Faculty Profiles - SAITO Akihiko

Papers - SAITO Akihiko

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Urinary podocalyxin is an early marker for podocyte injury in patients with diabetes: Establishment of a highly sensitive ELISA to detect urinary podocalyxin Reviewed

M. Hara, K. Yamagata, Y. Tomino, A. Saito, Y. Hirayama, S. Ogasawara, H. Kurosawa, S. Sekine, K. Yan

Diabetologia 55 ( 11 ) 2913 - 2919 2012.11

Language：English Publishing type：Research paper (scientific journal)

Aims/objective Nephropathy, a major complication of diabetes, is the leading cause of end-stage renal disease. Recent studies have demonstrated that podocyte injury is involved in the onset of and progression to renal insufficiency. Here, we describe a novel, highly sensitive ELISA for detecting urinary podocalyxin, a glycoconjugate on the podocyte apical surface that indicates podocyte injury, particularly in the early phase of diabetic nephropathy. Methods Urine samples from patients with glomerular diseases (n=142) and type 2 diabetes (n=71) were used to quantify urinary podocalyxin by ELISA. Urine samples were obtained from 69 healthy controls for whom laboratory data were within normal values. Podocalyxin was detected in urine by immunofluorescence, immunoelectron microscopy and western blotting. Results Morphologically, urinary podocalyxin was present as a vesicular structure
western blotting showed it as a positive band at 165-170 kDa. Levels of urinary podocalyxin were elevated in patients with various glomerular diseases and patients with diabetes. In patients with diabetes, urinary podocalyxin was higher than the cut-off value in 53.8% patients at the normoalbuminuric stage, 64.7% at the microalbuminuric stage and 66.7% at the macroalbuminuric stage. Positive correlations were observed between urinary podocalyxin levels and HbA1c, urinary β2 microglobulin, α1 microglobulin and urinary N-acetyl-β-D-glucosaminidase, although urinary podocalyxin levels were not correlated with other laboratory markers such as blood pressure, lipid level, serum creatinine, estimated GFR or proteinuria. Conclusions/interpretation Urinary podocalyxin may be a useful biomarker for detecting early podocyte injury in patients with diabetes. © The Author(s) 2012.

DOI： 10.1007/s00125-012-2661-7

Liver Angiotensinogen Is the Primary Source of Renal Angiotensin II Reviewed

Taiji Matsusaka, Fumio Niimura, Akihiro Shimizu, Ira Pastan, Akihiko Saito, Hiroyuki Kobori, Akira Nishiyama, Iekuni Ichikawa

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 23 ( 7 ) 1181 - 1189 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC NEPHROLOGY

Angiotensin II content in the kidney is much higher than in the plasma, and it increases more in kidney diseases through an uncertain mechanism. Because the kidney abundantly expresses angiotensinogen mRNA, transcriptional dysregulation of angiotensinogen within the kidney is one potential cause of increased renal angiotensin II in the setting of disease. Here, we observed that kidney-specific angiotensinogen knockout mice had levels of renal angiotensinogen protein and angiotensin II that were similar to those levels of control mice. In contrast, liver-specific knockout of angiotensinogen nearly abolished plasma and renal angiotensinogen protein and renal tissue angiotensin II. Immunohistochemical analysis in mosaic proximal tubules of megalin knockout mice revealed that angiotensinogen protein was incorporated selectively in megalin-intact cells of the proximal tubule, indicating that the proximal tubule reabsorbs filtered angiotensinogen through megalin. Disruption of the filtration barrier in a transgenic mouse model of podocyte-selective injury increased renal angiotensin II content and markedly increased both tubular and urinary angiotensinogen protein without an increase in renal renin activity, supporting the dependency of renal angiotensin II generation on filtered angiotensinogen. Taken together, these data suggest that liver-derived angiotensinogen is the primary source of renal angiotensinogen protein and angiotensin II. Furthermore, an abnormal increase in the permeability of the glomerular capillary wall to angiotensinogen, which characterizes proteinuric kidney diseases, enhances the synthesis of renal angiotensin II.

