Shedding of the Urinary Biomarker Kidney Injury Molecule-1 (KIM-1) Is Regulated by MAP Kinases and Juxtamembrane Region

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. 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.

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

“…2G), and shedding of the ectodomain of the epithelial cell adhesion molecule KIM-1 into the urine (Fig. 2H), which is consistent with proximal tubular injury (29,30). Knockdown of AIF in the absence of diabetes also resulted in hyperfiltration, as indicated by an increase in creatinine clearance (Fig.…”

Sepsis and Acute Kidney Injury

“…39 Hence, it is essential to have markers that enable early detection. Molecules such as kidney injury molecule-1 40 or neutrophil gelatinaseassociated lipocalin 41 demonstrate exciting potential for this reason. Table 1 summarizes a partial list of emerging biomarkers that are in various phases of validation in AKI.…”

Acute kidney injury in sepsis

“…Certain novel biomarkers may be better predictors of AKI. These include urinary interleukin-18 (IL-18) [13], neutrophil gelatinase associated lipocalin (NGAL) [14] and kidney injury molecule-1 (KIM-1) [15]. Interestingly, some of these biomarkers are noted to be higher in sepsis associated AKI compared to non-septic AKI.…”