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.

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F‐actin re‐organization via activating p38 in response to ox‐LDL

“…Cholesterol overload from its elevated carriers i.e . circulating LDLs, as was shown in the present study, might negatively influence the binding of podocyte SD proteins to each other, as which is assembled in lipid rafts and is playing a critical role in the formation of glomerular filtration barrier and maintenance of the interdigitating foot process pattern 42, 46, 47. We found in vivo and in vitro , SD proteins podocin and NEPH1 were dramatically decreased during the challenge of hypercholesterolaemia or ox‐LDL treatment.…”

The cholesterol-lowering agent methyl-β-cyclodextrin promotes glucose uptake via GLUT4 in adult muscle fibers and reduces insulin resistance in obese mice

“…Here, we showed that M␤CD has beneficial effects on plasma glucose levels in HFD-fed mice. M␤CD has biomedical and pharmaceutical interests and has been used in vivo with nontoxic effects (55); it has recently received FDA approval for the treatment of Niemann-Pick and Tangier diseases (60) and has been suggested as a potential novel treatment of diabetic nephropathy (39). Accordingly, M␤CD and its derivatives should be tested as possible drugs to treat insulin resistance.…”

Amiloride, a urokinase-type plasminogen activator receptor (uTPA) inhibitor, reduces proteinurea in podocytes

“…Under normal physiological status, the maturely differentiated podocytes are terminal cells without division and proliferation capacity that exist in a relatively stationary state. In contrast, damaged podocytes are hyperdynamic cells that bear similarity to tumor cells (Merscher-Gomez et al, 2013;Yu et al, 2013b). In vitro experiments have shown that these cells exhibit enhanced migration and invasion capacities; i.e.…”