DOI： 10.1681/ASN.2011121159

Significance of Urinary Full-Length and Ectodomain Forms of Megalin in Patients With Type 2 Diabetes Reviewed

Shinya Ogasawara, Michihiro Hosojima, Ryohei Kaseda, Hideyuki Kabasawa, Keiko Yamamoto-Kabasawa, Hiroyuki Kurosawa, Hiroyoshi Sato, Noriaki Iino, Tetsuro Takeda, Yoshiki Suzuki, Ichie Narita, Kunihiro Yamagata, Yasuhiko Tomino, Fumitake Gejyo, Yoshiaki Hirayama, Sakari Sekine, Akihiko Saito

DIABETES CARE 35 ( 5 ) 1112 - 1118 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER DIABETES ASSOC

OBJECTIVE-Megalin, an endocytic receptor in proximal tubule cells, is involved in the mechanisms of albuminuria in diabetic nephropathy (DN). To develop efficient novel biomarkers associated with the pathogenesis of DN, we investigated urinary megalin excretion in type 2 diabetes.
RESEARCH DESIGN AND METHODS-Sandwich enzyme-linked immunosorbent assay systems were established with monoclonal antibodies against the NH2 (amino [A]-megalin assay) and CO OH (C-megalin assay) termini of megalin to analyze urinary forms of megalin in 68 patients with type 2 diabetes.
RESULTS-The A-megalin assay mainly detected a megalin ectodomain form in the soluble urinary fraction, whereas the C-megalin assay identified a full-length form in both soluble and insoluble fractions. Urinary C-megalin levels were significantly high in patients with normoalbuminuria, were elevated in line with increased albuminuria, and showed a better association with estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73 m(2)) than did urinary albumin. In contrast, urinary A-megalin levels were increased in patients with normo- and microalbuminuria but not in those with macroalbuminuria. Urinary C-megalin levels were also positively associated with plasma inorganic phosphate and negatively with hemoglobin levels in those showing no features of bleeding and not taking vitamin D analogs, phosphate binders, or erythropoiesis-stimulating agents.
CONCLUSIONS-Urinary full-length megalin excretion as measured by the C-megalin assay is well associated with reduced eGFR and linked to the severity of DN, phosphate dysregulation, and anemia, whereas urinary excretion of megalin ectodomain as measured by the A-megalin assay may be associated with distinctive mechanisms of earlier DN in type 2 diabetes.

DOI： 10.2337/dc11-1684

New beneficial effects of alkali-extracted rice protein in type 2 diabetic Goto-Kakizaki rats Reviewed

Reiko Watanabe, Masatoshi Kubota, Risa Ito, Akihiko Saito, Mikio Fujii, Motoni Kadowaki

FASEB JOURNAL 26 2012.4

Effect of alkali-extracted rice protein on the renal function in type 2 diabetic rats Reviewed

Reiko Watanabe, Masatoshi Kubota, Akihiko Saito, Takehisa Kumagai, Motoni Kadowaki

AMINO ACIDS 41 S68 - S68 2011.7

Role of Megalin and Cubilin in the Metabolism of Vitamin D-3 Reviewed

Ryohei Kaseda, Michihiro Hosojima, Hiroyoshi Sato, Akihiko Saito

THERAPEUTIC APHERESIS AND DIALYSIS 15 14 - 17 2011.6

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Vitamin D deficiency is associated with various medical conditions including musculoskeletal disorders, infection, metabolic diseases, and cardiovascular disease. Megalin and cubilin, endocytic receptors in proximal tubule cells, are involved in the reabsorption of vitamin D binding protein from glomerular filtrates and the subsequent intracellular conversion of 25-hydroxyvitamin D-3 to biologically active 1 alpha,25-dihydroxyvitamin D-3. Dysfunction of these receptors, which is commonly found in patients with diabetic nephropathy, even at early stages, may explain why vitamin D deficiency is often complicated in these patients. Therapeutic strategies to protect the functions of these receptors from injury could be used to prevent vitamin D deficiency and its related disorders.

