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• W2069473606 abstract "The L1 cell adhesion molecule (CD171) is a multidomain membrane glycoprotein of the immunoglobulin superfamily. We evaluated its expression in human acute kidney injury and assessed its use as a tissue and urinary marker of acute tubular injury. Using immunohistochemical studies with antibodies to the extracellular or cytoplasmic domains, we compared L1 expression in normal kidneys in 24 biopsies taken from patients with acute tubular necrosis. L1 was found at the basolateral and the lateral membrane in all epithelial cells of the collecting duct in the normal kidney except for intercalated cells. In acute tubular necrosis, L1 lost its polarized distribution being found in both the basolateral and apical domains of the collecting duct. Further, it was induced in thick ascending limb and distal tubule cells. Apically expressed L1 found only when the cytoplasmic domain antibody was used in biopsy specimens of patients with acute tubular necrosis. The levels of urinary L1, normalized for creatinine, were significantly higher in all 24 patients with acute tubular necrosis compared to five patients with prerenal azotemia or to six patients with other causes of acute kidney injury. Our study shows that a soluble form of human L1 can be detected in the urine of patients with acute tubular necrosis and that this may be a marker of distal nephron injury. The L1 cell adhesion molecule (CD171) is a multidomain membrane glycoprotein of the immunoglobulin superfamily. We evaluated its expression in human acute kidney injury and assessed its use as a tissue and urinary marker of acute tubular injury. Using immunohistochemical studies with antibodies to the extracellular or cytoplasmic domains, we compared L1 expression in normal kidneys in 24 biopsies taken from patients with acute tubular necrosis. L1 was found at the basolateral and the lateral membrane in all epithelial cells of the collecting duct in the normal kidney except for intercalated cells. In acute tubular necrosis, L1 lost its polarized distribution being found in both the basolateral and apical domains of the collecting duct. Further, it was induced in thick ascending limb and distal tubule cells. Apically expressed L1 found only when the cytoplasmic domain antibody was used in biopsy specimens of patients with acute tubular necrosis. The levels of urinary L1, normalized for creatinine, were significantly higher in all 24 patients with acute tubular necrosis compared to five patients with prerenal azotemia or to six patients with other causes of acute kidney injury. Our study shows that a soluble form of human L1 can be detected in the urine of patients with acute tubular necrosis and that this may be a marker of distal nephron injury. Acute tubular necrosis (ATN) is the most common cause of acute kidney injury (AKI), resulting from septic, toxic, or ischemic insult.1.Thadhani R. Pascual M. Bonventre J. Acute renal failure.N Engl J Med. 1996; 334: 1448-1460Crossref PubMed Scopus (1511) Google Scholar, 2.Rosen S. Heyman S.N. Difficulties in understanding human ‘acute tubular necrosis’: limited data and flawed animal models.Kidney Int. 2001; 60: 1220-1224Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 3.Esson M.L. Schrier R.W. Diagnosis and treatment of acute tubular necrosis.Ann Intern Med. 2002; 137: 744-752Crossref PubMed Scopus (184) Google Scholar ATN is a potentially reversible process, but patients frequently die before renal recovery as a result of comorbid illness and ATN itself.3.Esson M.L. Schrier R.W. Diagnosis and treatment of acute tubular necrosis.Ann Intern Med. 2002; 137: 744-752Crossref PubMed Scopus (184) Google Scholar,4.Schrier R.W. Wang W. Poole B. et al.Acute renal failure: definitions, diagnosis, pathogenesis, and therapy.J Clin Invest. 2004; 114: 5-14Crossref PubMed Scopus (631) Google Scholar Morphological studies of human ATN have shown that all segments, including proximal tubules, thick ascending limbs (TALs), distal convoluted tubules, and collecting ducts (CD), could be injured, with loss of brush border, loss of cellular polarity, dedifferentiation, apoptosis, and shedding of viable or necrotic epithelial tubule cells from the basement membrane resulting in intraluminal obstruction.5.Solez K. Morel-Maroger L. Sraer J.D. The morphology of ‘acute tubular necrosis’ in man: analysis of 57 renal biopsies and a comparison with the glycerol model.Medicine (Baltimore). 