Cerebroside Sulfotransferase Deficiency Ameliorates L-selectin-dependent Monocyte Infiltration in the Kidney after Ureteral Obstruction

Abstract

Mononuclear cells infiltrating the interstitium are involved in renal tubulointerstitial injury. The unilateral ureteral obstruction (UUO) is an established experimental model of renal interstitial inflammation. In our previous study, we postulated that L-selectin on monocytes is involved in their infiltration into the interstitium by UUO and that a sulfated glycolipid, sulfatide, is the physiological L-selectin ligand in the kidney. Here we tested the above hypothesis using sulfatide- and L-selectin-deficient mice. Sulfatide-deficient mice were generated by gene targeting of the cerebroside sulfotransferase (Cst) gene. Although the L-selectin-IgG chimera protein specifically bound to sulfatide fraction in acidic lipids from wild-type kidney, it did not show such binding in fractions of Cst-/- mice kidney, indicating that sulfatide is the major L-selectin-binding glycolipid in the kidney. The distribution of L-selectin ligand in wild-type mice changed after UUO; sulfatide was relocated from the distal tubules to the peritubular capillaries where monocytes infiltrate, suggesting that sulfatide relocated to the endothelium after UUO interacted with L-selectin on monocytes. In contrast, L-selectin ligand was not detected in Cst-/- mice irrespective of UUO treatment. Compared with wild-type mice, Cst-/- mice showed a considerable reduction in the number of monocytes/macrophages that infiltrated the interstitium after UUO. The number of monocytes/macrophages was also reduced to a similar extent in L-selectin-/- mice. Our results suggest that sulfatide is a major L-selectin-binding molecule in the kidney and that the interaction between L-selectin and sulfatide plays a critical role in monocyte infiltration into the kidney interstitium. Mononuclear cells infiltrating the interstitium are involved in renal tubulointerstitial injury. The unilateral ureteral obstruction (UUO) is an established experimental model of renal interstitial inflammation. In our previous study, we postulated that L-selectin on monocytes is involved in their infiltration into the interstitium by UUO and that a sulfated glycolipid, sulfatide, is the physiological L-selectin ligand in the kidney. Here we tested the above hypothesis using sulfatide- and L-selectin-deficient mice. Sulfatide-deficient mice were generated by gene targeting of the cerebroside sulfotransferase (Cst) gene. Although the L-selectin-IgG chimera protein specifically bound to sulfatide fraction in acidic lipids from wild-type kidney, it did not show such binding in fractions of Cst-/- mice kidney, indicating that sulfatide is the major L-selectin-binding glycolipid in the kidney. The distribution of L-selectin ligand in wild-type mice changed after UUO; sulfatide was relocated from the distal tubules to the peritubular capillaries where monocytes infiltrate, suggesting that sulfatide relocated to the endothelium after UUO interacted with L-selectin on monocytes. In contrast, L-selectin ligand was not detected in Cst-/- mice irrespective of UUO treatment. Compared with wild-type mice, Cst-/- mice showed a considerable reduction in the number of monocytes/macrophages that infiltrated the interstitium after UUO. The number of monocytes/macrophages was also reduced to a similar extent in L-selectin-/- mice. Our results suggest that sulfatide is a major L-selectin-binding molecule in the kidney and that the interaction between L-selectin and sulfatide plays a critical role in monocyte infiltration into the kidney interstitium. Blood monocytes that extravasate to sites of inflammation differentiate into macrophages and induce inflammatory response and apoptosis of tubular epithelial cells leading to tubulointerstitial injury in renal inflammation (1.Nikolic-Paterson D.J. Atkins R.C. Nephrol. Dial. Transplant. 