DOI： 10.1111/j.1744-9987.2011.00920.x

Megalin is downregulated via LPS-TNF-alpha-ERK1/2 signaling pathway in proximal tubule cells Reviewed

Aya Takeyama, Hiroyoshi Sato, Taeko Soma-Nagae, Hideyuki Kabasawa, Akiyo Suzuki, Keiko Yamamoto-Kabasawa, Michihiro Hosojima, Reika Kaneko, Fumie Higuchi, Ryohei Kaseda, Shinya Ogasawara, Ichiei Narita, Akihiko Saito

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 407 ( 1 ) 108 - 112 2011.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Expression and function of megalin, an endocytic receptor in proximal tubule cells (PTCs), are reduced in diabetic nephropathy, involved in the development of proteinuria/albuminuria. Lipopolysaccharide (LPS) is chronically increased in diabetic sera, by the mechanism called metabolic endotoxemia. We investigated low-level LPS-mediated signaling that regulates megalin expression in immortalized rat PTCs (IRPTCs). Incubation of the cells with LPS (10 ng/ml) for 48 h suppressed megalin protein expression and its endocytic function. TNF-alpha mRNA expression was increased by LPS treatment, and knockdown of the mRNA with siRNA inhibited LPS-mediated downregulation of megalin mRNA expression at the 24-h time point. Incubation of IRPTCs with exogenous TNF-alpha also suppressed megalin mRNA and protein expression at the 24- and 48-h time points, respectively. MEK1 inhibitor PD98059 competed partially but significantly TNF-alpha-mediated downregulation of megalin mRNA expression. Collectively, low-level LPS-mediated TNF-alpha-ERK1/2 signaling pathway is involved in downregulation of megalin expression in IRPTCs. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.02.118

Proximal tubule cell hypothesis for cardiorenal syndrome in diabetes. Reviewed

Saito A, Kaseda R, Hosojima M, Sato H

International journal of nephrology 2011 957164 2010.12

Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis Reviewed

Takako Saeki, Shinichi Nishi, Naofumi Imai, Tomoyuki Ito, Hajime Yamazaki, Mitsuhiro Kawano, Motohisa Yamamoto, Hiroki Takahashi, Shoko Matsui, Shinji Nakada, Tomoki Origuchi, Akira Hirabayashi, Noriyuki Homma, Yutaka Tsubata, Takuma Takata, Yoko Wada, Akihiko Saito, Sachiko Fukase, Kunihiro Ishioka, Kana Miyazaki, Yasufumi Masaki, Hisanori Umehara, Susumu Sugai, Ichiei Narita

KIDNEY INTERNATIONAL 78 ( 10 ) 1016 - 1023 2010.11

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

IgG4-related disease is a recently recognized multi-organ disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells into several organs. Although the pancreas was the first organ recognized to be affected by IgG4-related disorder in the syndrome of autoimmune pancreatitis, we present here clinicopathological features of 23 patients diagnosed as having renal parenchymal lesions. These injuries were associated with a high level of serum IgG4 and abundant IgG4-positive plasma cell infiltration into the renal interstitium with fibrosis. In all patients, tubulointerstitial nephritis was the major finding. Although 14 of the 23 patients did not have any pancreatic lesions, their clinicopathological features were quite uniform and similar to those shown in autoimmune pancreatitis. These included predominance in middle-aged to elderly men, frequent association with IgG4-related conditions in other organs, high levels of serum IgG and IgG4, a high frequency of hypocomplementemia, a high serum IgE level, a patchy and diffuse lesion distribution, a swirling fibrosis in the renal pathology, and a good response to corticosteroids. Thus, we suggest that renal parenchymal lesions actually develop in association with IgG4-related disease, for which we propose the term 'IgG4-related tubulointerstitial nephritis.'