1979; 58: 362-376Crossref PubMed Scopus (386) Google Scholar, 6.Olsen S. Burdick J.F. Keown P.A. et al.Primary acute renal failure (‘acute tubular necrosis’) in the transplanted kidney: morphology and pathogenesis.Medicine (Baltimore). 1989; 68: 173-187Crossref PubMed Scopus (114) Google Scholar, 7.Olsen T.S. Hansen H.E. Olsen H.S. Tubular ultrastructure in acute renal failure: alterations of cellular surfaces (brush-border and basolateral infoldings).Virchows Arch A Pathol Anat Histopathol. 1985; 406: 91-104Crossref PubMed Scopus (23) Google Scholar, 8.Olsen T.S. Olsen H.S. Hansen H.E. Tubular ultrastructure in acute renal failure in man: epithelial necrosis and regeneration.Virchows Arch A Pathol Anat Histopathol. 1985; 406: 75-89Crossref PubMed Scopus (51) Google Scholar, 9.Olsen T.S. Hansen H.E. Ultrastructure of medullary tubules in ischemic acute tubular necrosis and acute interstitial nephritis in man.APMIS. 1990; 98: 1139-1148Crossref PubMed Scopus (36) Google Scholar, 10.Nadasdy T. Laszik Z. Blick K.E. et al.Human acute tubular necrosis: a lectin and immunohistochemical study.Hum Pathol. 1995; 26: 230-239Abstract Full Text PDF PubMed Scopus (47) Google Scholar, 11.Solez K. Racusen L.C. Marcussen N. et al.Morphology of ischemic acute renal failure, normal function, and cyclosporine toxicity in cyclosporine-treated renal allograft recipients.Kidney Int. 1993; 43: 1058-1067Abstract Full Text PDF PubMed Scopus (105) Google Scholar, 12.Racusen L.C. Fivush B.A. Li Y.L. et al.Dissociation of tubular cell detachment and tubular cell death in clinical and experimental ‘acute tubular necrosis’.Lab Invest. 1991; 64: 546-556PubMed Google Scholar During recovery, surviving dedifferentiated cells spread over the denuded basement membrane, undergo mitogenesis, and ultimately re-differentiate and re-establish normal epithelial polarity resulting in a normal functional epithelium.13.Lameire N. Van Biesen W. Vanholder R. Acute renal failure.Lancet. 2005; 365: 417-430Abstract Full Text Full Text PDF PubMed Scopus (726) Google Scholar, 14.Witzgall R. Brown D. Schwarz C. et al.Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells.J Clin Invest. 1994; 93: 2175-2188Crossref PubMed Scopus (531) Google Scholar, 15.Lin F. Moran A. Igarashi P. Intrarenal cells, not bone marrow–derived cells, are the major source for regeneration in postischemic kidney.J Clin Invest. 2005; 115: 1756-1764Crossref PubMed Scopus (383) Google Scholar However, the molecular events leading to tubular cell death and restoration of tubule integrity are complex and incompletely understood.1.Thadhani R. Pascual M. Bonventre J. Acute renal failure.N Engl J Med. 1996; 334: 1448-1460Crossref PubMed Scopus (1511) Google Scholar,12.Racusen L.C. Fivush B.A. Li Y.L. et al.Dissociation of tubular cell detachment and tubular cell death in clinical and experimental ‘acute tubular necrosis’.Lab Invest. 1991; 64: 546-556PubMed Google Scholar In particular, data about molecular alterations within the CDs during ATN remain sparse, due to the limited material available in human biopsies and to the differences between human ATN and currently used animal models in which the most injured segments are proximal tubules.2.Rosen S. Heyman S.N. Difficulties in understanding human ‘acute tubular necrosis’: limited data and flawed animal models.Kidney Int. 2001; 60: 1220-1224Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar Furthermore, there is an urgent need for biomarkers that could allow earlier detection of injury, identify the most affected nephron segments, guide timing of therapy, and screen patients at risk for renal injury.16.Han W.K. Bonventre J.V. Biologic markers for the early detection of acute kidney injury.Curr Opin Crit Care. 2004; 10: 476-482Crossref PubMed Scopus (169) Google Scholar,17.Zhou H. Hewitt S. Yuen P.S. et al.Acute kidney injury biomarkers—needs, present status, and future promise.NephSAP. 