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HNF3α targets Nckap1l and promotes renal fibrosis following ischemia-reperfusion injury

ABSTRACT: Ischemia-reperfusion injury-induced acute kidney injury is a major cause of chronic kidney disease, lacking effective interventions. We found elevated HNF3α expression in CKD patients, which correlated with collagen deposition, serum creatinine, and urea levels. Conditional knockout of HNF3α in renal tubular epithelial cells protected against IRI-induced renal fibrosis in vivo. To explore the mechanisms by which HNF3α promotes renal fibrosis, we transfected TKPTS cells with Hnf3a overexpression plasmids or control plasmids, and then performed transcriptome sequencing.

ORGANISM(S): Mus musculus

PROVIDER: GSE274962 | GEO | 2025/03/01

REPOSITORIES: GEO

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Project description: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+diet analysis (dataset 2) is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS4994' rel='noopener noreferrer' target='_blank'>MTBLS4994</a>.Mice+injury analysis (dataset 1) is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS4988' rel='noopener noreferrer' target='_blank'>MTBLS4988</a>.

Project description: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 <a href='https://www.ebi.ac.uk/metabolights/MTBLS4988' rel='noopener noreferrer' target='_blank'>MTBLS4988</a>.Mice+diet analysis (dataset 2) is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS4994' rel='noopener noreferrer' target='_blank'>MTBLS4994</a>.

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HNF3α targets Nckap1l and promotes renal fibrosis following ischemia-reperfusion injury

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