NLRX1 and TFEB in metabolism and renal diseases

Kidney disease and injury are a global major health issue that are, according the World Health Organization, associated with a rising morbidity and mortality. Studying the underlying pathophysiological mechanisms of renal injury can provide new targets for therapy or novel biomarkers. With the experimental studies presented in this thesis, we intended to provide novel insights into NLRX1 and TFEB functioning during renal disease development. In Chapter 2-6 we studied NLRX1 functioning in different mice models for acute and chronic kidney damage, urinary tract infection and metabolic syndrome. We show that NLRX1, despite a previously described role as pro-inflammatory regulator, appears not to play a role during upper urinary tract infection. In contrast, we found that the presence of NLRX1 in mice, on the one hand, inhibits acute oxidative stress and fibrosis development in the kidney, while on the other hand, NLRX1 contributes to metabolic syndrome, hepatic steatosis, and WesternDiet-associated kidney damage. The mechanism that possibly underlie this is the inhibitory effect of NLRX1 on mitochondrial oxidative metabolism that we identified in various cell types (TECs, hepatocytes and macrophages). Together, we unraveled an important new function of NLRX1, namely the regulation of mitochondrial homeostasis in both parenchymal cells and immune cells and found that NLRX1 is critical for proper kidney disease control. In Chapter 7, the molecular mechanisms underlying TFEB related Renal Cell Carcinoma (RCC) tumorigenesis were studied. We show by using transgenic mice overexpressing TFEB specifically in renal epithelial cells in a constitutive and inducible way that WNT is a potential therapeutic target for kidney cancer associated with TFEB overexpression.