Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus

Rabea Asleh, Farid M. Nakhoul, Rachel Miller-Lotan, Hoda Awad, Dan Farbstein, Nina S. Levy, Nakhoul Nakhoul, Theodore C. Iancu, Irena Manov, Michael Laue, Maret G. Traber, Katie M. Lebold, Andrew P. Levy

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

The haptoglobin (Hp) genotype is a major determinant of progression of nephropathy in individuals with diabetes mellitus (DM). The major function of the Hp protein is to bind and modulate the fate of extracorpuscular hemoglobin and its iron cargo. We have previously demonstrated an interaction between the Hp genotype and the DM on the accumulation of iron in renal proximal tubule cells. The primary objective of this study was to determine the intracellular localization of this iron in the proximal tubule cell and to assess its potential toxicity. Transmission electron microscopy demonstrated a marked accumulation of electron-dense deposits in the lysosomes of proximal tubules cells in Hp 2-2 DM mice. Energy-dispersive X-ray spectroscopy and electron energy loss spectroscopy were used to perform elemental analysis of these deposits and demonstrated that these deposits were iron rich. These deposits were associated with lysosomal membrane lipid peroxidation and loss of lysosomal membrane integrity. Vitamin E administration to Hp 2-2 DM mice resulted in a significant decrease in both intralysosomal iron-induced oxidation and lysosomal destabilization. Iron-induced renal tubular injury may play a major role in the development of diabetic nephropathy and may be a target for slowing the progression of renal disease.

Original languageEnglish
Pages (from-to)779-786
Number of pages8
JournalFree Radical Biology and Medicine
Volume53
Issue number4
DOIs
StatePublished - 15 Aug 2012

Bibliographical note

Funding Information:
This work was supported by a grant from the Israel Society Foundation (ISF) to F.M. Nakhoul and in part from Aboutboul Family in memory of Daniel Aboutboul and by grants from NIH ( R01DK085226 ) and the ISF to A.P.L. This work was also generously supported by a grant from the Slava Smolakovski Fund to the Rambam-Atidim Academic Excellence Program. The electron-microscopic analyses were supported by the Dan David Foundation to T.C.I. and I.M. M.L. thanks Gerd Fulda for operating the microscope. A.P.L. is the author of a patent which is owned by his institution that claims that the Hp genotype is predictive of DM complications. He is also a consultant for Haptocure which has licensed this patent from his institution. R.A., F.N., R.M.L., H.A., D.F., N.S.L., N.N., T.C.I., I.M., M.L., M.G.T., and K.M.L. were involved in generating research data and reviewing the manuscript. R.A., F.N., and A.P.L. wrote the manuscript.

Keywords

  • Diabetes
  • Haptoglobin genotype
  • Iron-induced injury
  • Lysosome
  • Nephropathy
  • Oxidative stress

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