The Tm7sf2 Gene Deficiency Protects Mice against Endotoxin-Induced Acute Kidney Injury

INTRODUCTION: <em>Tm7sf2</em> gene codifies for 3β-hydroxysterol Δ14-reductase, an endoplasmic reticulum resident protein involved in cholesterol biosynthesis (1, 2). Cholesterol is an essential component of plasma membranes, and it can also contribute to multiple cellular functions or to injury response. Connection between cholesterol metabolism and inflammation is exemplified by <em>Tm7sf2</em>-KO mice, that under stress conditions show an inflammatory phenotype (NF-kB activation and TNFα upregulation) (3). In mouse skin, the loss of <em>Tm7sf2</em> gene reduces cholesterol/cholesterol sulfate levels following inflammatory insults, and increases susceptibility to skin papillomas formation (4). AIM OF THE STUDY: Investigation of the role of <em>Tm7sf2</em> gene in renal cholesterol/lipid metabolism and inflammatory response, in an in vivo model of acute kidney injury induced by the administration of lipopolysaccharide (LPS). MATERIALS AND METHODS: Male C57BL/6, <em>Tm7sf2+/+</em>, and<em> Tm7sf2-/-</em> mice were intraperitoneally injected with a single dose of LPS (5mg/Kg) or vehicle (0.9% saline) and sacrificed at selected time points. - Blood urea nitrogen (BUN) and serum creatinine assessment - Hematoxylin/eosin (HE), Oil Red O (ORO) stain, and immunohistochemistry on kidney sections - Renal cortex lipid content (TLC); mRNA and protein analysis by qPCR or Western blotting, respectively RESULTS: <em>Tm7sf2</em>-null mice are protected against LPS-induced acute kidney injury without affecting kidney cholesterol levels. <em>Tm7sf2</em> insufficiency reduces renal LPS-triggered NF-κB activation and iNOS expression <em>Tm7sf2</em> deficiency reduces neutral lipids accumulation in kidney The lack of <em>Tm7sf2</em> gene leads to FXR activation CONCLUSIONS: - The lack of <em>Tm7sf2</em> gene results in kidney endotoxin tolerance state contributing to dampen the inflammatory response generated by LPS exposure, i.e. NF-kB activation/iNOS expression - Lower ectopic accumulation of triglycerides (TG) in KO kidney could reduce the lipotoxicity due to secondary metabolites generation - We hypotesize that increased FXR activation in Tm7sf2-/- kidney antagonizes NF-kB/iNOS proinflammatory pathway and TG biogenesis process