Molecular Cloning, Genomic Structure, and Expression Analysis of MUC20, a Novel Mucin Protein, Up-regulated in Injured Kidney

Abstract

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Here, we identify a cDNA encoding a novel mucin protein, shown previously to be up-regulated in IgAN patients, from a human kidney cDNA library. This protein contains a mucin tandem repeat of 19 amino acids consisting of many threonine, serine, and proline residues and likely to be extensively O-glycosylated; thus, this gene was classified in the mucin family and named MUC20. The human MUC20 gene contains at least four exons and is localized close to MUC4 on chromosome 3q29. We found variations in repeat numbers in the mucin tandem domain, suggesting polymorphism of this region. Northern blot and reverse transcription-PCR analyses revealed that human MUC20 mRNA was expressed most highly in kidney and moderately in placenta, colon, lung, prostate, and liver. Immunohistochemical analysis of human kidney revealed that MUC20 protein was localized in the proximal tubules. Immunoblotting analysis of MUC20 proteins produced in Madin-Darby canine kidney and HEK293 cells indicated the localization of MUC20 protein in a membrane fraction and extensive posttranslational modification. Immunoelectron microscopy of MUC20-producing Madin-Darby canine kidney cells demonstrated that MUC20 protein was localized on the plasma membrane. Expression of MUC20 mRNA in a human kidney cell line was up-regulated by tumor necrosis factor-α, phorbol 12-myristate 13-acetate, or lipopolysaccharide. Two species of MUC20 mRNA (hMUC20-L and hMUC20-S), resulting from alternative transcription, were identified in human tissue, whereas only one variant was observed in mouse tissues. Mouse MUC20 mRNA was expressed in the epithelial cells of proximal tubules, and the expression increased dramatically with the progression of lupus nephritis in the kidney of MRL/MpJ-lpr/lpr mice. Moreover, the expression of mouse MUC20 was augmented in renal tissues acutely injured by cisplatin or unilateral ureteral obstruction. These characteristics suggest that the production of MUC20 is correlated with development and progression of IgAN and other renal injuries. Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Here, we identify a cDNA encoding a novel mucin protein, shown previously to be up-regulated in IgAN patients, from a human kidney cDNA library. This protein contains a mucin tandem repeat of 19 amino acids consisting of many threonine, serine, and proline residues and likely to be extensively O-glycosylated; thus, this gene was classified in the mucin family and named MUC20. The human MUC20 gene contains at least four exons and is localized close to MUC4 on chromosome 3q29. We found variations in repeat numbers in the mucin tandem domain, suggesting polymorphism of this region. Northern blot and reverse transcription-PCR analyses revealed that human MUC20 mRNA was expressed most highly in kidney and moderately in placenta, colon, lung, prostate, and liver. Immunohistochemical analysis of human kidney revealed that MUC20 protein was localized in the proximal tubules. Immunoblotting analysis of MUC20 proteins produced in Madin-Darby canine kidney and HEK293 cells indicated the localization of MUC20 protein in a membrane fraction and extensive posttranslational modification. Immunoelectron microscopy of MUC20-producing Madin-Darby canine kidney cells demonstrated that MUC20 protein was localized on the plasma membrane. Expression of MUC20 mRNA in a human kidney cell line was up-regulated by tumor necrosis factor-α, phorbol 12-myristate 13-acetate, or lipopolysaccharide. Two species of MUC20 mRNA (hMUC20-L and hMUC20-S), resulting from alternative transcription, were identified in human tissue, whereas only one variant was observed in mouse tissues. Mouse MUC20 mRNA was expressed in the epithelial cells of proximal tubules, and the expression increased dramatically with the progression of lupus nephritis in the kidney of MRL/MpJ-lpr/lpr mice. Moreover, the expression of mouse MUC20 was augmented in