2001; 16: 3-7Crossref PubMed Scopus (132) Google Scholar, 2.Aliprantis A.O. Diez-Roux G. Mulder L.C. Zychlinsky A. Lang R.A. Immunol. Today. 1996; 17: 573-576Abstract Full Text PDF PubMed Scopus (66) Google Scholar). In the experimental model of kidney interstitial inflammation (3.Dziukas L.J. Sterzel R.B. Hodson C.J. Hoyer J.R. Lab. Investig. 1982; 47: 185-193PubMed Google Scholar, 4.Schreiner G.F. Harris K.P. Purkerson M.L. Klahr S. Kidney Int. 1988; 34: 487-493Abstract Full Text PDF PubMed Scopus (228) Google Scholar), unilateral ureteral obstruction (UUO) 1The abbreviations used are: UUO, unilateral ureteral obstruction; CST, cerebroside sulfotransferase; LEC-IgG, L-selectin-IgG chimera.1The abbreviations used are: UUO, unilateral ureteral obstruction; CST, cerebroside sulfotransferase; LEC-IgG, L-selectin-IgG chimera. leads to interstitial inflammation, interstitial fibrosis, and tubular atrophy (5.Diamond J.R. Am. J. Kidney Dis. 1995; 26: 133-140Abstract Full Text PDF PubMed Scopus (86) Google Scholar). Although infiltration of monocytes/macrophages into the interstitium following UUO is well documented, the mechanism involved in this process remains elusive. Monocyte infiltration is a multistep process in which chemokines and adhesion molecules play key roles. The initial step of this process involves the binding of monocytes to the endothelium of venules, mediated by various adhesion molecules such as selectins (6.Bevilacqua M.P. Nelson R.M. J. Clin. Invest. 1993; 91: 379-387Crossref PubMed Scopus (1062) Google Scholar). The selectin family consists of three members, designated P-, E-, and L-selectin. The P- and E-selectins are present on activated endothelial cells, whereas L-selectin is expressed on leukocytes. Results of our previous study in rats with UUO (7.Shikata K. Suzuki Y. Wada J. Hirata K. Matsuda M. Kawashima H. Suzuki T. Iizuka M. Makino H. Miyasaka M. J. Pathol. 1999; 188: 93-99Crossref PubMed Scopus (36) Google Scholar) suggested that L-selectin on monocytes mediates their infiltration into the interstitium, based on the observation that a neutralizing antibody against L-selectin inhibited monocyte infiltration. L-selectin was originally identified as a homing receptor to capture lymphocytes in the flowing bloodstream in lymph nodes (8.Gallatin W.M. Weissman I.L. Butcher E.C. Nature. 1983; 304: 30-34Crossref PubMed Scopus (1234) Google Scholar, 9.Lasky L.A. Singer M.S. Yednock T.A. Dowbenko D. Fennie C. Rodriguez H. Nguyen T. Stachel S. Rosen S.D. Cell. 1989; 56: 1045-1055Abstract Full Text PDF PubMed Scopus (378) Google Scholar, 10.Siegelman M.H. van de Rijn M. Weissman I.L. Science. 1989; 243: 1165-1172Crossref PubMed Scopus (312) Google Scholar). However, L-selectin ligands are expressed not only in lymphoid organs but also in other tissues (11.Tamatani T. Kuida K. Watanabe T. Koike S. Miyasaka M. J. Immunol. 1993; 150: 1735-1745PubMed Google Scholar, 12.Norgard-Sumnicht K.E. Varki N.M. Varki A. Science. 1993; 261: 480-483Crossref PubMed Scopus (172) Google Scholar, 13.Needham L.K. Schnaar R.L. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 1359-1363Crossref PubMed Scopus (181) Google Scholar). The main L-selectin-binding molecules are sialylated, fucosylated, and sulfated glycans on mucin-like molecules such as Gly-CAM-I and CD34, which are located on lymph node high endothelial venules and are involved in the homing (14.Imai Y. Lasky L.A. Rosen S.D. Nature. 