dc.description.abstract
The oxidoreductase Retinol Saturase (RetSat), known to catalyse the reaction of all-trans-retinol to all-trans-13,14-dihydroretinol, is highly expressed in metabolically active tissues and differentially regulated in metabolic disorders such as insulin resistance and type 2 diabetes. To date, RetSat has been shown to be involved in adipocyte differentiation, to act as an upstream regulator of hepatic glucose and lipid metabolism, to alter macrophage function, to affect avian vision and to be associated with the generation of reactive oxygen species (ROS). These effects appear to be independent of the originally described saturation reaction, suggesting alternative enzymatic reactions that may lead to the observed effects. RetSat is highly expressed in the metabolically active kidneys, which regulate the filtration, reabsorption and excretion of metabolites. The function of RetSat in the mouse kidney is completely unknown and its role in the development of metabolic diseases remains to be elucidated.
The aim of this study was to generate and characterize a mouse model with kidney-specific deletion of RetSat to investigate its function in the kidney. Loss of RetSat in adult male and female C57BL/6J mice resulted in profound proteinuria with additional hyperphosphaturia. Using a label-free quantification (LFQ) proteomics approach, we identified increased excretion of a number of proteins in 24 h urine, including RBP4 and FXYD5.
Middle-aged RetSat-deficient mice fed normal chow (NC) showed an increase in body weight that was independent of food intake, with no change in body composition or metabolic profile. Middle-aged male mice lacking RetSat showed hypercalciuria without the development of nephrocalcinosis and an unexpected hypophosphaturia. In addition, RNA-sequencing analysis revealed upregulation of the vitamin D receptor (Vdr) and differential mRNA expression of its target genes in whole kidney tissue. Subsequent Gene Ontology (GO) analysis revealed involvement in the biological process of cell junction assembly.
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RetSat-deficient mice fed with a high-fat diet (HFD) showed an increase in body weight that was independent of food intake, with a relative increase in fat mass, a decrease in lean mass, and impaired glucose clearance. In RetSat-deficient mice, relative energy expenditure (EE) changed without changes in respiratory exchange rate (RER), locomotor activity, or drinking volume. Interestingly, there was a reduction in absolute and relative kidney weight in RetSat-deficient mice in the fed state and less accumulation of fat droplets in the renal cortex.
In conclusion, we have successfully generated, validated and metabolically characterized a new mouse model with kidney-specific deletion of RetSat. In this thesis, we have identified a previously unknown link between the renal loss of RetSat and the upregulation of renal Vdr.
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