renal tissues acutely injured by cisplatin or unilateral ureteral obstruction. These characteristics suggest that the production of MUC20 is correlated with development and progression of IgAN and other renal injuries. Epithelial cell injury in renal tissue is a feature of many acute and chronic kidney diseases. Among the morphological changes observed are loss of the proximal tubular brush border, loss of cellular polarity, and dedifferentiation and apoptosis of the proximal tubule epithelial cells. During progression of renal injury, necrotic tubular epithelial cells detach from the basement membrane and cause intraluminal obstruction. After surviving dedifferentiated cells spread over the denuded basement membrane, functional epithelia are reformed by the dedifferentiated cells undergoing mitogenesis, redifferentiation, and re-establishment of normal epithelial polarity (1.Thadhani R. Pascual M. Bonventre J.V. N. Engl. J. Med. 1996; 334: 1448-1460Crossref PubMed Scopus (1513) Google Scholar, 2.Sheridan A.M. Bonventre J.V. Curr. Opin. Nephrol. Hypertens. 2000; 9: 427-434Crossref PubMed Scopus (250) Google Scholar). Although these processes are well described at the histological level, very little is known about the molecular levels involved. To date, some mucin proteins, such as MUC1, MUC3, and kidney injury molecule-1 (KIM-1), have been identified as proteins likely to regulate these renal events. MUC1 mRNA is expressed in the distal convoluted tubules and collecting ducts; MUC3 mRNA is in the proximal tubules and is overexpressed in renal cell carcinoma patients (3.Leroy X. Copin M.C. Devisme L. Buisine M.P. Aubert J.P. Gosselin B. Porchet N. Histopathology. 2002; 40: 450-457Crossref PubMed Scopus (42) Google Scholar). KIM-1 mRNA is drastically up-regulated in the epithelial cells of the regenerating proximal tubules following ischemia (4.Ichimura T. Bonventre J.V. Bailly V. Wei H. Hession C.A. Cate R.L. Sanicola M. J. Biol. Chem. 1998; 273: 4135-4142Abstract Full Text Full Text PDF PubMed Scopus (978) Google Scholar). In general, mucins are divided into two structurally and functionally distinct classes, the secreted and the transmembrane types. Human MUC2, MUC5A, MUC5B, MUC6, MUC7, MUC8, and MUC9 are classified as secreted types (5.Gum Jr., J.R. Hicks J.W. Toribara N.W. Siddiki B. Kim Y.S. J. Biol. Chem. 1994; 269: 2440-2446Abstract Full Text PDF PubMed Google Scholar, 6.Guyonnet-Duperat V. Audie J.P. Debailleul V. Laine A. Buisine M.P. Galiegue-Zouitina S. Pigny P. Degand P. Aubert J.P. Porchet N. Biochem. J. 1995; 305: 211-219Crossref PubMed Scopus (190) Google Scholar, 7.Desseyn J.L. 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McGuckin M.A. Gotley D.C. Eyre H.J. Sutherland G.R. Antalis T.M. Cancer Res. 1999; 59: 4083-4089PubMed Google Scholar, 20.Gum Jr., J.R. Crawley S.C. Hicks J.W. Szymkowski D.E. Kim Y.S. Biochem. Biophys. Res. Commun. 2002; 291: 466-475Crossref PubMed Scopus Google Scholar). we have identified cDNA with expression in renal tissues of patients with A nephropathy A expressed Madin-Darby canine of cDNA reverse unilateral ureteral the mRNA 1999; PubMed Scopus Google Scholar, J. H. S. J.C. R.J. Full Text Full Text PDF PubMed Scopus Google Scholar). a human kidney cDNA with one of these J. H. S. J.C. R.J. Full Text Full Text PDF PubMed Scopus Google Scholar), we a human cDNA encoding a novel mucin membrane protein, MUC20. we the molecular and expression analysis of MUC20 in human normal tissues as well as in of renal of the Human MUC20 cDNA and cDNA encoding human MUC20 was by a was on the of the identified as described previously J. H. S. J.C. R.J. Full Text Full Text PDF PubMed Scopus Google and with The was with from a human kidney cDNA following the of J. T. A Scholar). The were by and by After the were to the cDNA was A human was from and with the human MUC20 cDNA with by was as described previously M. H. M. T. H. 1998; Google Scholar). The human MUC20 were from the from and to and of the Mouse MUC20 the mouse two and with to human MUC20. We and the mouse from a mouse kidney cDNA by on the of these of the