2006; 5: 63-71Google Scholar The cell adhesion molecules (CAMs) play a key role in maintenance of tubule integrity by mediating cell–cell and cell–matrix interactions. Beyond their structural function, they are implicated in control of cell mitogenesis, differentiation, anchorage dependence, and apoptosis, all features of the recovering nephron.18.Zuk A. Bonventre J.V. Brown D. et al.Polarity, integrin, and extracellular matrix dynamics in the postischemic rat kidney.Am J Physiol. 1998; 275: C711-C731PubMed Google Scholar, 19.Abbate M. Brown D. Bonventre J.V. Expression of NCAM recapitulates tubulogenic development in kidneys recovering from acute ischemia.Am J Physiol. 1999; 277: F454-F463PubMed Google Scholar, 20.Frisch S.M. Francis H. Disruption of epithelial cell–matrix interactions induces apoptosis.J Cell Biol. 1994; 124: 619-626Crossref PubMed Scopus (2769) Google Scholar One of these CAMs, L1 (CD171) is a multidomain membrane glycoprotein of the immunoglobulin superfamily, expressed in neural, hematopoietic, and epithelial cells, which promotes many cellular activities by interacting with a group of CAMs, extracellular matrix molecules, and cell-surface receptors.21.Brümmendorf T. Kenwrick S. Rathjen F. Neural cell recognition molecule L1: from cell biology to human hereditary brain malformations.Curr Opin Neurobiol. 1998; 8: 87-97Crossref PubMed Scopus (213) Google Scholar,22.Kenwrick S. Watkins A. De Angelis E. Neural cell recognition molecule L1: relating biological complexity to human disease mutations.Hum Mol Genet. 2000; 9: 879-886Crossref PubMed Scopus (210) Google Scholar In addition to being expressed on the cell surface, L1 can be cleaved and released in a soluble form into extracellular space.23.Gutwein P. Mechtersheimer S. Riedle S. et al.ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles.FASEB J. 2003; 17: 292-294Crossref PubMed Scopus (184) Google Scholar The soluble L1 has been shown to stimulate cell migration and survival.24.Mechtersheimer S. Gutwein P. Agmon-Levin N. et al.Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins.J Cell Biol. 2001; 155: 661-673Crossref PubMed Scopus (28) Google Scholar L1 cleavage is enhanced under certain pathological conditions.25.Gutwein P. Stoeck A. Riedle S. et al.Cleavage of L1 in exosomes and apoptotic membrane vesicles released from ovarian carcinoma cells.Clin Cancer Res. 2005; 11: 2492-2501Crossref PubMed Scopus (162) Google Scholar In the kidney, L1 is strongly expressed in CDs and connecting segments on the basolateral membrane of principal cells.26.Debiec H. Christensen E.I. Ronco P.M. The cell adhesion molecule L1 is developmentally regulated in the renal epithelium and is involved in kidney branching morphogenesis.J Cell Biol. 1998; 143: 2067-2079Crossref PubMed Scopus (88) Google Scholar,27.Allory Y. Matsuoka Y. Bazille C. et al.The L1 cell adhesion molecule is induced in renal cancer cells and correlates with metastasis in clear cell carcinomas.Clin Cancer Res. 2005; 11: 1190-1197PubMed Google Scholar Considering its distribution in the kidney and its multifunctional potential, L1 is a candidate for playing a role in ATN, especially in CD injury and recovery. The aim of our study was to evaluate whether L1 expression is changed in human ATN and to assess its potential interest as a renal injury marker. We have analyzed L1 expression during ATN in a series of 24 human biopsies from native and grafted kidney, using multiple dual-immunostaining experiments with markers of differentiation (aquaporins 1, 2, and 3; Tamm–Horsfall protein; epithelial membrane antigen (EMA)), cell polarity (ZO-1), and proliferation (Ki-67). Herein, we report that L1 re-distributes to the apical membrane of CD and is upregulated in TAL during ATN. Furthermore, the differential analysis of L1 intra- and extracytoplasmic domains by distinct antibodies in renal tissue and urine fluid suggests that L1 is cleaved and released in tubule lumen and that L1 may be a biomarker for distal segment injury. Renal biopsies were obtained from patients with diagnosis of ATN. Their clinical and pathological characteristics are summarized in Table 1. In comparison with normal kidney where L1 is expressed on basolateral membranes of principal cells,26.Debiec H. Christensen E.I. Ronco