Autophagy gene ATG7 regulates albumin transcytosis in renal tubule epithelial cells

Am J Physiol Renal Physiol. 2021 Nov 1;321(5):F572-F586. doi: 10.1152/ajprenal.00172.2021. Epub 2021 Sep 20.

Abstract

Receptor-mediated albumin transport in proximal tubule epithelial cells (PTECs) is important to control proteinuria. Autophagy is an evolutionarily conserved degradation pathway, and its role in intracellular trafficking through interactions with the endocytic pathway has recently been highlighted. Here, we determined whether autophagy regulates albumin transcytosis in PTECs and suppresses albumin-induced cytotoxicity using human proximal tubule (HK-2) cells. The neonatal Fc receptor (FcRn), a receptor for albumin transcytosis, is partially colocalized with autophagosomes. Recycling of FcRn was attenuated, and FcRn accumulated in autophagy-related 7 (ATG7) knockdown HK-2 cells. Colocalization of FcRn with RAB7-positive late endosomes and RAB11-positive recycling endosomes was reduced in ATG7 knockdown cells, which decreased recycling of FcRn to the plasma membrane. In ATG7 or autophagy-related 5 (ATG5) knockdown cells and Atg5 or Atg7 knockout mouse embryonic fibroblasts, albumin transcytosis was significantly reduced and intracellular albumin accumulation was increased. Finally, the release of kidney injury molecule-1, a marker of tubule injury, from ATG7 or ATG5 knockdown cells was increased in response to excess albumin. In conclusion, suppression of autophagy in tubules impairs FcRn transport, thereby inhibiting albumin transcytosis. The resulting accumulation of albumin induces cytotoxicity in tubules.NEW & NOTEWORTHY Albumin transport in proximal tubule epithelial cells (PTECs) is important to control proteinuria. The neonatal Fc receptor (FcRn), a receptor for albumin transcytosis, is partially colocalized with autophagosomes. Recycling of FcRn to the plasma membrane was decreased in autophagy-related 7 (ATG7) knockdown cells. In addition, albumin transcytosis was decreased in ATG7 or autophagy-related 5 (ATG5) knockdown PTECs. Finally, release of kidney injury molecule-1 from ATG7 or ATG5 knockdown cells was increased in response to excess albumin.

Keywords: albumin; autophagy; autophagy-related 7; neonatal Fc receptor; transcytosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagosomes / genetics
  • Autophagosomes / metabolism*
  • Autophagy*
  • Autophagy-Related Protein 5 / genetics
  • Autophagy-Related Protein 5 / metabolism
  • Autophagy-Related Protein 7 / genetics
  • Autophagy-Related Protein 7 / metabolism*
  • Cell Line
  • Epithelial Cells / metabolism*
  • Fluorescein-5-isothiocyanate / analogs & derivatives*
  • Fluorescein-5-isothiocyanate / metabolism
  • Hepatitis A Virus Cellular Receptor 1 / metabolism
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / metabolism*
  • Mice
  • Receptors, Fc / genetics
  • Receptors, Fc / metabolism
  • Serum Albumin, Bovine / metabolism*
  • Transcytosis*
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism
  • rab7 GTP-Binding Proteins

Substances

  • Atg5 protein, mouse
  • Atg7 protein, mouse
  • Autophagy-Related Protein 5
  • Havcr1 protein, mouse
  • Hepatitis A Virus Cellular Receptor 1
  • Histocompatibility Antigens Class I
  • Receptors, Fc
  • fluorescein isothiocyanate bovine serum albumin
  • rab7 GTP-Binding Proteins
  • rab7 GTP-binding proteins, human
  • rab7 GTP-binding proteins, mouse
  • Serum Albumin, Bovine
  • rab11 protein
  • rab GTP-Binding Proteins
  • ATG7 protein, human
  • Autophagy-Related Protein 7
  • Fluorescein-5-isothiocyanate
  • Fc receptor, neonatal

Associated data

  • figshare/10.6084/m9.figshare.14528991
  • figshare/10.6084/m9.figshare.16404117
  • figshare/10.6084/m9.figshare.16160871