title: Cyclodextrin protects podocytes in diabetic kidney disease.
abstract: Diabetic kidney disease (DKD) remains the most common cause of end-stage kidney disease despite multifactorial intervention. We demonstrated that increased cholesterol in association with downregulation of ATP-binding cassette transporter ABCA1 occurs in normal human podocytes exposed to the sera of patients with type 1 diabetes and albuminuria (DKD(+)) when compared with diabetic patients with normoalbuminuria (DKD(-)) and similar duration of diabetes and lipid profile. Glomerular downregulation of ABCA1 was confirmed in biopsies from patients with early DKD (n = 70) when compared with normal living donors (n = 32). Induction of cholesterol efflux with cyclodextrin (CD) but not inhibition of cholesterol synthesis with simvastatin prevented podocyte injury observed in vitro after exposure to patient sera. Subcutaneous administration of CD to diabetic BTBR (black and tan, brachiuric) ob/ob mice was safe and reduced albuminuria, mesangial expansion, kidney weight, and cortical cholesterol content. This was followed by an improvement of fasting insulin, blood glucose, body weight, and glucose tolerance in vivo and improved glucose-stimulated insulin release in human islets in vitro. Our data suggest that impaired reverse cholesterol transport characterizes clinical and experimental DKD and negatively influences podocyte function. Treatment with CD is safe and effective in preserving podocyte function in vitro and in vivo and may improve the metabolic control of diabetes.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Sandra
authors.initials: S
authors.lastname: Merscher-Gomez
authors.forename: Johanna
authors.initials: J
authors.lastname: Guzman
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Pedigo
authors.forename: Markku
authors.initials: M
authors.lastname: Lehto
authors.forename: Robier
authors.initials: R
authors.lastname: Aguillon-Prada
authors.forename: Armando
authors.initials: A
authors.lastname: Mendez
authors.forename: Mariann I
authors.initials: MI
authors.lastname: Lassenius
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.forename: Taehyun
authors.initials: T
authors.lastname: Yoo
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Villarreal
authors.forename: Dony
authors.initials: D
authors.lastname: Maiguel
authors.forename: Kevin
authors.initials: K
authors.lastname: Johnson
authors.forename: Ronald
authors.initials: R
authors.lastname: Goldberg
authors.forename: Viji
authors.initials: V
authors.lastname: Nair
authors.forename: Ann
authors.initials: A
authors.lastname: Randolph
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nelson
authors.forename: George W
authors.initials: GW
authors.lastname: Burke
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.forename: Alessia
authors.initials: A
authors.lastname: Fornoni
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000096:biosynthesis*; D000328:Adult; D000419:Albuminuria / Q000503:physiopathology; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003505:Cyclodextrins / Q000494:pharmacology / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000097:blood / Q000503:physiopathology*; D015536:Down-Regulation; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects; D007678:Kidney Glomerulus / Q000503:physiopathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008875:Middle Aged; D050199:Podocytes / Q000187:drug effects* / Q000473:pathology
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D003505:Cyclodextrins; D002784:Cholesterol