P.M. The cell adhesion molecule L1 is developmentally regulated in the renal epithelium and is involved in kidney branching morphogenesis.J Cell Biol. 1998; 143: 2067-2079Crossref PubMed Scopus (88) Google Scholar,27.Allory Y. Matsuoka Y. Bazille C. et al.The L1 cell adhesion molecule is induced in renal cancer cells and correlates with metastasis in clear cell carcinomas.Clin Cancer Res. 2005; 11: 1190-1197PubMed Google Scholar the distribution of L1 was wider in renal biopsies with ATN, whether in native or grafted kidneys. In addition to CDs, L1 was expressed at the apical membrane of distinct tubules (Figure 1a), most of them being TAL labeled by Tamm–Horsfall protein (Figure 1b). Dual staining with anti-aquaporin 1 showed that proximal tubules, including the S3 segments, never expressed L1 (Figure 1a). A fraction of tubules with L1 apical staining were aquaporin 2 and 3 negative, Tamm–Horsfall negative, but EMA positive (Figure 1c). Most of them were probably distal convoluted tubules even though some could be injured TALs with complete loss of Tamm–Horsfall protein expression.Table 1Clinical and pathological features in ATN patients with renal biopsyCaseGenderAge (years)Creat. at biopsy (μmol l−1)KidneyEtiology for AKI in native kidneyEtiology for ESRD before grafted kidneyAKI to biopsy (days)Time from graft to biopsy (days)Tubular lesionsL1 apicalOutcomeB1M54800NativeNSAID3+++++FRB2F41689NativeRhabdomyolysis1++++FRB3M591100NativeHypovolemia4++++FRB4M32600NativeRhabdomyolysis4+++FRB5M71447NativeCisplatin6++++++DB6F82600NativeAminosides10++++PRB7F57480NativeHypovolemia10++++PRB8F56800NativeHypovolemia5+++++ESRFB9F53568NativeHypovolemia2+++++FRB10F14323NativeNSAID1++++FRB11M70560NativeHypovolemia7+++FRB12M19800NativeVancomycin6++++++PRB13M611000GraftedFSGS10++++FRB14F38500GraftedIgA N8++++++FRB15M311200GraftedPolycystic kidney8+++FRB16M62250GraftedDiabetic N13+++++FRB17M42141GraftedPolycystic kidney26++++FRB18F39250GraftedDiabetic N25+++FRB19F66600GraftedFSGS10++++FRB20M64310GraftedUndetermined21+++FRB21M49264GraftedVascular N28++++FRB22M43400GraftedMPGN14++++FRB23M15420GraftedMembranous N4++++FRB24M20400GraftedUndetermined15+++FRAKI, acute kidney injury; ATN, acute tubular necrosis; D, death; ESRD, end-stage renal disease; F, female; FR, full recovery; FSGS, focal segmental glomerulosclerosis; M, male; MPGN, membranoproliferative glomerulopathy; N, nephropathy; NSAID, non-steroidal anti-inflammatory drugs; PR, partial recovery.Creat. at biopsy, plasmatic creatinine assessed at biopsy; AKI to biopsy (days), time between acute renal failure diagnosis and biopsy. Open table in a new tab AKI, acute kidney injury; ATN, acute tubular necrosis; D, death; ESRD, end-stage renal disease; F, female; FR, full recovery; FSGS, focal segmental glomerulosclerosis; M, male; MPGN, membranoproliferative glomerulopathy; N, nephropathy; NSAID, non-steroidal anti-inflammatory drugs; PR, partial recovery. Creat. at biopsy, plasmatic creatinine assessed at biopsy; AKI to biopsy (days), time between acute renal failure diagnosis and biopsy. Morphological injuries of TALs and CDs were observed both in native and grafted kidneys, with TALs and CDs disruption and large cast of cell debris filling the lumen (Figure 2). All cases showed the same alteration of L1 expression, that is, its upregulation in TAL and its delocalization to the apical membrane in CD, regardless of the cause. Most TALs expressing L1 were severely injured with a flattened epithelium and a dilated lumen (Figure 2a and b). The CDs that expressed L1 at the apical membrane had flattened epithelium (Figure 2c and d), whereas CDs with predominant basolateral L1 expression were mostly with a normal appearance (Figure 2a and b). Interestingly, detached cells with a viable appearance were seen within the CD lumen, aggregating to themselves and expressing L1 on their membranes (Figure 2c and d). We investigated further whether the L1 apical expression was associated with cell regeneration. Dual staining with the cell cycle marker Ki-67 showed positive nuclei within proximal tubules, TAL (data not shown), and CD, but regardless of L1 expression (Figure 2e). The apical delocalization of L1 in CDs raised the question of a total