title: 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.
authors.affiliation: Nephrology, Institute of Physiology, University of Zurich, Zurich, Switzerland.|Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Meliana
authors.initials: M
authors.lastname: Riwanto
authors.affiliation: Nephrology, Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Sarika
authors.initials: S
authors.lastname: Kapoor
authors.affiliation: Nephrology, Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rodriguez
authors.affiliation: Nephrology, Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Ilka
authors.initials: I
authors.lastname: Edenhofer
authors.affiliation: Nephrology, Institute of Physiology, University of Zurich, Zurich, Switzerland.|Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
authors.affiliation: Nephrology, Institute of Physiology, University of Zurich, Zurich, Switzerland.|Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Rudolf P
authors.initials: RP
authors.lastname: Wüthrich
mesh_terms: D000332:Aerobiosis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology; D018450:Disease Progression; D005943:Gluconeogenesis / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D003847:Deoxyglucose