Polycystic kidney disease (PKD) is one of the most common inherited disorders, being the fourth leading cause of kidney failure in humans. PKD is characterized by the formation of multiple cysts in the kidney. The expansion and proliferation of cysts play a key role in reducing kidney function and leading to chronic renal failure. There are two rat models of PKD: Han:SPRD rats which phenotypically resemble human autosomal dominant polycystic kidney disease (ADPKD), and PCK rats which are an orthologous model of autosomal recessive polycystic kidney disease (ARPKD). Han:SPRD develop cortical cysts which originate from proximal tubules of the nephrons, whereas PCK develop medullary cysts which originate from the collecting duct.
The aim of this thesis was to examine whether the transport and the metabolism of glucose in the kidney play a pathogenic role in cyst proliferation and expansion in these two rat models of PKD. We hypothesized that the generation of an osmotic diuresis by inhibition of sodium-glucose cotransporters (SGLT) in the proximal tubules will force the fluid transport from cysts to the tubular lumen, thereby reducing cyst expansion and improving the decline in renal function. Furthermore, based on the knowledge of an increased demand of glucose by aerobic glycolysis in proliferating epithelial cells in PKD (Warburg effect) we selectively blocked glucose metabolism with the glucose analog 2-deoxyglucose (2DG) to test its beneficial effect in PKD.
We first tested the dual SGLT inhibitor phlorizin in Han:SPRD rats and found a significant positive effect, i.e. phlorizin ameliorated the cyst expansion and improved the decline in renal function and reduced albuminuria. We then tested the selective SGLT2 inhibitor dapagliflozin (DAPA) in Han:SPRD rats and found that DAPA did not reduce cyst expansion but had a slight positive effect on renal function and also reduced albuminuria. In contrast, DAPA unexpectedly increased cyst expansion and accelerated the functional decline of renal function and increased albuminuria in PCK rats, presumably because of a strong osmotic effect in the collecting duct.
We then investigated the energy metabolism in cystic tissues of Han:SPRD rats and confirmed the upregulation of genes involved in glycolysis and the downregulation of genes involved in gluconeogenesis, thus demonstrating that the Warburg effect is present in the cystic kidneys of Han:SPRD rats. When using 2DG to block glycolysis we found an important reduction of cyst growth and a slower decline of renal function and less albuminuria.
Altogether our experimental studies in two different rat models of PKD show that glucose transport and metabolism play an important role for cyst growth and expansion. This sets the basis for using these potential targets in the future treatment of PKD.