loss of cell polarity during the pathological process. Two observations argued against this hypothesis. First, aquaporin 2 was normally kept at the apical membrane of principal cells in all cases. Similarly, aquaporin 3 was normally expressed at the basolateral membrane of principal cells (Figure 2d). Second, we performed an immunostaining of the ZO-1 protein, a major component of the zonula occludens junction implicated in the cell polarity control. In normal CD, ZO-1 immunostaining gave a strong punctate and linear pattern at the lateral subapical domain (Figure 3b and e). We did not observe any alteration of this pattern in injured CD, even when L1 was completely delocalized to the apical membrane (Figure 3f). Considering that L1 could be cleaved in these pathological conditions, we compared L1 immunostaining obtained with the two different antibodies specific for the cytoplasmic domain and extracellular Ig-like domain, respectively (Figure 4a). In normal CD, we observed a strict colocalization of these antibodies with a basolateral pattern (Figure 4b–d). In most injured CDs, the extracellular moiety recognized by monoclonal antibody (mAb)272 was not detected at the apical membrane, whereas a strong staining corresponding to the intracytoplasmic moiety was observed with the polyclonal antibody (Figure 4e). These observations suggested that the ectodomain could be released within the tubular lumen. To investigate which molecular forms of L1 are present in the urine under pathological conditions, we analyzed prospectively the urine fluid of 24 patients with ATN (15 native and 9 grafted kidneys). Clinical characteristics of these patients are summarized in Table 2. The intra- and extracytoplasmic domains of the L1 protein were detected by western blot. In controls and in patients with prerenal azotemia, we observed no L1 or a faint band at 220 kDa both detected by the monoclonal (Figure 5) and the polyclonal antibody (data not shown), suggesting a low basal release of the complete L1. In the patients with ATN, a broad band at 140 kDa was detected by the mAb directed at the ectodomain (Figure 5), whereas the polyclonal antibody specific for the intracellular domain failed to detect any protein (data not shown). These data support our hypothesis of a cleavage of L1 ectodomain in tubular lumen, during ATN or the following repair steps. Urine samples from patients with other causes of AKI had low amount of both complete and soluble forms of L1 (Figure 5).Table 2Clinical features in ATN patients with L1 detected in urine samplesCaseGenderAge (years)Creat. at UA (μmol l−1)Etiology for AKI in native kidneyEtiology for ESRD before grafted kidneyTime from graft to UA (days)OutcomeAbsolute L1 (ng ml−1)Normalized L1 (ng mg−1 UCr)N1M86175Rhabdomyolysis—FR1.201.32N2M38250Rhabdomyolysis—FR1.451.70N3F14180Rhabdomyolysis—D1.302.70N4M60180Hypovolemia—D1.502.02N5M78516Hypovolemia—D2.252.27N6M68752Hypovolemia—PR1.502.14N7M76523Hypovolemia—PR1.602.46N8M96572Septic shock—FR1.502.50N9M46250Septic shock—FR1.501.64N10M78588Septic shock—FR1.601.70N11M62242Cardiac arrest—D1.402.91N12F61323Cardiac arrest—FR1.451.81N13M331187Malaria—FR1.302.60N14M69320Toxic—FR1.201.33N15M58248Toxic—FR1.251.28G1F50850—Undetermined7FR1.702.29G2M36530—Malformative U12FR1.902.10G3F44864—IgA N6FR2.102.12G4M40732—MPGN8FR1.902.11G5H41835—Polycystic kidney4FR2.402.18G6F45478—Lupus nephritis11FR1.601.30G7M68170—ANCA vasculitis12PR1.902.10G8M62362—Diabetic N2FR1.401.50G9F58358—Hyperoxaluria8FR1.201.26ANCA, antineutrophil cytoplasmic antibodies; AKI, acute kidney injury; ATN, acute tubular necrosis; D, death; ESRD, end-stage renal disease; F, female; FR, full recovery; M, male; MPGN, membranoproliferative glomerulopathy; N, nephropathy; PR, partial recovery; U, uropathy; UA, urine analysis (L1 western blot); UCr, urinary creatinine concentration.Creat at UA, plasmatic creatinine assessed at urine analysis; N, native kidney; G, grafted kidney. Open table in a new tab ANCA, antineutrophil cytoplasmic antibodies; AKI, acute kidney injury; ATN, acute tubular necrosis; D, death; ESRD, end-stage renal disease; F, female; FR, full recovery; M, male; MPGN, membranoproliferative glomerulopathy; N, nephropathy; PR, partial