title: Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by bilateral renal cyst formation. Recent identification of signaling cascades deregulated in ADPKD has led to the initiation of several clinical trials, but an approved therapy is still lacking. Using a metabolomic approach, we identify a pathogenic pathway in this disease that can be safely targeted for therapy. We show that mutation of PKD1 results in enhanced glycolysis in cells in a mouse model of PKD and in kidneys from humans with ADPKD. Glucose deprivation resulted in lower proliferation and higher apoptotic rates in PKD1-mutant cells than in nondeprived cells. Notably, two distinct PKD mouse models treated with 2-deoxyglucose (2DG), to inhibit glycolysis, had lower kidney weight, volume, cystic index and proliferation rates as compared to nontreated mice. These metabolic alterations depend on the extracellular signal-related kinase (ERK) pathway acting in a dual manner by inhibiting the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) axis on the one hand while activating the mTOR complex 1 (mTORC1)-glycolytic cascade on the other. Enhanced metabolic rates further inhibit AMPK. Forced activation of AMPK acts in a negative feedback loop, restoring normal ERK activity. Taken together, these data indicate that defective glucose metabolism is intimately involved in the pathobiology of ADPKD. Our findings provide a strong rationale for a new therapeutic strategy using existing drugs, either individually or in combination.
authors.affiliation: Division of Genetics and Cell Biology, Dulbecco Telethon Institute at Dibit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Isaline
authors.initials: I
authors.lastname: Rowe
authors.forename: Marco
authors.initials: M
authors.lastname: Chiaravalli
authors.forename: Valeria
authors.initials: V
authors.lastname: Mannella
authors.forename: Valeria
authors.initials: V
authors.lastname: Ulisse
authors.forename: Giacomo
authors.initials: G
authors.lastname: Quilici
authors.forename: Monika
authors.initials: M
authors.lastname: Pema
authors.forename: Xuewen W
authors.initials: XW
authors.lastname: Song
authors.forename: Hangxue
authors.initials: H
authors.lastname: Xu
authors.forename: Silvia
authors.initials: S
authors.lastname: Mari
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.forename: York
authors.initials: Y
authors.lastname: Pei
authors.forename: Giovanna
authors.initials: G
authors.lastname: Musco
authors.forename: Alessandra
authors.initials: A
authors.lastname: Boletta
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D003847:Deoxyglucose / Q000494:pharmacology; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000502:physiology; D050396:TRPP Cation Channels / Q000235:genetics / Q000502:physiology
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D003847:Deoxyglucose; D005947:Glucose; D011494:Protein Kinases; D050396:TRPP Cation Channels