DOI： 10.1038/ki.2010.271

Molecular Mechanisms of Receptor-Mediated Endocytosis in the Renal Proximal Tubular Epithelium Reviewed

Akihiko Saito, Hiroyoshi Sato, Noriaki Iino, Tetsuro Takeda

JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY 2010 403272 2010

Language：English Publisher：HINDAWI PUBLISHING CORPORATION

Receptor-mediated endocytosis is a pivotal function of renal proximal tubule epithelial cells (PTECs) to reabsorb and metabolize substantial amounts of proteins and other substances in glomerular filtrates. The function accounts for the conservation of nutrients, including carrier-bound vitamins and trace elements, filtered by glomeruli. Impairment of the process results in a loss of such substances and development of proteinuria, an important clinical sign of kidney disease and a risk marker for cardiovascular disease. Megalin is a multiligand endocytic receptor expressed at clathrin-coated pits of PTEC, playing a central role in the process. Megalin cooperates with various membrane molecules and interacts with many intracellular adaptor proteins for endocytic trafficking. Megalin is also involved in signaling pathways in the cells. Megalin-mediated endocytic overload leads to damage of PTEC. Further studies are needed to elucidate the mechanism of megalin-mediated endocytosis and develop strategies for preventing the damage of PTEC.

DOI： 10.1155/2010/403272

Megalin and nonmuscle myosin heavy chain IIA interact with the adaptor protein Disabled-2 in proximal tubule cells Reviewed

Kiyoko Hosaka, Tetsuro Takeda, Noriaki Iino, Michihiro Hosojima, Hiroyoshi Sato, Ryohei Kaseda, Keiko Yamamoto, Asako Kobayashi, Fumitake Gejyo, Akihiko Saito

KIDNEY INTERNATIONAL 75 ( 12 ) 1308 - 1315 2009.6

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Megalin plays a critical role in the endocytosis of albumin and other filtered low-molecular-weight proteins. Here we studied the interaction between megalin and Disabled-2 (Dab2), an adaptor protein that binds to the cytoplasmic domain of megalin and appears to control its trafficking. We co-immunoprecipitated megalin and Dab2 from cultured proximal tubule cells and identified the proteins by liquid chromatography and tandem mass spectrometry. We found two proteins associated with the megalin/Dab2 complex, nonmuscle myosin heavy chain IIA (NMHC-IIA) and beta-actin. Subcellular fractionation followed by sucrose velocity gradient separation showed that megalin, Dab2, and NMHC-IIA existed as a complex in the same endosomal fractions. In vitro pull-down assays demonstrated that NMHC-IIA was bound to the carboxyl-terminal region of Dab2, but not to megalin's cytoplasmic domain. We then transfected COS-7 cells with plasmids that induced the expression of Dab2, NMHC-IIA, and the megalin minireceptor, a truncated form of megalin. Co-immunoprecipitation studies showed that the minireceptor and NMHC-IIA co-immunoprecipitated only with Dab2. Furthermore, the uptake of (125)I-lactoferrin, an endocytic ligand of megalin, by rat yolk sac-derived megalin-expressing L2 cells was inhibited by blebbistatin, a specific inhibitor of nonmuscle myosin II. Our study shows that NMHC-IIA is functionally linked to megalin by interaction with Dab2 and is likely involved in megalin-mediated endocytosis in proximal tubule cells. Kidney International (2009) 75, 1308-1315; doi:10.1038/ki.2009.85; published online 1 April 2009

DOI： 10.1038/ki.2009.85

Regulation of Megalin Expression in Cultured Proximal Tubule Cells by Angiotensin II Type 1A Receptor- and Insulin-Mediated Signaling Cross Talk Reviewed

Michihiro Hosojima, Hiroyoshi Sato, Keiko Yamamoto, Ryohei Kaseda, Taeko Soma, Asako Kobayashi, Akiyo Suzuki, Hideyuki Kabasawa, Aya Takeyama, Kenji Ikuyama, Noriaki Iino, Akira Nishiyama, Thomas J. Thekkumkara, Tetsuro Takeda, Yoshiki Suzuki, Fumitake Gejyo, Akihiko Saito

ENDOCRINOLOGY 150 ( 2 ) 871 - 878 2009.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ENDOCRINE SOC

