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Megalin contributes to kidney accumulation and nephrotoxicity of colistin

Takahiro Suzuki1, Hiroaki Yamaguchi, Jiro Ogura

  • 1Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.

Antimicrobial Agents and Chemotherapy
|October 9, 2013
PubMed

Insights

Colistin

Area of Science:

  • Nephrology
  • Pharmacology
  • Molecular Biology

Background:

  • Colistin is crucial for treating multidrug-resistant Gram-negative bacterial infections.
  • Nephrotoxicity limits colistin dosage, but its mechanisms remain unclear.
  • Megalin, an endocytosis receptor in renal proximal tubules, is investigated for its role in colistin's kidney effects.

Purpose of the Study:

  • To elucidate the role of megalin in colistin-induced kidney accumulation and toxicity.
  • To investigate colistin's interaction with megalin.
  • To explore potential strategies for preventing colistin nephrotoxicity.

Main Methods:

  • Vesicle assay to examine colistin-megalin binding.
  • Evaluation of colistin levels in kidney, urine, and plasma of megalin-shedding rats.
  • Assessment of colistin nephrotoxicity with megalin ligands and colchicine.

Main Results:

  • Cytochrome c competitively inhibited colistin binding to megalin.
  • Colistin accumulation in renal proximal tubules was reduced in megalin-shedding rats.
  • Coadministration of colistin with megalin ligands (cytochrome c, albumin fragments) or colchicine significantly reduced urinary N-acetyl-β-d-glucosaminidase (NAG) excretion, a marker of kidney damage.

Conclusions:

  • Colistin functions as a megalin ligand.
  • Megalin is critical for colistin's accumulation in the kidneys and subsequent nephrotoxicity.
  • Megalin ligands present a potential therapeutic target for mitigating colistin-induced kidney damage.

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