Inhibition of Aerobic Glycolysis Attenuates Disease Progression in Polycystic Kidney Disease

Abstract

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.

Involvement of the Warburg effect in non‐tumor diseases processes

“…Warburg effect accelerates cyst expansion in PKD. Riwanto et al () show that glycolytic shift occur in cyst epithelial cells from PKD. A significant increase in the transcript levels of aerobic glycolysis enzymes and a decrease in mitochondrial oxidation are caused in PKD, which forces the cyst epithelial cells to generate ATP by aerobic glycolysis pathway.…”

The combination of metformin and 2‐deoxyglucose significantly inhibits cyst formation in miniature pigs with polycystic kidney disease

“…At present, both drugs have been used alone or in combination for the treatment of cancer in Phase I and II clinical trials (Cheong et al, 2011), and an inhibitory effect on cancer cell proliferation has been reported. As polycystic kidney cells exhibit similar abnormalities as cancer cells in terms of glucose metabolism and proliferation, 2DG and metformin have been tested as monotherapies for the short-term treatment of PKD in rodents (Chiaravalli et al, 2016;Riwanto et al, 2016). However, no study has investigated the possibility of using a combination of these two agents for the long-term treatment of PKD.…”

“…Studies have found that either direct inhibition of mTOR signalling using rapamycin or indirect inhibition using the AMPK agonist metformin can reverse the glycolytic phenotype of ADPKD cells in vitro (Riwanto et al, 2016). AMPK is a crucial molecule in the regulation of energy metabolism (Hardie, 2008;Rehman et al, 2014).…”

Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease

“…In recent years, there has been increasing evidence demonstrating the utility of investigating these parallels such that available cancer drugs can be repurposed to treat ADPKD 4–6 . It should not be surprising that these drugs work in light of the fact that there are many metabolic pathways shared between cancer and cystic disease which have been associated with epithelial proliferation, cell death pathways, and consequent cyst formation in ADPKD.…”

“…While there is a great deal known about the signaling defects underlying this disease, an enormous effort to evaluate targetable pathways, and new discoveries frequently added, there are still no ADPKD specific therapies currently available. Efforts in our 4 and other 5,6 laboratories have focused on metabolic reprogramming in PKD which in many cases shows a striking similarity to malignancy. Through conventional principles that drive oncologic research, studies on cyst formation in PKD can lead to re-purposing of effective cancer drugs for use in these patients.…”