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

doi:10.1016/j.freeradbiomed.2012.06.015

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 journal › Article › peer-review

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 language	English
Pages (from-to)	779-786
Number of pages	8
Journal	Free Radical Biology and Medicine
Volume	53
Issue number	4
DOIs	https://doi.org/10.1016/j.freeradbiomed.2012.06.015
State	Published - 15 Aug 2012
Externally published	Yes

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

ASJC Scopus subject areas

Biochemistry
Physiology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.freeradbiomed.2012.06.015

Cite this

Asleh, R., Nakhoul, F. M., Miller-Lotan, R., Awad, H., Farbstein, D., Levy, N. S., Nakhoul, N., Iancu, T. C., Manov, I., Laue, M., Traber, M. G., Lebold, K. M., & Levy, A. P. (2012). Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus. Free Radical Biology and Medicine, 53(4), 779-786. https://doi.org/10.1016/j.freeradbiomed.2012.06.015

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

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.",

keywords = "Diabetes, Haptoglobin genotype, Iron-induced injury, Lysosome, Nephropathy, Oxidative stress",

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

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.",

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Asleh, R, Nakhoul, FM, Miller-Lotan, R, Awad, H, Farbstein, D, Levy, NS, Nakhoul, N, Iancu, TC, Manov, I, Laue, M, Traber, MG, Lebold, KM & Levy, AP 2012, 'Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus', Free Radical Biology and Medicine, vol. 53, no. 4, pp. 779-786. https://doi.org/10.1016/j.freeradbiomed.2012.06.015

TY - JOUR

T1 - Poor lysosomal membrane integrity in proximal tubule cells of haptoglobin 2-2 genotype mice with diabetes mellitus

AU - Asleh, Rabea

AU - Nakhoul, Farid M.

AU - Miller-Lotan, Rachel

AU - Awad, Hoda

AU - Farbstein, Dan

AU - Levy, Nina S.

AU - Nakhoul, Nakhoul

AU - Iancu, Theodore C.

AU - Manov, Irena

AU - Laue, Michael

AU - Traber, Maret G.

AU - Lebold, Katie M.

AU - Levy, Andrew P.

N1 - 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.

PY - 2012/8/15

Y1 - 2012/8/15

N2 - 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.

AB - 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.

KW - Diabetes

KW - Haptoglobin genotype

KW - Iron-induced injury

KW - Lysosome

KW - Nephropathy

KW - Oxidative stress

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U2 - 10.1016/j.freeradbiomed.2012.06.015

DO - 10.1016/j.freeradbiomed.2012.06.015

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C2 - 22749805

AN - SCOPUS:84864416943

SN - 0891-5849

VL - 53

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JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

IS - 4

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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