recovery; U, uropathy; UA, urine analysis (L1 western blot); UCr, urinary creatinine concentration. Creat at UA, plasmatic creatinine assessed at urine analysis; N, native kidney; G, grafted kidney. Quantitation of L1 in the urine was performed by enzyme-linked immunosorbent assay (ELISA). Both absolute urinary human L1 concentration and L1 concentration normalized for urinary creatinine level were much higher in patients with ATN than in those with other causes of AKI (Tables 2 and 3).Table 3Comparison of urinary L1 levels in patients with various causes of AKIGroupAbsolute L1 (ng ml−1), mean±s.d.Normalized L1 (ng mg−1 UCr), mean±s.d.PaL1 values were compared between ATN and other groups using ANOVA.ATN (n=24)1.59±0.331.97±0.49—Prerenal (n=5)0.14±0.030.19±0.08<0.001Other AKI (n=6)0.30±0.070.40±0.09<0.001Controls (n=12)0.09±0.040.07±0.03<0.001AKI, acute kidney injury; ANOVA, analysis of variance; ATN, acute tubular necrosis; UCr, urinary creatinine concentration.a L1 values were compared between ATN and other groups using ANOVA. Open table in a new tab AKI, acute kidney injury; ANOVA, analysis of variance; ATN, acute tubular necrosis; UCr, urinary creatinine concentration. Although ATN is a frequent pathological process, molecular data are mostly limited to the S3 proximal segment and CD/TAL have been rarely investigated so far. In previous works, we have shown that the L1 CAM is strictly restricted to the basolateral membrane of principal cells of CD and connecting segments in normal kidney.26.Debiec H. Christensen E.I. Ronco P.M. The cell adhesion molecule L1 is developmentally regulated in the renal epithelium and is involved in kidney branching morphogenesis.J Cell Biol. 1998; 143: 2067-2079Crossref PubMed Scopus (88) Google Scholar,27.Allory Y. Matsuoka Y. Bazille C. et al.The L1 cell adhesion molecule is induced in renal cancer cells and correlates with metastasis in clear cell carcinomas.Clin Cancer Res. 2005; 11: 1190-1197PubMed Google Scholar Herein, we report that L1 expression is severely altered during ATN, with an upregulation in TAL, a loss of the basolateral expression, and an apical re-distribution in CD. By contrast, L1 is not induced in the S3 proximal segment. We also show that a cleaved form of L1 shows up in the urine in patients with ATN but not in those with prerenal azotemia, and that patients with ATN had significantly greater urinary L1 level than those with other causes of AKI. L1 is involved through homophilic interactions in cell–cell adhesion,21.Brümmendorf T. Kenwrick S. Rathjen F. Neural cell recognition molecule L1: from cell biology to human hereditary brain malformations.Curr Opin Neurobiol. 1998; 8: 87-97Crossref PubMed Scopus (213) Google Scholar,22.Kenwrick S. Watkins A. De Angelis E. Neural cell recognition molecule L1: relating biological complexity to human disease mutations.Hum Mol Genet. 2000; 9: 879-886Crossref PubMed Scopus (210) Google Scholar and the loss of its basolateral expression could contribute to detachment of CD epithelial cells or back-leakage of tubular fluid.28.Kwon O. Nelson W.J. Sibley R. et al.Backleak, tight junctions, and cell–cell adhesion in postischemic injury to the renal allograft.J Clin Invest. 1998; 101: 2054-2064Crossref PubMed Scopus (114) Google Scholar However, other CAM playing a role in CD cohesion maintenance could partially or completely compensate this effect. In particular, E-cadherin remained normally expressed on the basolateral membrane of CD cells in our series (data not shown), and the cells expressing L1 on the apical membrane remained cohesive. During ATN, proximal tubule cells lose their polarity and the integrity of their tight junctions is disrupted as shown in the postischemic transplanted kidney.28.Kwon O. Nelson W.J. Sibley R. et al.Backleak, tight junctions, and cell–cell adhesion in postischemic injury to the renal allograft.J Clin Invest. 1998; 101: 2054-2064Crossref PubMed Scopus (114) Google Scholar The Na+/K+-ATPase and integrins are redistributed to the apical surface in cell cultures,29.Gailit J. Colflesh D. Rabiner I. et al.Redistribution and dysfunction of integrins in cultured renal epithelial cells exposed to oxidative stress.Am J Physiol. 