1993; 361: 555-557Crossref PubMed Scopus (332) Google Scholar). L-selectin also binds to a sulfated glycolipid, sulfatide (15.Suzuki Y. Toda Y. Tamatani T. Watanabe T. Suzuki T. Nakao T. Murase K. Kiso M. Hasegawa A. Tadano-Aritomi K. Ishizuka I. Miyasaka M. Biochem. Biophys. Res. Commun. 1993; 190: 426-434Crossref PubMed Scopus (154) Google Scholar, 16.Imai Y. True D.D. Singer M.S. Rosen S.D. J. Cell Biol. 1990; 111: 1225-1232Crossref PubMed Scopus (125) Google Scholar, 17.Alon R. Feizi T. Yuen C.T. Fuhlbrigge R.C. Springer T.A. J. Immunol. 1995; 154: 5356-5366PubMed Google Scholar), and chondroitin sulfate and heparin/heparan sulfate proteoglycans (18.Nelson R.M. Cecconi O. Roberts W.G. Aruffo A. Linhardt R.J. Bevilacqua M.P. Blood. 1993; 82: 3253-3258Crossref PubMed Google Scholar, 19.Green P.J. Yuen C.T. Childs R.A. Chai W. Miyasaka M. Lemoine R. Lubineau A. Smith B. Ueno H. Nicolaou K.C. Glycobiology. 1995; 5: 29-38Crossref PubMed Scopus (79) Google Scholar, 20.Li Y.F. Kawashima H. Watanabe N. Miyasaka M. FEBS Lett. 1999; 444: 201-205Crossref PubMed Scopus (18) Google Scholar). We have recently shown that collagen XVIII interacts with L-selectin (21.Kawashima H. Watanabe N. Hirose M. Sun X. Atarashi K. Kimura T. Shikata K. Matsuda M. Ogawa D. Heljasvaara R. Rehn M. Pihlajaniemi T. Miyasaka M. J. Biol. Chem. 2003; 278: 13069-13076Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). Furthermore, chemically synthesized 3′-sulfo Lewisa and 3′-sulfo Lewisx oligosaccharides were found to be potent L-selectin ligands as are sialyl Lewisa/Lewisx determinants or sulfatide (22.Green P.J. Tamatani T. Watanabe T. Miyasaka M. Hasegawa A. Kiso M. Yuen C.T. Stoll M.S. Feizi T. Biochem. Biophys. Res. Commun. 1992; 188: 244-251Crossref PubMed Scopus (174) Google Scholar). Results of our previous study (7.Shikata K. Suzuki Y. Wada J. Hirata K. Matsuda M. Kawashima H. Suzuki T. Iizuka M. Makino H. Miyasaka M. J. Pathol. 1999; 188: 93-99Crossref PubMed Scopus (36) Google Scholar) suggested that sulfatide is an L-selectin ligand in the rat kidney and contributes to the interstitial monocyte infiltration following UUO. These conclusions were based on the histochemical distribution of sulfatide, demonstrated by an anti-sulfatide monoclonal antibody that was very close to that of L-selectin ligand detected by an L-selectin-IgG chimera protein before and after ureteric ligation and that exogenously added anti-L-selectin monoclonal antibody or sulfatide considerably inhibited monocyte infiltration (7.Shikata K. Suzuki Y. Wada J. Hirata K. Matsuda M. Kawashima H. Suzuki T. Iizuka M. Makino H. Miyasaka M. J. Pathol. 1999; 188: 93-99Crossref PubMed Scopus (36) Google Scholar). Sulfoglycolipids are comprised of acidic glycolipids containing sulfate esters on their oligosaccharides. They have been implicated in a variety of physiological functions through their interactions with extracellular matrix proteins, cellular adhesion receptors, blood coagulation systems, complement activation systems, cation transporter systems, and microorganisms (23.Ishizuka I. Prog. Lipid Res. 1997; 36: 245-319Crossref PubMed Scopus (222) Google Scholar). The distribution of sulfoglycolipids is tissue-specific and they are abundant in myelin sheaths, spermatozoa, renal tubular cells, and epithelial cells of the gastrointestinal tract (23.Ishizuka I. Prog. Lipid Res. 1997; 36: 245-319Crossref PubMed Scopus (222) Google Scholar). Sulfation of glycolipids is catalyzed by cerebroside sulfotransferase (CST, EC 2.8.2.11), which is located in the Golgi apparatus (24.Honke K. Tsuda M. Hirahara Y. Ishii A. Makita A. Wada Y. J. Biol. Chem. 1997; 272: 4864-4868Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). Recently, Cst-null mice were generated by gene targeting to elucidate the physiological functions of sulfoglycolipids (25.Honke K. Hirahara Y. Dupree J. Suzuki K. Popko B. Fukushima K. Fukushima J. Nagasawa T. Yoshida N. Wada Y. Taniguchi N. