Lotte Kors

Background: Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (E. coli) are one of the most prominent infections that have serious impact on kidney functioning and the development of chronic kidney disease. NOD-like receptor (NLR)X1 is an innate immune receptor that is important for immune metabolism and regulation, with as yet an unknown role in UTI and the pathophysiology of pyelonephritis. Methods: Wild-type (WT) and NLRX1 Knock-out (KO) female mice were subjected to UTI by intravesically inoculation of uropathogenic E. coli and sacrificed at 24h and 48h after infection after which bacterial burden and the inflammatory response in the bladder and kidney were studied. Ex vivo we studied the role of NLRX1 during the LPS induced pro-inflammatory cytokine response and phagocytosis of E. coli by granulocytes and monocytes. Results: Here, we report that during early experimental UTI NLRX1 absence reduces bacterial clearance in the bladder and dampens the inflammatory cytokine response, whereas in the kidney NLRX1 does not affect bacterial burden or cytokine response. In addition, we found that NLRX1 is not essential for the pro-inflammatory cytokine secretion by granulocytes and monocytes in response to LPS nor for bacterial phagocytosis. Conclusion: Together, we report that NLRX1 is important in enhancing the early host defense against uropathogenic E. coli in the bladder but does not affect the development of pyelonephritis.

Background: Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (E. coli) are one of the most prominent infections that have serious impact on kidney functioning and the development of chronic kidney disease. NOD-like receptor (NLR)X1 is an innate immune receptor that is important for immune metabolism and regulation, with as yet an unknown role in UTI and the pathophysiology of pyelonephritis. Methods: Wild-type (WT) and NLRX1 Knock-out (KO) female mice were subjected to UTI by intravesically inoculation of uropathogenic E. coli and sacrificed at 24h and 48h after infection after which bacterial burden and the inflammatory response in the bladder and kidney were studied. Ex vivo we studied the role of NLRX1 during the LPS induced pro-inflammatory cytokine response and phagocytosis of E. coli by granulocytes and monocytes. Results: Here, we report that during early experimental UTI NLRX1 absence reduces bacterial clearance in the bladder and dampens the inflammatory cytokine response, whereas in the kidney NLRX1 does not affect bacterial burden or cytokine response. In addition, we found that NLRX1 is not essential for the pro-inflammatory cytokine secretion by granulocytes and monocytes in response to LPS nor for bacterial phagocytosis. Conclusion: Together, we report that NLRX1 is important in enhancing the early host defense against uropathogenic E. coli in the bladder but does not affect the development of pyelonephritis.

Obesity and dyslipidaemia are features of the metabolic syndrome and risk factors for chronic kidney disease. The cellular mechanisms connecting metabolic syndrome with chronic kidney disease onset and progression remain largely unclear. We show that proximal tubular epithelium is a target site for lipid deposition upon overnutrition with a cholesterol‐rich Western‐type diet. Affected proximal tubule epithelial cells displayed giant vacuoles of lysosomal or autophagosomal origin, harbouring oxidised lipoproteins and concentric membrane layer structures (multilamellar bodies), reminiscent of lysosomal storage diseases. Additionally, lipidomic analysis revealed renal deposition of cholesterol and phospholipids, including lysosomal phospholipids. Proteomic profiles of renal multilamellar bodies were distinct from those of epidermis or lung multilamellar bodies and of cytoplasmic lipid droplets. Tubular multilamellar bodies were observed in kidney biopsies of obese hypercholesterolaemic patients, and the concentration of the phospholipidosis marker di‐docosahexaenoyl (22:6)‐bis(monoacylglycerol) phosphate was doubled in urine from individuals with metabolic syndrome and chronic kidney disease. The enrichment of proximal tubule epithelial cells with phospholipids and multilamellar bodies was accompanied by enhanced inflammation, fibrosis, tubular damage markers, and higher urinary electrolyte content. Concomitantly to the intralysosomal lipid storage, a renal transcriptional response was initiated to enhance lysosomal degradation and lipid synthesis. In cultured proximal tubule epithelial cells, inhibition of cholesterol efflux transport or oxysterol treatment induced effects very similar to the in vivo situation, such as multilamellar body and phospholipid amassing, and induction of damage, inflammatory, fibrotic, and lipogenic molecules. The onset of phospholipidosis in proximal tubule epithelial cells is a novel pathological trait in metabolic syndrome‐related chronic kidney disease, and emphasises the importance of healthy lysosomes and nutrition for kidney well‐being. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background: Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (E. coli) are one of the most prominent infections that have serious impact on kidney functioning and the development of chronic kidney disease. NOD-like receptor (NLR)X1 is an innate immune receptor that is important for immune metabolism and regulation, with as yet an unknown role in UTI and the pathophysiology of pyelonephritis. Methods: Wild-type (WT) and NLRX1 Knock-out (KO) female mice were subjected to UTI by intravesically inoculation of uropathogenic E. coli and sacrificed at 24h and 48h after infection after which bacterial burden and the inflammatory response in the bladder and kidney were studied. Ex vivo we studied the role of NLRX1 during the LPS induced pro-inflammatory cytokine response and phagocytosis of E. coli by granulocytes and monocytes. Results: Here, we report that during early experimental UTI NLRX1 absence reduces bacterial clearance in the bladder and dampens the inflammatory cytokine response, whereas in the kidney NLRX1 does not affect bacterial burden or cytokine response. In addition, we found that NLRX1 is not essential for the pro-inflammatory cytokine secretion by granulocytes and monocytes in response to LPS nor for bacterial phagocytosis. Conclusion: Together, we report that NLRX1 is important in enhancing the early host defense against uropathogenic E. coli in the bladder but does not affect the development of pyelonephritis.