of MUC20 mRNA was a cDNA following the analysis of human MUC20 the primary was the as a and from the human kidney as a were and as the analysis of the mouse MUC20 the primary was the as a and from kidney as a The were by and as of and mouse were with The were by on a a membrane and at with described the human blot two the and the were by and the and and the with the human MUC20 cDNA as a the mouse the to the was by the and with the mouse MUC20 cDNA as a was of at at and at a of the of Human MUC20 in these were from the following human cell and were from and human kidney cell and were from the and cell were as by the were from these cell as described J. L. M. T. E. Wilson M. T. J. Google Scholar). To repeat the tandem in the human MUC20 gene from these cell were by the and the described The were by on a a membrane and by blot analysis a to the repeat of as a Northern tissue Northern of human and mouse tissues were from and with the human human or mouse as described was as described previously M. H. M. T. H. 1998; Google Scholar). The resulting were with a from human lung, placenta, and were from Human kidney cell and were from and as cell cells were with phorbol 12-myristate or tumor necrosis was with was following the was the described The were as human MUC20 and and mouse MUC20 and The mRNA were from was reverse was with on The the were as mouse MUC20 and and mouse and The mRNA were from and was by of a human MUC20 cDNA by into the a human kidney and Madin-Darby canine kidney were from The cells were in the of as of the cell the human and were into or HEK293 cells as described in the and were were by and the production of MUC20 protein in line was by analysis with was the of human MUC20 a to cells were in and and The resulting were to cellular and the were at to the membrane and the were protein were by with primary and and were with the cells were in and with with in After with and the cells were with normal and The cells were with human MUC20 or at The cells were and with of at was with The cells were with in and in were with a at MRL/MpJ-lpr/lpr were at and was renal injury was in by of cisplatin and and were to renal the ureteral was in as described J. J. Nephrol. 2002; PubMed Scopus (132) Google Scholar). mRNA in the kidney was by and the of was as described N. Biochem. PubMed Scopus Google Scholar). In and were from mouse MUC20 cDNA by the following and and and with the mouse MUC20 cDNA as a a a of mouse was by and with the mouse cDNA as a After the into the by of with and were and a and MRL/MpJ-lpr/lpr and were with and by with in were in the at of were at and with by one with After in and in a the were with and in in After with in the were with and were at The resulting were with at with at and at by a with at Immunohistochemical of was as by in Scholar). After the were with in and with of Human and Mouse MUC20 is a gene expression was shown to be up-regulated in renal tissues of IgAN patients J. H. S. J.C. R.J. Full Text Full Text PDF PubMed Scopus Google Scholar). To the cDNA to the we a human kidney cDNA with on the of A was and analysis revealed encoding amino acids with suggesting that this protein is a membrane protein A and In this protein tandem of 19 amino acids consisting of threonine, serine, and proline residues likely to be extensively of the of this tandem to we named this MUC20. A D.J. J. Biol. 1990; PubMed Scopus Google of the mouse at the revealed that mouse and the to the human MUC20 a the of these we a mouse from a mouse kidney cDNA library. the amino of the proteins by the human and mouse The of mouse consisting of amino characteristics to human such as and mucin of amino acids in region. The are most in the and in the amino in the the and of the mucin tandem of mouse MUC20 with of human the of and in this is and of Human MUC20 we the of human MUC20. of a human with the human MUC20 we of the revealed that the human MUC20 cDNA was from the of the tandem in the mucin whereas the cDNA only was from a human cDNA with the human MUC20 of the protein with human MUC20 revealed of amino acids at the of we the of human