Direct lysosomal uptake of α2-microglobulin contributes to chemically induced nephropathy

Ana Maria Cuervo, Heinz Hildebrand, Ernst M. Bomhard, J. Fred Dice

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Background. An abnormal accumulation of α2-microglobulin (α2μ) in kidney lysosomes of male rats has been described in the nephropathy resulting from exposure to a variety of chemicals. The increment in lysosomal levels of α2μ cannot be explained by a decrease in its proteolytic susceptibility. Because a portion of α2μ resides in the cytosol of kidney cells, we decided to analyze whether this cytosolic form also contributes to the abnormal lysosomal accumulation of α2μ after exposure to chemicals. Methods. Intact kidney lysosomes were isolated from untreated or 2,2,4-trimethylpentane (TMP) treated rats, and their ability to take up α2μ was compared. Results. α2μ can be directly transported into isolated lysosomes in the presence of the heat shock cognate protein of 73 kDa (hsc73). α2μ specifically binds to a lysosomal membrane glycoprotein of 96 kDa, previously identified as the receptor for the hsc73-mediated lysosomal pathway of protein degradation. In rats exposed to TMP, the specific lysosomal transport of α2μ increases, as well as the ability of lysosomes to directly transport other substrates for this pathway The increased lysosomal transport is mainly due to an increase in the levels of the receptor protein in the lysosomal membrane. Conclusions. The hsc73-mediated lysosomal pathway contributes to the normal degradation of α2μ in rat kidney and liver, and the activity of this pathway is increased after exposure to TMP. Our results suggest that the chemically induced accumulation of cytosolic α2μ in lysosomes is mediated by an increased rate of direct uptake into lysosomes.

Original languageEnglish (US)
Pages (from-to)529-545
Number of pages17
JournalKidney International
Volume55
Issue number2
DOIs
StatePublished - 1999
Externally publishedYes

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Lysosomes
Heat-Shock Proteins
Lysosome-Associated Membrane Glycoproteins
Kidney
Cytosol
Proteolysis
Liver

Keywords

  • Cathepsin
  • Heat shock protein
  • Hyaline droplet nephropathy
  • Lysosomes
  • Membrane transport
  • Protein degradation

ASJC Scopus subject areas

  • Nephrology

Cite this

Direct lysosomal uptake of α2-microglobulin contributes to chemically induced nephropathy. / Cuervo, Ana Maria; Hildebrand, Heinz; Bomhard, Ernst M.; Dice, J. Fred.

In: Kidney International, Vol. 55, No. 2, 1999, p. 529-545.

Research output: Contribution to journalArticle

Cuervo, Ana Maria ; Hildebrand, Heinz ; Bomhard, Ernst M. ; Dice, J. Fred. / Direct lysosomal uptake of α2-microglobulin contributes to chemically induced nephropathy. In: Kidney International. 1999 ; Vol. 55, No. 2. pp. 529-545.
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abstract = "Background. An abnormal accumulation of α2-microglobulin (α2μ) in kidney lysosomes of male rats has been described in the nephropathy resulting from exposure to a variety of chemicals. The increment in lysosomal levels of α2μ cannot be explained by a decrease in its proteolytic susceptibility. Because a portion of α2μ resides in the cytosol of kidney cells, we decided to analyze whether this cytosolic form also contributes to the abnormal lysosomal accumulation of α2μ after exposure to chemicals. Methods. Intact kidney lysosomes were isolated from untreated or 2,2,4-trimethylpentane (TMP) treated rats, and their ability to take up α2μ was compared. Results. α2μ can be directly transported into isolated lysosomes in the presence of the heat shock cognate protein of 73 kDa (hsc73). α2μ specifically binds to a lysosomal membrane glycoprotein of 96 kDa, previously identified as the receptor for the hsc73-mediated lysosomal pathway of protein degradation. In rats exposed to TMP, the specific lysosomal transport of α2μ increases, as well as the ability of lysosomes to directly transport other substrates for this pathway The increased lysosomal transport is mainly due to an increase in the levels of the receptor protein in the lysosomal membrane. Conclusions. The hsc73-mediated lysosomal pathway contributes to the normal degradation of α2μ in rat kidney and liver, and the activity of this pathway is increased after exposure to TMP. Our results suggest that the chemically induced accumulation of cytosolic α2μ in lysosomes is mediated by an increased rate of direct uptake into lysosomes.",
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N2 - Background. An abnormal accumulation of α2-microglobulin (α2μ) in kidney lysosomes of male rats has been described in the nephropathy resulting from exposure to a variety of chemicals. The increment in lysosomal levels of α2μ cannot be explained by a decrease in its proteolytic susceptibility. Because a portion of α2μ resides in the cytosol of kidney cells, we decided to analyze whether this cytosolic form also contributes to the abnormal lysosomal accumulation of α2μ after exposure to chemicals. Methods. Intact kidney lysosomes were isolated from untreated or 2,2,4-trimethylpentane (TMP) treated rats, and their ability to take up α2μ was compared. Results. α2μ can be directly transported into isolated lysosomes in the presence of the heat shock cognate protein of 73 kDa (hsc73). α2μ specifically binds to a lysosomal membrane glycoprotein of 96 kDa, previously identified as the receptor for the hsc73-mediated lysosomal pathway of protein degradation. In rats exposed to TMP, the specific lysosomal transport of α2μ increases, as well as the ability of lysosomes to directly transport other substrates for this pathway The increased lysosomal transport is mainly due to an increase in the levels of the receptor protein in the lysosomal membrane. Conclusions. The hsc73-mediated lysosomal pathway contributes to the normal degradation of α2μ in rat kidney and liver, and the activity of this pathway is increased after exposure to TMP. Our results suggest that the chemically induced accumulation of cytosolic α2μ in lysosomes is mediated by an increased rate of direct uptake into lysosomes.

AB - Background. An abnormal accumulation of α2-microglobulin (α2μ) in kidney lysosomes of male rats has been described in the nephropathy resulting from exposure to a variety of chemicals. The increment in lysosomal levels of α2μ cannot be explained by a decrease in its proteolytic susceptibility. Because a portion of α2μ resides in the cytosol of kidney cells, we decided to analyze whether this cytosolic form also contributes to the abnormal lysosomal accumulation of α2μ after exposure to chemicals. Methods. Intact kidney lysosomes were isolated from untreated or 2,2,4-trimethylpentane (TMP) treated rats, and their ability to take up α2μ was compared. Results. α2μ can be directly transported into isolated lysosomes in the presence of the heat shock cognate protein of 73 kDa (hsc73). α2μ specifically binds to a lysosomal membrane glycoprotein of 96 kDa, previously identified as the receptor for the hsc73-mediated lysosomal pathway of protein degradation. In rats exposed to TMP, the specific lysosomal transport of α2μ increases, as well as the ability of lysosomes to directly transport other substrates for this pathway The increased lysosomal transport is mainly due to an increase in the levels of the receptor protein in the lysosomal membrane. Conclusions. The hsc73-mediated lysosomal pathway contributes to the normal degradation of α2μ in rat kidney and liver, and the activity of this pathway is increased after exposure to TMP. Our results suggest that the chemically induced accumulation of cytosolic α2μ in lysosomes is mediated by an increased rate of direct uptake into lysosomes.

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