Mitochondrial dysfunction is the most prominent source of oxidative stress in acute and chronic kidney disease. NLRX1 is a receptor of the innate immune system that is ubiquitously expressed and localized in mitochondria. We investigated whether NLRX1 may act at the interface of metabolism and innate immunity in a model of oxidative stress. Using a chimeric mouse model for renal ischemia-reperfusion injury, we found that NLRX1 protects against mortality, mitochondrial damage, and epithelial cell apoptosis in an oxidative stress–dependent fashion. We found that NLRX1 regulates oxidative phosphorylation and cell integrity, whereas loss of NLRX1 results in increased oxygen consumption, oxidative stress, and subsequently apoptosis in epithelial cells during ischemia-reperfusion injury. In line, we found that NLRX1 expression in human kidneys decreased during acute renal ischemic injury and acute cellular rejection. Although first implicated in immune regulation, we propose that NLRX1 function extends to the control of mitochondrial activity and prevention of oxidative stress and apoptosis in tissue injury.

TFE-fusion renal cell carcinomas (TFE-fusion RCCs) are caused by chromosomal translocations that lead to overexpression of the TFEB and TFE3 genes (Kauffman et al., 2014). The mechanisms leading to kidney tumor development remain uncharacterized and effective therapies are yet to be identified. Hence, the need to model these diseases in an experimental animal system (Kauffman et al., 2014). Here, we show that kidney-specific TFEB overexpression in transgenic mice, resulted in renal clear cells, multi-layered basement membranes, severe cystic pathology, and ultimately papillary carcinomas with hepatic metastases. These features closely recapitulate those observed in both TFEB- and TFE3-mediated human kidney tumors. Analysis of kidney samples revealed transcriptional induction and enhanced signaling of the WNT β-catenin pathway. WNT signaling inhibitors normalized the proliferation rate of primary kidney cells and significantly rescued the disease phenotype in vivo. These data shed new light on the mechanisms underlying TFE-fusion RCCs and suggest a possible therapeutic strategy based on the inhibition of the WNT pathway.

Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain receptors (NLRs) are families of pattern recognition receptors that, together with inflammasomes, sense and respond to highly conserved pathogen motifs and endogenous molecules released upon cell damage or stress. Evidence suggests that TLRs, NLRs and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome have important roles in kidney diseases through regulation of inflammatory and tissue-repair responses to infection and injury. In this Review, we discuss the pathological mechanisms that are related to TLRs, NLRs and NLRP3 in various kidney diseases. In general, these receptors are protective in the host defence against urinary tract infection, but can sustain and self-perpetuate tissue damage in sterile inflammatory and immune-mediated kidney diseases. TLRs, NLRs and NLRP3, therefore, have become promising drug targets to enable specific modulation of kidney inflammation and suppression of immunopathology in kidney disease.