MUC20 as and the one by cDNA as We the the encoding the of The was found from the of the MUC20 gene A and These the of alternative that to the of the human MUC20 To the that the cDNA was produced from mRNA we of cDNA on MUC20 mRNA from human kidney of shown in of a species of and analysis revealed that of these the as the These that at least two in the encoding two of the protein with These suggest that is expressed highly in human whereas was in these was from human the of the of to that of mouse that the mouse MUC20 be the of the of human MUC20 gene with the of the human from that are in localized on chromosome 3q29. We found that the MUC4 gene is very close to the of a of transmembrane mucin at this and blot analyses of revealed that these into two of from to of the whereas the other a to and by to the and the and This was named the blot analysis of human revealed two from or with a was the revealed the of a to the of the MUC20 gene is this is and tissues or cells that this gene is in In blot analysis of mouse revealed the of or the of the mouse MUC20 gene as a The of the mouse MUC20 on mouse chromosome very to that of the human MUC20 four exons of the the repeat numbers of the tandem in human MUC20 a with in the cDNA and in the These to polymorphism of this of human MUC20 and from other revealed the of and types of human MUC20 To the of the repeat numbers in this domain, the of human MUC20 in from human cell were by and the repeat numbers were from the of the The to in the as well as resulting in cell shown in the to or these polymorphism in the mucin tandem of the human MUC20 Expression of MUC20 in Human and Mouse the expression of from human tissues was to Northern blot and analyses A and MUC20 mRNA was in kidney and moderately in placenta, lung, prostate, and colon, and the of human MUC20 as a in the of MUC20 mRNA was by the to the in the suggesting that expression of mRNA be or in these tissues mouse MUC20 mRNA was highly expressed in kidney human kidney was a to the of human MUC20. to a proximal tubules, was to identify the types of in the The that MUC20 protein is localized in the proximal tubules in the or distal tubules cell from human and were found to levels of MUC20 mRNA of these cell is known as a renal tubular epithelial line from of a with renal D.J. P. H. J. Cancer 51: PubMed Scopus Google Scholar), was to in to shown in with phorbol 12-myristate 13-acetate, or tumor necrosis factor-α, or increased MUC20 mRNA expression in this cell of MUC20 the localization of MUC20 protein, we human MUC20-producing and cells from and HEK293 cells. These cells human MUC20 of a and the production of MUC20 protein was by of in the The cells were and the were to the In two of and were the were observed in the fraction the The were with the of these proteins on was from that of the proteins from cells and Immunoelectron microscopy with demonstrated MUC20 on the plasma membrane of the MUC20-producing cells whereas the cells with such cells in the of the with the or of Mouse MUC20 mRNA in the expression of MUC20 mRNA changes progression of renal injury in the levels of MUC20 mRNA were in the MRL/MpJ-lpr/lpr is a well known human lupus nephritis PubMed Scopus Google Scholar, 9: PubMed Scopus Google Scholar). MRL/MpJ-lpr/lpr were at and renal injury was by the in is a of a renal in with the in MUC20 mRNA expression increased in the renal tissues progression of the injury To the types of cells that MUC20 mRNA and the in in analysis was on kidney from MRL/MpJ-lpr/lpr MUC20 a we the in a the been shown to in the proximal tubules M. L.A. 1999; PubMed Scopus Google Two and the of MUC20 mRNA we the with In MRL/MpJ-lpr/lpr with renal MUC20 mRNA was in the of epithelial cells the proximal tubules in of the distal tubules and the was observed in In in MRL/MpJ-lpr/lpr in the in the cells of proximal tubules were augmented we observed in MUC20 mRNA expression in MRL/MpJ-lpr/lpr from to In MRL/MpJ-lpr/lpr with a of cells with the MUC20 The renal from MRL/MpJ-lpr/lpr with a to To the expression of MUC20 mRNA in renal we in acute renal is by of as or by The of