Cyclodextrin protects podocytes in diabetic kidney disease

Sandra Merscher-Gomez, Johanna Guzman, Christopher E. Pedigo, Markku Lehto, Robier Aguillon-Prada, Armando Mendez, Mariann I. Lassenius, Carol Forsblom, Tae Hyun Yoo, Rodrigo Villarreal, Dony Maiguel, Kevin Johnson, Ronald Goldberg, Viji Nair, Ann Randolph, Matthias Kretzler, Robert G. Nelson, George W. Burke, Per Henrik Groop, Alessia Fornoni

Research output: Contribution to journalArticle

52 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3817-3827
Number of pages11
JournalDiabetes
Volume62
Issue number11
DOIs
Publication statusPublished - 2013 Nov 1

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Podocytes
Cyclodextrins
Diabetic Nephropathies
Cholesterol
Albuminuria
Down-Regulation
Insulin
Glucose
Simvastatin
ATP-Binding Cassette Transporters
Living Donors
Serum
Type 1 Diabetes Mellitus
Chronic Kidney Failure
Blood Glucose
Fasting
Body Weight
Kidney
Lipids
Biopsy

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Merscher-Gomez, S., Guzman, J., Pedigo, C. E., Lehto, M., Aguillon-Prada, R., Mendez, A., ... Fornoni, A. (2013). Cyclodextrin protects podocytes in diabetic kidney disease. Diabetes, 62(11), 3817-3827. https://doi.org/10.2337/db13-0399
Merscher-Gomez, Sandra ; Guzman, Johanna ; Pedigo, Christopher E. ; Lehto, Markku ; Aguillon-Prada, Robier ; Mendez, Armando ; Lassenius, Mariann I. ; Forsblom, Carol ; Yoo, Tae Hyun ; Villarreal, Rodrigo ; Maiguel, Dony ; Johnson, Kevin ; Goldberg, Ronald ; Nair, Viji ; Randolph, Ann ; Kretzler, Matthias ; Nelson, Robert G. ; Burke, George W. ; Groop, Per Henrik ; Fornoni, Alessia. / Cyclodextrin protects podocytes in diabetic kidney disease. In: Diabetes. 2013 ; Vol. 62, No. 11. pp. 3817-3827.
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Merscher-Gomez, S, Guzman, J, Pedigo, CE, Lehto, M, Aguillon-Prada, R, Mendez, A, Lassenius, MI, Forsblom, C, Yoo, TH, Villarreal, R, Maiguel, D, Johnson, K, Goldberg, R, Nair, V, Randolph, A, Kretzler, M, Nelson, RG, Burke, GW, Groop, PH & Fornoni, A 2013, 'Cyclodextrin protects podocytes in diabetic kidney disease', Diabetes, vol. 62, no. 11, pp. 3817-3827. https://doi.org/10.2337/db13-0399

Cyclodextrin protects podocytes in diabetic kidney disease. / Merscher-Gomez, Sandra; Guzman, Johanna; Pedigo, Christopher E.; Lehto, Markku; Aguillon-Prada, Robier; Mendez, Armando; Lassenius, Mariann I.; Forsblom, Carol; Yoo, Tae Hyun; Villarreal, Rodrigo; Maiguel, Dony; Johnson, Kevin; Goldberg, Ronald; Nair, Viji; Randolph, Ann; Kretzler, Matthias; Nelson, Robert G.; Burke, George W.; Groop, Per Henrik; Fornoni, Alessia.

In: Diabetes, Vol. 62, No. 11, 01.11.2013, p. 3817-3827.

Research output: Contribution to journalArticle

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AU - Merscher-Gomez, Sandra

AU - Guzman, Johanna

AU - Pedigo, Christopher E.

AU - Lehto, Markku

AU - Aguillon-Prada, Robier

AU - Mendez, Armando

AU - Lassenius, Mariann I.

AU - Forsblom, Carol

AU - Yoo, Tae Hyun

AU - Villarreal, Rodrigo

AU - Maiguel, Dony

AU - Johnson, Kevin

AU - Goldberg, Ronald

AU - Nair, Viji

AU - Randolph, Ann

AU - Kretzler, Matthias

AU - Nelson, Robert G.

AU - Burke, George W.

AU - Groop, Per Henrik

AU - Fornoni, Alessia

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N2 - 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.

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Merscher-Gomez S, Guzman J, Pedigo CE, Lehto M, Aguillon-Prada R, Mendez A et al. Cyclodextrin protects podocytes in diabetic kidney disease. Diabetes. 2013 Nov 1;62(11):3817-3827. https://doi.org/10.2337/db13-0399