title: Targeting of sodium-glucose cotransporters with phlorizin inhibits polycystic kidney disease progression in Han:SPRD rats.
abstract: 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.
authors.affiliation: 1] Division of Nephrology, University Hospital, Zürich, Switzerland [2] Institute of Physiology, University of Zürich, Zürich, Switzerland [3] Department of Nephrology, Kidney Institute of PLA, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, PRC.
authors.forename: Xueqi
authors.initials: X
authors.lastname: Wang
authors.forename: Suhua
authors.initials: S
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Daniela
authors.initials: D
authors.lastname: Spichtig
authors.forename: Sarika
authors.initials: S
authors.lastname: Kapoor
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
authors.forename: Nilufar
authors.initials: N
authors.lastname: Mohebbi
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Serra
authors.forename: Daniel
authors.initials: D
authors.lastname: Rodriguez
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.forename: Changlin
authors.initials: C
authors.lastname: Mei
authors.forename: Rudolf P
authors.initials: RP
authors.lastname: Wüthrich
mesh_terms: D000419:Albuminuria / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006029:Glycosuria / Q000378:metabolism; D006579:Heterozygote; D019394:Ki-67 Antigen / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010695:Phlorhizin / Q000494:pharmacology*; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D051247:Sodium-Glucose Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D064804:Urological Agents / Q000494:pharmacology*
chemical_list: D019394:Ki-67 Antigen; D051247:Sodium-Glucose Transport Proteins; D064804:Urological Agents; D010695:Phlorhizin; D020928:Mitogen-Activated Protein Kinases