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.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, characterized by progressive development of innumerable cysts in both kidneys
This observation was confirmed by quantitative real-time PCR analysis which demonstrated upregulation of key genes involved in the glycolysis pathway (Hk1, Hk2, Ldha) and downregulation of key genes involved in the gluconeogenesis pathway (Fbp1, Fbp2, G6pc) in the kidney tissues of Cy/+ rats versus +/+ rats (Fig 1C)
Similar observations were obtained in the primary cell cultures of human ADPKD and Normal human kidney epithelial cells (NHK) cells; intracellular ATP levels and lactate in the cellular medium were higher in ADPKD cells as compared to NHK cells, and the levels were diminished upon incubation of ADPKD cells with 2DG (Fig 2D and 2E)
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, characterized by progressive development of innumerable cysts in both kidneys. The development and relentless growth of cysts lead to kidney enlargement and compression of renal parenchyma, leading to subsequent loss of renal function [1,2]. Recent studies have indicated that various signaling cascades are dysregulated in ADPKD, including activation of PLOS ONE | DOI:10.1371/journal.pone.0146654. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
