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

Cholesterol is essential for diverse cellular functions and cellular and whole-body cholesterolhomeostasis is highly controlled. Cholesterol can also influence cellular susceptibility to injury.The connection between cholesterol metabolism and inflammation is exemplified by theTm7sf2 gene, the absence of which reveals an essential role in cholesterol biosynthesis understress conditions but also results in an inflammatory phenotype, i.e. NF-κB activation andTNFα up-regulation. Here, by using Tm7sf2+/+and Tm7sf2−/− mice, we investigated whetherthe Tm7sf2 gene, through its role in cholesterol biosynthesis under stress conditions, isinvolved in the renal failure induced by the administration of LPS. We found that the loss ofTm7sf2 gene results in significantly reduced blood urea nitrogen levels accompanied bydecreased renal inflammatory response and neutral lipid accumulation. The increased expressionof fatty acids catabolic enzymes reduces the need of the renal autophagy, a known crucialnutrient-sensing pathway in lipid metabolism. Moreover, we observed that the Tm7sf2 insufficiencyis responsible for the inhibition of the NF-κB signalling thus dampening the inflammatoryresponse and leading to a reduced renal damage. These results suggest a pivotal role forTm7sf2 in renal inflammatory and lipotoxic response under endotoxemic conditions.