation after renal IRI. Notably, treatment with avasimibe, a SOAT inhibitor, significantly attenuated TLT maturation and improved renal inflammation and fibrosis in HFD-fed mice subjected to IRI. Together, our findings suggest the importance of dysregulated lipid metabolism, particularly SOAT1-dependent CE accumulation, in the pathophysiology of CKDs associated with TLT formation.

Mice+injury analysis (dataset 1) is reported in the current study MTBLS4988.
Mice+diet analysis (dataset 2) is reported in MTBLS4994.