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Angiotensin II type-1 receptor-associated protein interacts with transferrin receptor-1 and promotes its

Eriko Abe1,2, Akio Yamashita3, Keigo Hirota1

  • 1Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Scientific Reports
|October 17, 2022
PubMed

Insights

Angiotensin II type-1 receptor-associated protein (ATRAP) suppresses kidney fibrosis by reducing cell-surface transferrin receptor 1 (TfR1). This action impacts iron metabolism and oxidative stress, offering new therapeutic targets for chronic kidney disease.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Biochemistry

Background:

  • Kidney fibrosis is a central mechanism in chronic kidney disease progression.
  • Angiotensin II type-1 receptor-associated protein (ATRAP) has been implicated in kidney fibrosis, with previous studies suggesting AT1R-independent actions.
  • The precise molecular mechanisms underlying ATRAP's role in kidney fibrosis remain unclear.

Purpose of the Study:

  • To elucidate the AT1R-independent molecular mechanisms of ATRAP in kidney fibrosis.
  • To identify novel ATRAP-interacting proteins.
  • To investigate the functional relationship between ATRAP and transferrin receptor 1 (TfR1) in the context of kidney fibrosis.

Main Methods:

  • Mass spectrometry-based proteomics to identify ATRAP-interacting proteins.
  • Immunoprecipitation and Western blotting to confirm protein-protein interactions.
  • Cell-based assays to assess cell-surface protein expression, cellular iron levels, and oxidative stress signaling.

Main Results:

  • Proteomic analysis identified 376 candidate ATRAP-interacting proteins, enriched for functions in vesicle trafficking and membrane transport.
  • Transferrin receptor 1 (TfR1), a key regulator of cellular iron uptake, was identified as an ATRAP interactor.
  • Enhanced ATRAP expression led to decreased cell-surface TfR1 levels, reduced cellular iron uptake, and attenuated oxidative stress signaling, independent of overall TfR1 expression.

Conclusions:

  • ATRAP acts as a suppressor of TfR1 by promoting its internalization.
  • This ATRAP-TfR1 interaction influences cellular iron metabolism and oxidative stress pathways relevant to kidney fibrosis.
  • Targeting the ATRAP-TfR1 axis presents a potential therapeutic strategy for mitigating kidney fibrosis.

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