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4227-4232Crossref PubMed Scopus (264) Google Scholar). The Cst-/- mice completely lack sulfatide in the brain and seminolipid in the testis and manifest some neurological disorders because of myelin dysfunction as well as spermatogenesis arrest (25.Honke K. Hirahara Y. Dupree J. Suzuki K. Popko B. Fukushima K. Fukushima J. Nagasawa T. Yoshida N. Wada Y. Taniguchi N. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4227-4232Crossref PubMed Scopus (264) Google Scholar, 26.Ishibashi T. Dupree J.L. Ikenaka K. Hirahara Y. Honke K. Peles E. Popko B. Suzuki K. Nishino H. Baba H. J. Neurosci. 2002; 22: 6507-6514Crossref PubMed Google Scholar). These observations emphasize the critical roles of sulfoglycolipids in the intercellular interactions during myelin formation and spermatogenesis. Because sulfatide is rich in renal tubular cells, its involvement in renal function such as ion transport has been suggested (23.Ishizuka I. Prog. Lipid Res. 1997; 36: 245-319Crossref PubMed Scopus (222) Google Scholar). However, the Cst-null mice do not exhibit signs of renal failure or apparent histological abnormality in the kidney (25.Honke K. Hirahara Y. Dupree J. Suzuki K. Popko B. Fukushima K. Fukushima J. Nagasawa T. Yoshida N. Wada Y. Taniguchi N. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4227-4232Crossref PubMed Scopus (264) Google Scholar). A detailed analysis with some stress would be desirable to elucidate the biological function of sulfatide in the kidney. Here we tested the hypothesis that interaction between sulfatide and L-selectin mediates infiltration of monocytes into the kidney interstitium, using sulfatide- and L-selectin-deficient mice. The present results established the critical role of their interaction in monocyte infiltration that occurs in the inflamed kidney. Animals—Cst-/- mice and L-selectin-/- mice were generated as described previously (25.Honke K. Hirahara Y. Dupree J. Suzuki K. Popko B. Fukushima K. Fukushima J. Nagasawa T. Yoshida N. Wada Y. Taniguchi N. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4227-4232Crossref PubMed Scopus (264) Google Scholar, 27.Arbones M.L. Ord D.C. Ley K. Ratech H. Maynard-Curry C. Otten G. Capon D.J. Tedder T.F. Immunity. 1994; 1: 247-260Abstract Full Text PDF PubMed Scopus (749) Google Scholar). All experimental protocols described in the present study were approved by the Ethics Review Committee for Animal Experimentation of Okayama University Graduate School of Medicine and Dentistry. Lipid Extraction and Analysis—Pooled kidneys (1.4-2 g) from 8- to 12-week-old mice of each genotype and sex were extracted with 19 volumes of chloroform/methanol (2:1 by volume) and then with 10 volumes of chloroform/methanol/water (60:120:9 by volume). The pooled extracts (the were by using the chloroform/methanol/water containing by volume) and by volume) K. T. H. Suzuki K. K. Ishizuka I. J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar). were with the was extracted from kidney with chloroform/methanol/water by volume) by chloroform/methanol (2:1 by volume). The extracts were and to a with chloroform/methanol/water by volume) and acidic glycolipids were with in and using a The glycolipids were to a and with by volume). glycolipids were to a and with L-selectin-IgG chimera (11.Tamatani T. Kuida K. Watanabe T. Koike S. Miyasaka M. J. Immunol. 1993; 150: 1735-1745PubMed Google Scholar), by as described previously T. S. D. Biochem. 1994; PubMed Scopus Google Scholar). mice were to UUO as described previously (3.Dziukas L.J. Sterzel R.B. Hodson C.J. Hoyer J.R. Lab. Investig. 