Translational characterization of cellular and tissular metabolic perturbations in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. ADPKD is characterized by the bilateral development of renal cysts and leads to end-stage renal disease around the age of 60 years. Cystogenesis starts already in childhood. ADPKD results from mutations in PKD1 and PKD2 genes, encoding the polycystins (PCs) 1 and 2, respectively.The alterations of intracellular Ca²+ homeostasis caused by PC deficiency leads to a 'cancer-like' cell phenotype, with proliferation, loss of polarity and aerobic glycolysis ('Warburg effect'). Furthermore, the overall carbohydrate metabolism seems to be affected in case of ADPKD, with defects in insulin secretion and insulin resistance. We postulate that cellular and tissular metabolic alterations appear early in ADPKD, i.e. in the pediatric patient. A translational approach will allow us to test this hypothesis starting from (i) a human model of either collecting- or proximal- tubule cells derived from the urine of ADPKD children with preserved renal function and healthy matched controls, and (ii) a large genotyped pediatric cohort of ADPKD patients. The impact of the functional loss of PCs on transmembrane transport (particularly, the role of the co-transporter SGLT2) and on glucose metabolism (particularly, the shift towards aerobic glycolysis) will be evaluated in vitro by 'tracer metabolomics' using 13C glucose and 13C glutamine. The renal metabolism (reflected by the quantification of the renal uptake of 18F-labeled 2-deoxy-glucose in positron emission tomography) will be compared in vivo in ADPKD patients (with preserved renal function and architecture) versus healthy subjects. Finally, the global glucose metabolism will be characterized in silico in the international ADPedKD registry and correlated with the decline of the renal function.