Dysregulated signaling cascades alter energy metabolism and promote cell proliferation and cyst expansion in polycystic kidney disease (PKD). Here we tested whether metabolic reprogramming towards aerobic glycolysis (“Warburg effect”) plays a pathogenic role in male heterozygous Han:SPRD rats (Cy/+), a chronic progressive model of PKD. Using microarray analysis and qPCR, we found an upregulation of genes involved in glycolysis (Hk1, Hk2, Ldha) and a downregulation of genes involved in gluconeogenesis (G6pc, Lbp1) in cystic kidneys of Cy/+ rats compared with wild-type (+/+) rats. We then tested the effect of inhibiting glycolysis with 2-deoxyglucose (2DG) on renal functional loss and cyst progression in 5-week-old male Cy/+ rats. Treatment with 2DG (500 mg/kg/day) for 5 weeks resulted in significantly lower kidney weights (-27%) and 2-kidney/total-body-weight ratios (-20%) and decreased renal cyst index (-48%) compared with vehicle treatment. Cy/+ rats treated with 2DG also showed higher clearances of creatinine (1.98±0.67 vs 1.41±0.37 ml/min), BUN (0.69±0.26 vs 0.40±0.10 ml/min) and uric acid (0.38±0.20 vs 0.21±0.10 ml/min), and reduced albuminuria. Immunoblotting analysis of kidney tissues harvested from 2DG-treated Cy/+ rats showed increased phosphorylation of AMPK-α, a negative regulator of mTOR, and restoration of ERK signaling. Assessment of Ki-67 staining indicated that 2DG limits cyst progression through inhibition of epithelial cell proliferation. Taken together, our results show that targeting the glycolytic pathway may represent a promising therapeutic strategy to control cyst growth in PKD.
The sodium-glucose-cotransporter-2 (SGLT2) inhibitor dapagliflozin (DAPA) induces glucosuria and osmotic diuresis via inhibition of renal glucose reabsorption. Since increased diuresis retards the progression of polycystic kidney disease (PKD), we investigated the effect of DAPA in the PCK rat model of PKD. DAPA (10 mg/kg/d) or vehicle was administered by gavage to 6 week old male PCK rats (n=9 per group). Renal function, albuminuria, kidney weight and cyst volume were assessed after 6 weeks of treatment. Treatment with DAPA markedly increased glucose excretion (23.6 ± 4.3 vs 0.3 ± 0.1 mmol/d) and urine output (57.3 ± 6.8 vs 19.3 ± 0.8 ml/d). DAPA-treated PCK rats had higher clearances for creatinine (3.1 ± 0.1 vs 2.6 ± 0.2 ml/min) and BUN (1.7 ± 0.1 vs 1.2 ± 0.1 ml/min) after 3 weeks, and developed a 4-fold increase in albuminuria. Ultrasound imaging and histological analysis revealed a higher cyst volume and a 23% higher total kidney weight after 6 weeks of DAPA treatment. At week 6 the renal cAMP content was similar between DAPA and vehicle, and staining for Ki67 did not reveal an increase in cell proliferation. In conclusion, the inhibition of glucose reabsorption with the SGLT2-specific inhibitor DAPA caused osmotic diuresis, hyperfiltration, albuminuria and an increase in cyst volume in PCK rats. The mechanisms which link glucosuria to hyperfiltration, albuminuria and enhanced cyst volume in PCK rats remain to be elucidated.
Renal tubular epithelial cell proliferation and transepithelial cyst fluid secretion are key features in the progression of polycystic kidney disease (PKD). As the role of the apical renal sodium-glucose cotransporters in these processes is not known, we tested whether phlorizin inhibits cyst growth and delays renal disease progression in a rat model of PKD. Glycosuria was induced by subcutaneous injection of phlorizin in male heterozygous (Cy/+) and wild-type Han:SPRD rats. Phlorizin induced immediate and sustained glycosuria and osmotic diuresis in these rats. Cy/+ rats treated with phlorizin for 5 weeks showed a significant increase in creatinine clearance, a lower 2-kidneys/body weight ratio, a lower renal cyst index, and reduced urinary albumin excretion as compared with vehicle-treated Cy/+ rats. Measurement of Ki67 staining found significantly lower cell proliferation in dilated tubules and cysts of Cy/+ rats treated with phlorizin, as well as a marked inhibition of the activated MAP kinase pathway. In contrast, the mTOR pathway remained unaltered. Phlorizin dose dependently inhibited MAP kinase in cultured tubular epithelial cells from Cy/+ rats. Thus, long-term treatment with phlorizin significantly inhibits cystic disease progression in a rat model of PKD. Hence, induction of glycosuria and osmotic diuresis (glycuresis) by renal sodium-glucose cotransporters inhibition could have a therapeutic effect in polycystic kidney disease.Kidney International advance online
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