1982; 47: 185-193PubMed Google Scholar). the was with a the of the and mice from the were used as the mice were and the and kidneys were of the were for and L-selectin-/- mice and wild-type mice were on in the as Cst-/- mice and were and the kidneys for kidney was into was in and in were with for The other of each was in and with a were used for for L-selectin and sulfatide were detected by the as described previously (7.Shikata K. Suzuki Y. Wada J. Hirata K. Matsuda M. Kawashima H. Suzuki T. Iizuka M. Makino H. Miyasaka M. J. Pathol. 1999; 188: 93-99Crossref PubMed Scopus (36) Google Scholar). the were with for and with or anti-sulfatide monoclonal antibody (7.Shikata K. Suzuki Y. Wada J. Hirata K. Matsuda M. Kawashima H. Suzuki T. Iizuka M. Makino H. Miyasaka M. J. Pathol. 1999; 188: 93-99Crossref PubMed Scopus (36) Google Scholar, Y. H. K. Y. M. T. S. T. J. H. T. M. Kiso M. Hasegawa A. J. Biochem. Google Scholar) for chimera or was used as a for (7.Shikata K. Suzuki Y. Wada J. Hirata K. Matsuda M. Kawashima H. Suzuki T. Iizuka M. Makino H. Miyasaka M. J. Pathol. 1999; 188: 93-99Crossref PubMed Scopus (36) Google Scholar, T. Kuida K. Watanabe T. Koike S. Miyasaka M. J. Immunol. 1993; 150: 1735-1745PubMed Google Scholar). the were with antibody or antibody for The were in with and a infiltration into the renal interstitium was by using a rat monoclonal antibody against In the were with for and protein binding was by with and for The were with for was used as a for the were with antibody for was by the in containing for the were with a The were then with Cell of cells were by 10 the of the and high Cell number was expressed to the described by and Atkins T. Atkins R.C. Kidney Int. 1990; Full Text PDF PubMed Scopus Google Scholar). are expressed as between were for using analysis of by A the of a in Cst-null the of the kidney glycolipids were between and mice a and as described before K. T. H. Suzuki K. K. Ishizuka I. J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar), glycolipids from and kidneys of Cst-null mice were shown in to sulfatide were in to which is the of sulfatide in of CST, These results that is for the of sulfatide in the kidney. a for L-selectin in the ligands for L-selectin in kidney, acidic lipids were extracted from the kidney and their to L-selectin was by shown in the bound to a with sulfatide in the acidic fraction from the wild-type kidney as well as the brain sulfatide, whereas it did not to with the results of Suzuki (15.Suzuki Y. Toda Y. Tamatani T. Watanabe T. Suzuki T. Nakao T. Murase K. Kiso M. Hasegawa A. Tadano-Aritomi K. Ishizuka I. Miyasaka M. Biochem. Biophys. Res. Commun. 1993; 190: 426-434Crossref PubMed Scopus (154) Google Scholar). In Cst-/- kidney, sulfatide from the acidic fraction with the results in and the to was also completely These results that the L-selectin ligand in fraction of kidney is in were detected in Cst-/- or wild-type mice before UUO A and UUO in tubular and in the interstitium of the kidney and In contrast, the kidney showed signs of tubular or atrophy and The kidneys of L-selectin-/- and wild-type mice were also similar to the kidneys not of L-selectin and in with the distal tubules where sulfatide is expressed in wild-type kidney and was in the kidney of Cst-/- mice and the results of that the major L-selectin ligand in the kidney is ureteric the of in the distal tubules a in the interstitium and peritubular capillaries and of after ureteral obstruction was also in the interstitium of Cst-/- mice and of the with showed a similar with that of anti-sulfatide antibody before and after ureteral was in the kidney was used as a analysis of the