1993; 264: F149-F157PubMed Google Scholar and the actin network is altered in the ischemia–reperfusion model.30.Kellerman P.S. Bogusky R.T. Microfilament disruption occurs very early in ischemic proximal tubule cell injury.Kidney Int. 1992; 42: 896-902Abstract Full Text PDF PubMed Scopus (73) Google Scholar,31.Molitoris B.A. Dahl R. Geerdes A. Cytoskeleton disruption and apical redistribution of proximal tubule Na(+)-K(+)-ATPase during ischemia.Am J Physiol. 1992; 263: F488-F495PubMed Google Scholar In agreement with previous studies that failed to detect such a loss of polarity in CD, our data do not support that L1 apical expression during ATN is related to a loss of polarity in principal cells.32.Kwon O. Corrigan G. Myers B.D. et al.Sodium reabsorption and distribution of Na+/K+-ATPase during postischemic injury to the renal allograft.Kidney Int. 1999; 55: 963-975Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar In our study, aquaporins 2 and 3 remained normally expressed on the apical and basolateral membrane, respectively. Furthermore, we did not detect any change in the ZO-1 pattern in injured CD. The dual staining with distinct anti-L1 antibodies recognizing intra- or extracytoplasmic domain gave some insight into the L1 processing. In nearly all cases, only the intracytoplasmic moiety could be detected on the apical membrane, suggesting that the extracytoplasmic part has been cleaved and released within the lumen. Because of the retrospective design of the study, no urine fluid was available for the investigated renal biopsies. Therefore, we analyzed 24 urine samples from additional patients with an ATN diagnosis. In normal control samples, the L1 protein was absent or present in low amount only in a complete form of 220 kDa. By contrast, in patients with ATN, we observed that the L1 extracellular fragment was significantly detected in urine samples, whereas the intracellular domain was absent. These data strongly suggest that L1 is expressed on the apical membrane, further cleaved, and then released within the tubule lumen. Similarly, kidney injury molecule-1 is a CAM expressed at apical membrane, cleaved by a metalloproteinase, and released in the urine fluid.33.Ichimura T. Bonventre J.V. Bailly V. et al.Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury.J Biol Chem. 1998; 273: 4135-4142Crossref PubMed Scopus (973) Google Scholar Whether L1 is actually cleaved within the tubule lumen by metalloproteinase and/or plasmin remains to be demonstrated. Bonventre and co-workers proposed that kidney injury molecule-1 could be involved in tubule restoration by mediating interactions between viable detached cells and denuded matrix.34.Bailly V. Zhang Z. Meier W. et al.Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration.J Biol Chem. 2002; 277: 39739-39748Crossref PubMed Scopus (272) Google Scholar Such a role could be discussed for L1 in CD and TAL, where L1 may mediate interaction with laminin-5, which is induced during ischemic injury and repair.35.Zuk A. Matlin K.S. Induction of a laminin isoform and alpha(3)beta(1)-integrin in renal ischemic injury and repair in vivo.Am J Physiol Renal Physiol. 2002; 283: F971-F984Crossref PubMed Scopus (9) Google Scholar In contrast, L1 could exert an adverse effect by promoting aggregation of cells within the lumen and favoring tubule obstruction, as shown in this work. Our observations strongly suggest that L1 could be a potential biomarker of distal injury during AKI. Most molecules as yet reported, including kidney injury molecule-1 and interleukin-18 are biomarkers of S3 proximal segment injury in animal models and human AKI conditions.36.Han W.K. Bailly V. Abichandani R. et al.Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury.Kidney Int. 2002; 62: 237-244Abstract Full Text Full Text PDF PubMed Scopus (1346) Google Scholar,37.Parikh C.R. Abraham E. Ancukiewicz M. et al.Urine IL-18 is an early diagnostic marker for acute kidney in" @default.
• W2069473606 created "2016-06-24" @default.
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• W2069473606 title "The L1 cell adhesion molecule is a potential biomarker of human distal nephron injury in acute tubular necrosis" @default.
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