MUC20 mRNA were by at following In the cisplatin renal in mouse was by and increased and to as previously H. T. S. A. 1994; PubMed Scopus Google In this a in MUC20 expression was observed renal progression To of the are acute renal we the MUC20 mRNA by kidney from and mice. The shown in revealed a species of MUC20 to in the and other were the progression of renal In the renal injury and were by the changes in mRNA levels and in the in and mRNA levels were observed at and following and the of MUC20 mRNA increased in We the molecular gene and cellular localization analyses of a novel mucin protein, is up-regulated in renal tissues renal To date, mucin gene have been found on human and In this human chromosome was shown to of mucin MUC4, and the at least two (hMUC20-L and are produced from the human MUC20 gene by alternative transcription, only one of the been identified in mouse tissues. Immunoblotting analysis of human MUC20 produced in cells MUC20 in the membrane Immunoelectron analysis of human MUC20 protein produced in cells demonstrated that the of to was on the plasma membrane. human MUC20 protein is a membrane protein localized on the plasma membrane. We found molecular MUC20 protein in and cells the molecular of human MUC20 amino is the of the molecular be to posttranslational on The at the of is likely a the at the is localized on the plasma membrane, the be a secreted this be by localization analysis in the Northern blot and analyses demonstrated that the of human and mouse MUC20 are expressed in the Immunohistochemical analysis of normal human kidney and in analysis of renal from MRL/MpJ-lpr/lpr and normal revealed that MUC20 is produced in the of proximal tubules in that of distal tubules. The of the increased the development of glomerulonephritis in MRL/MpJ-lpr/lpr mice. Although the other were well by of and MRL/MpJ-lpr/lpr This of the by that were in these This analysis MUC20 expression in a of cells in the of is a of MRL/MpJ-lpr/lpr S. Wilson J. Med. PubMed Scopus Google Scholar). cell of plasma and to be cell or types MUC20 mRNA and MUC20 in these cells. these suggest that the expression of MUC20 mRNA in renal the epithelial cells of the proximal tubules, was with the progression of lupus in MUC20 expression in these suggest that MUC20 in In normal human MUC1 mRNA to the distal convoluted tubules, and collecting whereas the expression of MUC3 and KIM-1 is to the proximal tubules (3.Leroy X. Copin M.C. Devisme L. Buisine M.P. Aubert J.P. Gosselin B. Porchet N. Histopathology. 2002; 40: 450-457Crossref PubMed Scopus (42) Google Scholar, T. Bonventre J.V. Bailly V. Wei H. Hession C.A. Cate R.L. Sanicola M. J. Biol. Chem. 1998; 273: 4135-4142Abstract Full Text Full Text PDF PubMed Scopus (978) Google Scholar). Expression of MUC3 and KIM-1 is up-regulated in renal cell carcinoma patients and (3.Leroy X. Copin M.C. Devisme L. Buisine M.P. Aubert J.P. Gosselin B. Porchet N. Histopathology. 2002; 40: 450-457Crossref PubMed Scopus (42) Google Scholar, T. Bonventre J.V. Bailly V. Wei H. Hession C.A. Cate R.L. Sanicola M. J. Biol. Chem. 1998; 273: 4135-4142Abstract Full Text Full Text PDF PubMed Scopus (978) Google Scholar). MUC1 expression levels have been correlated with of patients with renal cell carcinoma M. T. M. T. J. 1999; PubMed Scopus Google Scholar). we have found that human MUC20 mRNA was up-regulated in renal tissues of patients with IgAN as with the IgAN or normal these were observed in IgAN renal tissues of patients with J. H. S. J.C. R.J. Full Text Full Text PDF PubMed Scopus Google Scholar). 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These suggest that cell is a MUC20. is that the amino of human and mouse MUC20 in the domain, with in the amino acids in the other This species that this a in MUC20 analyses of the of MUC20 are in In we have identified the cDNA a novel mucin membrane protein, is expressed in human and proximal tubules and up-regulated renal of MUC20 and the of MUC20 protein in the development and progression of renal diseases. We M. J. H. T. and E. and we M. and M. in We the of H. M. S. and N. with