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Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
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AMPK protects proximal tubular epithelial cells from lysosomal dysfunction and dedifferentiation induced by

Louise Pierre1,2, Florian Juszczak2, Valentine Delmotte1

  • 1Laboratory of Biochemistry and Cell Biology, Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium.

Autophagy
|December 15, 2024
PubMed

Insights

Lipid stress impairs kidney proximal tubule cells by damaging lysosomes and reducing autophagic flux. Activating AMP-activated protein kinase (AMPK) preserves lysosomal function and cell differentiation, offering a protective strategy against metabolic kidney disease.

Area of Science:

  • Nephrology
  • Cell Biology
  • Metabolic Diseases

Background:

  • Renal proximal tubules are vulnerable to injury in metabolic diseases like obesity.
  • Dysregulated lipid metabolism, organelle dysfunction, and oxidative stress in proximal tubular epithelial cells (PTECs) drive kidney fibrosis and failure.
  • AMP-activated protein kinase (AMPK) decline is implicated in obesity-induced kidney disease.

Purpose of the Study:

  • To investigate the impact of lipid stress on autophagic flux and lysosomes in PTECs.
  • To explore the role of lysosomes in the lipotoxic phenotype of PTECs.
  • To determine if AMPK activation can protect PTECs from lipid-induced damage.

Main Methods:

  • Primary PTECs were challenged with palmitate (a fatty acid) to mimic lipid stress.
  • Lysosomal function, including acidification and autophagic flux, was assessed.
  • AMPK activity was modulated using activators to evaluate its protective effects.
  • PTEC differentiation markers were analyzed to assess cell health.

Main Results:

  • Palmitate exposure led to impaired lysosomal acidification and autophagosome accumulation within 6 hours.
  • Lysosomal quality control failed to restore pH, driving PTEC dedifferentiation.
  • Preventing AMPK activity decline with activators preserved lysosomal acidification and PTEC differentiation.
  • Lysosomes are central to the lipotoxic phenotype in PTECs.

Conclusions:

  • Lysosomes are critical for maintaining PTEC homeostasis and are a key target in lipotoxicity.
  • AMPK plays a vital role in protecting lysosomes from lipid stress.
  • Targeting AMPK may offer a therapeutic strategy for metabolic kidney diseases.
Keywords:
AMPKAutophagychronic kidney diseaselipid accumulationobesityproximal tubules

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