Impairment of proximal tubular endocytosis of glomerular-filtered proteins including albumin results in the development of proteinuria/albuminuria in patients with chronic kidney disease. However, the mechanisms regulating the proximal tubular function are largely unknown. This study aimed to investigate the role of angiotensin II type 1A receptor (AT(1A)R)- and insulin-mediated signaling pathways in regulating the expression of megalin, a multiligand endocytic receptor in proximal tubule cells (PTCs). Opossum kidney PTC-derived OK cells that stably express rat AT(1A)R but are deficient in endogenous angiotensin II receptors (AT(1A)R-OK cells) were used for this study. Treatment of the cells with angiotensin II suppressed mRNA and protein expression of megalin at 3- and 24-h incubation time points, respectively. Cellular uptake and degradation of albumin and receptor-associated protein, megalin's endocytic ligands were suppressed 24 h after angiotensin II treatment. The AT(1A)R-mediated decrease in megalin expression was partially prevented by ERK inhibitors. Insulin competed with the AT(1A)R-mediated ERK activation and decrease in megalin expression. Inhibitors of phosphatidylinositol 3- kinase (PI3K), a major component of insulin signaling, also suppressed megalin expression, and activation of the insulin receptor substrate (IRS)/PI3K system was prevented by angiotensin II. Collectively the AT(1A)R-mediated ERK signaling is involved in suppressing megalin expression in the OK cell line, and insulin competes with this pathway. Conversely, the insulin-IRS/PI3K signaling, with which angiotensin II competes, tends to stimulate megalin expression. In conclusion, there is AT(1A)R- and insulin-mediated competitive signaling cross talk to regulate megalin expression in cultured PTCs. (Endocrinology 150: 871 - 878, 2009)

DOI： 10.1210/en.2008-0886

Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria Reviewed

Yaeko Motoyoshi, Taiji Matsusaka, Akihiko Saito, Ira Pastan, Thomas E. Willnow, Shuki Mizutani, Iekuni Ichikawa

KIDNEY INTERNATIONAL 74 ( 10 ) 1262 - 1269 2008.11

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Megalin, a member of the LDL receptor family, is expressed on the apical membrane of proximal tubules and serves as an endocytic scavenger of filtered proteins and hence might contribute to the tubule injury as a consequence of glomerular disease. To study its role, we crossed megalin knockout mosaic mice (lacking megalin expression in 60% of proximal tubule cells) with NEP25 mice (a transgenic line expressing human CD25 in the podocyte). Treatment of this transgenic mouse with the immunotoxin causes nephrotic syndrome, focal segmental glomerulosclerosis and tubule-interstitial injury. Following this treatment, the double transgenic mice had massive non-selective proteinuria and mild glomerular and tubular injury. Comparison of megalin-containing to megalin-deficient proximal tubule cells within each kidney showed that albumin, immunoglobulin light chain, IgA and IgG were preferentially accumulated in proximal tubule cells expressing megalin. Tubule injury markers such as heme-oxygenase-1, monocyte chemoattractant protein-1 and cellular apoptosis were also preferentially found in these megalin-expressing cells. These results show that megalin plays a pivotal role in the reabsorption of small to large molecular size proteins and provides direct in vivo evidence that reabsorption of filtered proteins triggers events leading to tubule injury.

DOI： 10.1038/ki.2008.405

Anemia is a predictive factor for the development of CKD only in man, but not in woman, of general Japanese population Reviewed

Noriaki Iino, Ichiei Narita, Akihiko Saito, Fumitake Gejyo

NEPHROLOGY 13 A34 - A34 2008.5

Alterations in serum phosphate levels predict the long-term response to intravenous calcitriol therapy in dialysis patients with secondary hyperparathyroidism Reviewed

Kiyoko Hosaka, Junichiro James Kazama, Suguru Yamamoto, Yumi Ito, Noriaki Iino, Hiroki Maruyama, Akihiko Saito, Ichiei Narita, Fumitake Gejyo

JOURNAL OF BONE AND MINERAL METABOLISM 26 ( 2 ) 185 - 190 2008.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER TOKYO