kidneys of wild-type and Cst-/- mice with kidneys of wild-type and Cst-/- mice before and after UUO were to analysis with as described with the distal tubular epithelial cells in the kidney of wild-type mice. peritubular and were for the the with from the distal tubules to the interstitium and peritubular capillaries after UUO. a high of the and the with was in Cst-/- kidney irrespective of UUO in the of Cst-/- elucidate sulfatide is for the monocyte infiltration into the renal interstitium in our ureteral obstruction the extent of number of monocytes/macrophages in the interstitium after UUO was between Cst-null and wild-type mice. Because monocyte infiltration as as after UUO (3.Dziukas L.J. Sterzel R.B. Hodson C.J. Hoyer J.R. Lab. Investig. 1982; 47: 185-193PubMed Google Scholar), it was after UUO in the present were with a monoclonal was in the kidney was used as a was in the number of monocytes/macrophages between Cst-/- mice and wild-type mice before UUO UUO, was a in the number of cells with in wild-type mice However, the number of monocytes/macrophages by UUO was to of that before UUO in Cst-/- mice and suggesting that sulfatide is for the infiltration of monocytes into the renal analysis of infiltrating monocytes/macrophages in the renal interstitium of Cst-/- mice. of kidneys of wild-type and Cst-/- mice with or UUO was as shown in The of cells were in 10 the of the and high All are expressed as by analysis of by in the of L-selectin-/- the of L-selectin to the monocyte infiltration into the interstitium, the number of monocytes/macrophages into the interstitium after UUO was between L-selectin-/- and wild-type mice. Although was in the number of monocytes/macrophages between mice before UUO, the number of cells by UUO was reduced in L-selectin-deficient mice The of the of infiltrated monocytes/macrophages by UUO was the between Cst-/- and L-selectin-/- mice, suggesting that sulfatide on the endothelial cells of peritubular capillaries is the major ligand for L-selectin on the monocytes they the interstitium. The in the number of monocytes/macrophages after UUO in Cst-/- and L-selectin-/- mice the of other as Our previous results that interaction between sulfatide in the kidney and L-selectin on monocytes mediates monocyte infiltration into the kidney interstitium (7.Shikata K. Suzuki Y. Wada J. Hirata K. Matsuda M. Kawashima H. Suzuki T. Iizuka M. Makino H. Miyasaka M. J. Pathol. 1999; 188: 93-99Crossref PubMed Scopus (36) Google Scholar). was based on the following of L-selectin function by a neutralizing antibody against monocyte infiltration after UUO in rats (7.Shikata K. Suzuki Y. Wada J. Hirata K. Matsuda M. Kawashima H. Suzuki T. Iizuka M. Makino H. Miyasaka M. J. Pathol. 1999; 188: 93-99Crossref PubMed Scopus (36) Google sulfatide binds specifically to L-selectin through the sulfated (15.Suzuki Y. Toda Y. Tamatani T. Watanabe T. Suzuki T. Nakao T. Murase K. Kiso M. Hasegawa A. Tadano-Aritomi K. Ishizuka I. Miyasaka M. Biochem. Biophys. Res. Commun. 1993; 190: 426-434Crossref PubMed Scopus (154) Google L-selectin ligand from the distal tubules to the interstitium and peritubular capillaries by UUO as sulfatide (7.Shikata K. Suzuki Y. Wada J. Hirata K. Matsuda M. Kawashima H. Suzuki T. Iizuka M. Makino H. Miyasaka M. J. Pathol. 1999; 188: 93-99Crossref PubMed Scopus (36) Google and exogenously sulfatide monocyte infiltration after UUO (7.Shikata K. Suzuki Y. Wada J. Hirata K. Matsuda M. Kawashima H. Suzuki T. Iizuka M. Makino H. Miyasaka M. J. Pathol. 