Defective glycolysis and the use of 2-deoxy-d-glucose in polycystic kidney disease: from animal models to humans

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited renal disease characterized by bilateral renal cyst formation. ADPKD is one of the most common rare disorders, accounting for ~10% of all patients with end-stage renal disease (ESRD). ADPKD is a chronic disorder in which the gradual expansion of cysts that form in a minority of nephrons eventually causes loss of renal function due to the compression and degeneration of the surrounding normal parenchyma. Numerous deranged pathways have been identified in the cyst-lining epithelia, prompting the design of potential therapies. Several of these potential treatments have proved effective in slowing down disease progression in pre-clinical animal studies, while only one has subsequently been proven to effectively slow down disease progression in patients, and it has recently been approved for therapy in Europe, Canada and Japan. Among the affected cellular functions and pathways, recent investigations have described metabolic derangement in ADPKD as a major trait offering additional opportunities for targeted therapies. In particular, increased aerobic glycolysis (the Warburg effect) has been described as a prominent feature of ADPKD kidneys and its inhibition using the glucose analogue 2-deoxy-D-glucose (2DG) proved effective in slowing down disease progression in preclinical models of the disease. At the same time, previous clinical experiences have been reported with 2DG, showing that this compound is well tolerated in humans with minimal and reversible side effects. In this work, we review the literature and speculate that 2DG could be a good candidate for a clinical trial in humans affected by ADPKD.

Increased expression and phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoforms in urinary exosomes in pre-eclampsia

“…Altered renal energy metabolism is a common characteristic of many forms of kidney disease [1–4]. In particular, changes in expression and activity of glycolytic enzymes have been demonstrated in several kidney diseases including polycystic kidney disease, ischaemic acute kidney injury and diabetic nephropathy [2, 4–6]. Pre-eclampsia is a systemic hypertensive disorder of pregnancy, which is a major cause of maternal and perinatal morbidity and mortality [7].…”

Role of Bicaudal C1 in renal gluconeogenesis and its novel interaction with the CTLH complex

“…In addition, cystic growth in PC1-deficient kidneys is fueled by a Warburg-like metabolic switch characterized by increased anaerobic glycolysis at the expense of oxidative phosphorylation [ 7 ]. How PKD1 attenuates glycolysis is unknown [ 8 ].…”

Activation of the Calcium-Sensing Receptor Corrects the Impaired Mitochondrial Energy Status Observed in Renal Polycystin-1 Knockdown Cells Modeling Autosomal Dominant Polycystic Kidney Disease

“…They demonstrated that PC1 lacking cells consume high levels of glucose, preferentially using it in aerobic glycolysis for their energy production (Rowe et al, 2013 ). Indeed, mitochondrial abnormality exists from an early phase of ADPKD, underlining a relationship between mitochondria and renal polycystic diseases (Li et al, 2012 ; Rowe et al, 2013 ; Magistroni and Boletta, 2017 ; Padovano et al, 2017 ). In line, an association between mitochondria abnormalities and cystogenesis has been reported in cyst-lining cells in ADPKD model mice and in rats (Ishimoto et al, 2017 ).…”