Role of meprin A in renal tubular epithelial cell injury

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C Herzog1, R Seth, S V Shah

  • 1Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Kidney International
|March 23, 2007
PubMed

Insights

Meprin A, a kidney enzyme, shows altered localization and increased urinary fragments during acute kidney injury (AKI). Its inhibition protects against cisplatin damage, suggesting meprin A as a therapeutic target and urinary fragments as potential AKI biomarkers.

Area of Science:

  • Biochemistry
  • Nephrology
  • Enzymology

Background:

  • Meprins are zinc-dependent metalloproteinases highly expressed in kidney and intestinal brush-border membranes.
  • They degrade extracellular matrix proteins, process bioactive proteins, and modulate inflammatory responses.
  • Meprin A's role in acute kidney injury (AKI) has not been fully elucidated.

Purpose of the Study:

  • To investigate the function of meprin A in cisplatin-induced nephrotoxicity, a model of AKI.
  • To assess meprin A as a potential biomarker for AKI.
  • To evaluate meprin A inhibition as a therapeutic strategy for AKI.

Main Methods:

  • Examined meprin A localization in proximal tubules of mice subjected to cisplatin nephrotoxicity.
  • Quantified meprin A alpha- and beta-subunits and a cleaved beta-subunit fragment in urine.
  • Assessed serum creatinine, blood urea nitrogen (BUN), and kidney injury molecule-1 (KIM-1) levels.
  • Evaluated the effects of meprin A inhibition on cisplatin nephrotoxicity and histological markers.

Main Results:

  • Meprin A localization shifted from normal brush-border membranes in AKI.
  • A cleaved meprin A beta-subunit fragment, absent in controls, significantly increased in urine during cisplatin nephrotoxicity, preceding rises in serum creatinine and BUN.
  • Meprin A inhibition significantly reduced serum creatinine, BUN, and urinary KIM-1, along with decreased leukocyte infiltration and apoptosis.

Conclusions:

  • Urinary excretion of a meprin A beta-subunit fragment serves as an early biomarker for AKI.
  • Meprin A plays a significant role in cisplatin-induced nephrotoxicity.
  • Meprin A inhibition demonstrates therapeutic potential for AKI, positioning it as a viable therapeutic target.

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