Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more

Abstract

The kidney injury molecule-1 (designated as Kim-1 in rodents, KIM-1 in humans) mRNA was identified using techniques of representational difference analysis, a PCR-based technique [ 1 ], which we carried out to find genes whose expression was markedly upregulated 24–48 h after ischaemia in the rat [ 2 ]. Kim-1 was the gene found to be most highly upregulated in this screen. A large pharmaceutical company consortium, using an unbiased genomic approach to evaluate genes upregulated with the nephrotoxin cisplatin, determined that Kim-1 was upregulated more than any other of the 30 000 genes tested [ 3 ]. There are a large number of studies in animals showing robust Kim-1 protein production in the affected segments of the proximal tubule whenever a toxin or pathophysiological state results in dedifferentiation of the epithelium (e.g. [ 4–6 ]). Dedifferentiation is a very early manifestation of the epithelial cell response to injury [ 7 ]. KIM-1 is also expressed, at much lower levels, in lymphocytes and has also been referred to as T-cell immunoglobulin mucin (TIM)-1 and HAVCR-1, hepatitis A virus cellular receptor-1. The protein has also been reported to be expressed in the cochlea in response to cisplatin-induced injury [ 8 ]. The KIM/TIM family consists of eight members in mice, six in rats and three in humans [ 9,10 ]. Using standard northern or western blot analyses and immunocytochemistry, KIM-1 gene or protein expression is undetectable in the normal kidney. With injury KIM-1 mRNA is rapidly made and protein is generated and localized at very high levels on the apical membrane of proximal tubule in that region where the tubule is most affected. In the case of experimental ischaemia in rodents, Kim-1 expression is predominantly in the S3 segment of the proximal tubule. In human ischaemic and toxic acute kidney injury (AKI) it is found in the three segments of the proximal tubule. KIM-1 is a type I cell membrane glycoprotein which contains, in its extracellular portion, a novel six-cysteine immunoglobulin-like domain, two N -glycosylation sites and a T/SP rich domain characteristic of mucin-like O -glycosylated proteins. The structure of the protein led us to initially believe it had adhesion molecule properties [ 11 ] (Figure 1 ). KIM-1 is also expressed at high levels in patients with clear cell-type renal cell carcinoma (RCC) [ 12 ]. RCC, like renal tubular injury, is associated with proximal tubule cell dedifferentiation. Structure of KIM-1. KIM-1 is a type 1 membrane glycoprotein that contains, in its extracellular portion, a novel six-cysteine immunoglobulin-like domain, two N -glycosylation sites and a T/SP rich domain characteristic of mucin-like O -glycosylated proteins. There is one transmembrane domain and a short intracellular domain with a tyrosine phosphorylation signalling motif present in the renal form (KIM-1b). We are beginning to appreciate the functional role of KIM-1 in the kidney. KIM-1 confers on epithelial cells the ability to recognize and phagocytose dead cells that are present in the post-ischaemic kidney and contribute to the obstruction of the tubule lumen that characterizes AKI. KIM-1 is a phosphatidylserine receptor that recognizes apoptotic cells directing them to lysosomes. It also serves as a receptor for oxidized lipoproteins and hence is adept at recognizing apoptotic cell ‘eat me’ signals. Given these properties KIM-1 is unique in being the first non-myeloid phosphatidylserine receptor that transforms epithelial cells into semi-professional phagocytes [ 13,14 ]. In addition to the facilitation of clearance of the apoptotic debris from the tubular lumen, KIM-1 may play an important role in limiting the autoimmune response to injury since it is known in many systems that phagocytosis of apoptotic bodies is one mechanism for limiting the proinflammatory response. Acute protective responses, however, may not necessarily translate to chronic effects of KIM-1 expression, a clinically relevant issue, since we [ 15 ] and others [ 16 ] have found that many individuals with chronic renal failure express the KIM-1 protein in their proximal tubules. The ectodomain of KIM-1 is shed from cells in vitro [ 11 ] and in vivo into the urine in rodents [ 4,5 ] and humans [ 17 ] after proximal tubular kidney injury or in patients with RCC [ 12 ]. This shedding is regulated, at least in part, by MAP kinase signalling pathways that are activated with stress [ 18 ]. Metalloproteinase activity results in the release of soluble KIM-1. Mutagenesis studies demonstrate that the juxtamembrane protein secondary structure affects susceptibility to the metalloproteinase-mediated KIM-1 cleavage [ 18 ]. The role of shed KIM-1 within the tubule remains unknown and the implications of the long-term expression of KIM-1 in patients with chronic kidney disease, albeit, at levels lower than that found in AKI, remain to be defined. There were a number of characteristics of KIM-1 that led us to believe that the p