Calcitriol therapy is a central strategy for the treatment of uremic secondary hyperparathyroidism. Although indiscriminate use of calcitriol may lead to worse outcomes, it is difficult to make a decision to discontinue calcitriol therapy when its parathyroid suppression effect remains unsatisfactory. In this study, intravenous calcitriol was administered to 120 chronic hemodialysis patients. Therapy continued for 48 weeks or until plasma intact parathyroid hormone (iPTH) levels decreased to below 300 pg/ml or until the development of any significant adverse effect. Of the 120 patients, the treatment goal was achieved in 47 patients during the first 4 weeks, in 10 during the next 4 weeks, and in 22 patients thereafter. Logistic regression analysis and stepwise regression analysis revealed that iPTH levels were the only significant predictor of the response to calcitriol therapy at weeks 0 and 4. Besides iPTH, the inorganic phosphate (P) levels were another significant predictor of the ultimate response to calcitriol therapy at week 8. The point of best discrimination for successful treatment was P = 6.0 mg/dl at week 8, or P level at week 8/pretreatment P level = 1.0. In conclusion, the P level at week 8 is a predictor of the response to calcitriol therapy for uremic secondary hyperparathyroidism. Changes in treatment are recommended if patients show unsatisfactory parathyroid suppression with a hyperphosphatemic tendency.

DOI： 10.1007/s00774-007-0809-1

Localization of megalin in rat vestibular dark cells and endolymphatic sac epithelial cells Reviewed

Maki Arai, Kunihiro Mizuta, Akihiko Saito, Yasuyuki Hashimoto, Satoshi Iwasaki, Takahiro Watanabe, Hiroyuki Mineta

ACTA OTO-LARYNGOLOGICA 128 ( 6 ) 627 - 633 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：INFORMA HEALTHCARE

Conclusion: Megalin immunoreactivity was observed in kidney proximal tubule cells, vestibular dark cells, and epithelial cells of the endolymphatic sac. Endocytic mechanisms appear to differ between the endolymphatic sac and proximal tubule cells. We speculate that megalin is secreted by a certain type of cell into the endolymphatic space, and is then absorbed from the endolymphatic space by another type of cell to maintain endolymphatic sac homeostasis. Objectives: We previously detected megalin immunoreactivity in the rat cochlear duct. Megalin may be involved in endocytosis in the vestibular organ and endolymphatic sac. To examine this possibility, we extended our immunocytochemical investigation to the rat inner ear cells with special attention to vestibular dark cells and endolymphatic sac. Materials and methods: We observed immunoreactivity of megalin under light and electron microscopy. The primary antibody was rabbit polyclonal antibody that had been raised against rat immunoaffmity-purified megalin. Results: The luminal membrane and subapical area of dark cells in the semicircular canal were immunolabeled. The stainable substance in the endolymphatic space was strongly stained. The cytoplasm of epithelial cells was also stained in various patterns.

DOI： 10.1080/00016480701668531

Role of megalin, a proximal tubular endocytic receptor, in calcium and phosphate homeostasis Reviewed

Akihiko Saito, Noriaki Iino, Tetsuro Takeda, Fumitake Gejyo

THERAPEUTIC APHERESIS AND DIALYSIS 11 S23 - S26 2007.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Megalin is expressed at the apical membranes of proximal tubule cells, acting as an endocytic receptor for a variety of ligands filtered by glomeruli. Megalin, also known as a Ca(2+)-binding receptor, is thought to be involved in systemic and intrarenal calcium and phosphate homeostasis. The complex of 25( OH) D(3) and vitamin D-binding protein is endocytosed via megalin into proximal tubule cells, leading to the activation of 25( OH) D3 to 1, 25( OH) D3 in the cells. Megalin knockout mice revealed impaired osteogenesis due to vitamin D deficiency. Megalin is also involved in the metabolism of parathyroid hormone and the regulation of the sodium phosphate cotransporter NaPi-IIa. Decreased expression of megalin may be associated with the pathogenesis of hyperphosphaturia observed in patients with Dent's disease. Further studies will elucidate more detailed roles of megalin in pathological states and the mechanisms for interacting with other molecules for the endocytic functions.

