title: The Tm7sf2 Gene Deficiency Protects Mice against Endotoxin-Induced Acute Kidney Injury.
abstract: Cholesterol is essential for diverse cellular functions and cellular and whole-body cholesterol homeostasis is highly controlled. Cholesterol can also influence cellular susceptibility to injury. The connection between cholesterol metabolism and inflammation is exemplified by the Tm7sf2 gene, the absence of which reveals an essential role in cholesterol biosynthesis under stress conditions but also results in an inflammatory phenotype, i.e. NF-κB activation and TNFα up-regulation. Here, by using Tm7sf2+/+and Tm7sf2-/- mice, we investigated whether the Tm7sf2 gene, through its role in cholesterol biosynthesis under stress conditions, is involved in the renal failure induced by the administration of LPS. We found that the loss of Tm7sf2 gene results in significantly reduced blood urea nitrogen levels accompanied by decreased renal inflammatory response and neutral lipid accumulation. The increased expression of fatty acids catabolic enzymes reduces the need of the renal autophagy, a known crucial nutrient-sensing pathway in lipid metabolism. Moreover, we observed that the Tm7sf2 insufficiency is responsible for the inhibition of the NF-κB signalling thus dampening the inflammatory response and leading to a reduced renal damage. These results suggest a pivotal role for Tm7sf2 in renal inflammatory and lipotoxic response under endotoxemic conditions.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06124 Perugia, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Gatticchi
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06124 Perugia, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bellezza
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06124 Perugia, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Del Sordo
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06124 Perugia, Italy.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Peirce
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06124 Perugia, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sidoni
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06124 Perugia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Roberti
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06124 Perugia, Italy.
authors.forename: Alba
authors.initials: A
authors.lastname: Minelli
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001806:Blood Urea Nitrogen; D002784:Cholesterol / Q000235:genetics; D004731:Endotoxins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D004731:Endotoxins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; D010088:Oxidoreductases; C022672:delta(14)-sterol reductase