Shedding of the urinary biomarker kidney injury molecule-1 (KIM-1) is regulated by MAP kinases and juxtamembrane region

Zhiwei Zhang, Benjamin D. Humphreys, Joseph V. Bonventre

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Kidney injury molecule-1 (KIM-1) is markedly upregulated in renal proximal tubule cells by stimuli that promote dedifferentiation, including ischemic or toxic injury, as well as in cases of tubulointerstitial disease, polycystic kidney disease, and renal cell carcinoma. Structurally, KIM-1 possesses a single transmembrane domain and undergoes membrane-proximal cleavage, which leads to the release of soluble KIM-1 ectodomain into the urine. The abstract for this article has been revised by the editorial office; please review and approve or correct as needed. Urinary KIM-1 ectodomain is a promising sensitive and specific biomarker for acute kidney injury in humans, and therefore it is important to determine what regulates KIM-1 shedding. We found that constitutive cleavage of KIM-1 is mediated by ERK activation, and that cleavage is accelerated by p38 MAP kinase activation. After cleavage, a 14-kD membrane-bound fragment of KIM-1, which contains two highly conserved tyrosine residues, was tyrosine-phosphorylated. Mutagenesis studies demonstrated that the juxtamembrane secondary structure, not the primary amino acid sequence, was critical to the cleavage of KIM-1.

Original languageEnglish
Pages (from-to)2704-2714
Number of pages11
JournalJournal of the American Society of Nephrology
Volume18
Issue number10
DOIs
StatePublished - Oct 1 2007
Externally publishedYes

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