Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney

Abstract

Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from oxidative phosphorylation toward glycolysis allowing cells to be transiently independent of oxygen supply. Here we show that GC7 decreases protein expression of the renal GLUT1 glucose transporter leading to a decrease in transcellular glucose flux. At the same time, GC7 modifies the native energy source of the proximal cells from glutamine toward glucose use. Thus, GC7 acutely and reversibly reprogrammes function and metabolism of kidney cells to make glucose its single substrate, and thus allowing cells to be oxygen independent through anaerobic glycolysis. The physiological consequences are an increase in the renal excretion of glucose and lactate reflecting a decrease in glucose reabsorption and an increased glycolysis. Such a reversible reprogramming of glucose handling and oxygen dependence of kidney cells by GC7 represents a pharmacological opportunity in ischaemic as well as hyperglycaemia-associated pathologies from renal origin.

The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles

“…They observed a decrease in the protein content of complexes II and V and an increase in complex III, in parallel with a metabolic shift from oxidative to glycolytic metabolism. The same result has also been obtained in renal cells treated with GC7 that impaired eIF5A hypusination of both isoforms [ 78 , 79 ]. However, cells treated with siVA show a significant increase in respiration coupled to oxidative phosphorylation.…”

“…It is known that a deficiency in dhps or chronic treatment with DHPS inhibitors, like GC7, enhances glucose tolerance and glycemia in different mouse models of diabetes (HFD [ 72 , 73 ], STZ [ 48 , 74 ] humanized mouse model of T1D [ 75 ], db/db [ 76 ], NOD [ 77 ]). Searching for the impact of GC7 mediated eIF5A inhibition on renal glucose metabolism, Cougnon et al [ 78 ] reported that GC7 decreased protein expression of the renal GLUT1 glucose transporter in cultured proximal cells resulting in a decrease in trans-cellular glucose flux. In parallel, GC7 modified the native energy supply of the proximal cells from glutamine toward glucose use.…”

“…Thus, GC7 acutely and reversibly reprograms the function and metabolism of kidney cells to make glucose its single substrate, and therefore permits cells to be oxygen-independent through anaerobic glycolysis. The physiological consequences in GC7-treated mice [ 78 ] are an increase in the renal excretion of glucose and lactate reflecting a decrease in glucose reabsorption and an increased glycolysis, a phenomenon also reported in cultured proximal cells [ 79 ]. How eIF5A can repress GLUT1 expression remains to be determined since the GLUT1 sequence does not contains any polyproline motif and its mRNA sequence does not harbor the consensus sequence required to link eIF5A (Fig.…”

“…a Schema of the glucose handling pathway modified by eIF5A inhibition. b Immunofluorescence of GLUT1 expression in cortex from control and GC7 treated mouse (Modified from Cougnon et al [ 78 ]) …”

“…The addition of a mitochondrial uncoupling protonophore showed that the maximal respiratory capacity was significantly higher in siVA treated cells than in the siControl. The opposite occurs in renal cells in which GC7 reduced drastically the basal oxygen consumption rate indicating a decrease in the mitochondrial oxidative phosphorylation and an enhancement in anaerobic glycolysis [ 78 , 79 ]. This reversible GC7 induced mitochondrial “silencing” is accompanied by a non-lethal decrease in the mitochondrial potential [ 78 , 79 ].…”