||Merscher-Gomez S, Guzman J, Pedigo CE, Lehto M, Aguillon-Prada R, Mendez A,
Lassenius MI, Forsblom C, Yoo T, Villarreal R, Maiguel D, Johnson K, Goldberg R,
Nair V, Randolph A, Kretzler M, Nelson RG, Burke GW, Groop PH, Fornoni A
||Alessia Fornoni on 7/10/2013
|Volume : Pages
||62 : 3817 - 3827
||Diabetic kidney disease remains the most common cause of end-stage kidney
disease despite multifactorial intervention. We demonstrated that increased
cholesterol in association with down-regulation 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 to diabetic
patients with normoalbuminuria (DKD-) and similar duration of diabetes and lipid
profile. Glomerular down-regulation of ABCA1 was confirmed in biopsies from
patients with early DKD (n=70) when compared to 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 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, 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.