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

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