1999; 188: 93-99Crossref PubMed Scopus (36) Google Scholar). The present study the above results and that L-selectin ligand is in mice and that monocyte infiltration after UUO is reduced in mice to the extent as in L-selectin-deficient mice. the of this B. R.L. Kidney Int. 2002; Full Text Full Text PDF PubMed Scopus (86) Google Scholar) that of to the kidneys with L-selectin is with a reduction of apoptosis of tubular epithelial cells and interstitial to our L-selectin on the monocytes with sulfatide in the is expressed in the distal tubules in kidney, where is In the renal interstitium is that sulfatide mediates after UUO. after UUO, sulfatide from the distal tubules to the interstitium and peritubular where monocytes are to extravasate into the interstitium. L-selectin and sulfatide to on the peritubular sulfatide, which from the distal tubules to the interstitium, mediates and of monocytes into the kidney interstitium. Recently, it was demonstrated that the number of and the of was reduced in L-selectin-deficient mice M. D. J. C. J. Immunol. PubMed Scopus Google Scholar). The in mice. the distribution of sulfatide following are also is that sulfatide is from tubular epithelial cells and into the interstitium and peritubular A similar has been in protein G.F. Harris K.P. Purkerson M.L. Klahr S. Kidney Int. 1988; 34: 487-493Abstract Full Text PDF PubMed Scopus (228) Google Scholar). The other is that sulfatide is synthesized in the interstitium and peritubular following ureteric In to interstitial infiltration of cells is also in and of kidney. and their ligands have been shown to monocyte infiltration in a variety of kidney inflammation. on the peritubular is implicated in monocyte infiltration in K. Shikata K. Matsuda M. K. H. M. Makino H. PubMed Scopus Google Scholar). of L-selectin ligands on and endothelium is suggested to be involved in kidney J. T. R. J. Am. Nephrol. Google Scholar). and have been shown to infiltration during renal failure K. Ley K. PubMed Scopus Google Scholar, K. Ley K. J. PubMed Scopus Google Scholar). of the selectin family to monocyte infiltration in the kidney. In the present study, monocyte infiltration by UUO was but not in L-selectin-deficient mice. The be to and T. Y. T. M. S. R. N. S. Kidney Int. 2002; Full Text Full Text PDF PubMed Scopus (18) Google Scholar). However, was in the number of infiltrated monocytes/macrophages by UUO between mice and L-selectin-deficient mice B. R.L. Kidney Int. 2002; Full Text Full Text PDF PubMed Scopus (86) Google Scholar). that and to monocyte infiltration in has been demonstrated to specifically to L-selectin and (15.Suzuki Y. Toda Y. Tamatani T. Watanabe T. Suzuki T. Nakao T. Murase K. Kiso M. Hasegawa A. Tadano-Aritomi K. Ishizuka I. Miyasaka M. Biochem. Biophys. Res. Commun. 1993; 190: 426-434Crossref PubMed Scopus (154) Google Scholar, 16.Imai Y. True D.D. Singer M.S. Rosen S.D. J. Cell Biol. 1990; 111: 1225-1232Crossref PubMed Scopus (125) Google Scholar, 17.Alon R. Feizi T. Yuen C.T. Fuhlbrigge R.C. Springer T.A. J. Immunol. 1995; 154: 5356-5366PubMed Google Scholar, A. W. G. B. Cell. Full Text PDF PubMed Scopus (264) Google Scholar). In sulfatide to inflammation and mediated by M.S. Miyasaka M. Suzuki Y. Kawashima H. Iizuka M. Hasegawa A. Kiso M. R.L. Suzuki T. Int. Immunol. 1995; PubMed Scopus Google Scholar) showed the of sulfatide in injury. the other R. Varki N.M. Varki A. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: PubMed Scopus Google Scholar) that sulfatide on cells as a ligand and by interaction with leading to The present study in that sulfatide plays a critical role as an L-selectin-binding molecule during the process of inflammation. In we demonstrated that sulfatide is a major L-selectin-binding molecule in the kidney and mediates monocyte infiltration in Our results suggest that of the interaction of sulfatide and L-selectin be a for the of interstitial We G. for and of the