DOI： 10.1111/j.1744-9987.2007.00514.x

Tubulointerstitial nephritis associated with IgG4-related systemic disease Reviewed

Takako Saeki, Akihiko Saito, Hajime Yamazaki, Iwao Emura, Naofumi Imai, Mitsuhiro Ueno, Shinichi Nishi, Syoji Miyamura, Fumitake Gejyo

Clinical and Experimental Nephrology 11 ( 2 ) 168 - 173 2007.6

Language：English Publishing type：Research paper (scientific journal)

We report three patients with tubulointerstitial nephritis (TIN) with high serum IgG4 concentrations. None of the patients had notable pancreatic lesions when the TIN developed, although one had a history of autoimmune pancreatitis (AIP). Nevertheless, the clinicopathological findings were quite similar to those of AIP. They were all middle-aged to elderly men. Sialadenitis and lymphadenopathy were often evident. Serum total IgG and IgG4 concentrations were elevated and hypocomplementemia was observed. Although antinuclear antibodies were positive, anti-Ro and anti-La antibodies were negative. Renal biopsy showed dense lymphoplasmacytic infiltration with fibrosis in the renal interstitium, and the infiltrated plasma cells had strong immunoreactivity for IgG4. Furthermore, lymphoplasmacytic infiltration and abundant IgG4-positive plasma cells were observed in the salivary glands of a patient. Steroid therapy was effective for TIN in all three patients. The present findings support the recently proposed concept of IgG4-related systemic disease, and suggest that IgG4 is associated not only with AIP but also with other systemic lymphoplasmacytic diseases, including TIN. The conditions responsible for the pathogenesis of TIN need to be considered, irrespective of the presence of AIP. © 2007 Japanese Society of Nephrology.

DOI： 10.1007/s10157-007-0464-9

Megalin-mediated endocytosis of cystatin C in proximal tubule cells Reviewed

Ryohei Kaseda, Noriaki Iino, Michihiro Hosojima, Tetsuro Takeda, Kiyoko Hosaka, Asako Kobayashi, Keiko Yamamoto, Akiyo Suzuki, Ayaka Kasai, Yoshiki Suzuki, Fumitake Gejyo, Akihiko Saito

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 357 ( 4 ) 1130 - 1134 2007.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Serum levels of cystatin C, an endogenous cysteine protemase inhibitor, are often used as an indicator of glomerular filtration rate. Although it is known that cystatin C is filtered by glomeruli and metabolized in proximal tubule cells (PTC), the precise molecular mechanism underlying this process is undetermined. Using quartz-crystal microbalance analyses, we demonstrate that cystatin C binds directly to megalin, an endocytic receptor in PTC, in a Ca(+)-dependent manner. We also find that cystatin C is endocytosed specifically via megalin in rat yolk sac epithelium-derived L2 cells which share a variety of characteristics with PTC. Finally, it? vivo studies using kidney-specific megalin knockout mice provide evidence that megalin mediates proximal tubular uptake of cystatin C. We conclude that megalin is an endocytic receptor of cystatin C in PTC. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.04.072

Functional characterization of a novel missense CLCN5 mutation causing alterations in proximal tubular endocytic machinery in Dent's disease Reviewed

Atsuhito Tanuma, Hiroyoshi Sato, Tetsuro Takeda, Michihiro Hosojima, Hiroaki Obayashi, Hitomi Hama, Noriaki Iino, Kiyoko Hosaka, Ryohei Kaseda, Naofumi Imai, Mitsuhiro Ueno, Maya Yamazaki, Kenji Sakimura, Fumitake Gejyo, Akihiko Saito

NEPHRON PHYSIOLOGY 107 ( 4 ) P87 - P97 2007

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Background/Aims: Mutations of the endosomal chloride/ proton exchanger gene, CLCN5, cause Dent's disease, an X-linked recessive proximal tubular disorder. The renal endocytic system was found to be affected in clcn5 knockout mice. However, the impaired endocytic machinery of Dent's disease patients has not been thoroughly investigated. Methods: The CLCN5 gene was sequenced in a Japanese patient with Dent's disease and his family. The loss-of-function phenotype of the missense CLCN5 mutation was investigated by gene expression in Xenopus oocytes and CHO cells. Immunohistochemical analysis was performed on kidney biopsy specimens for endocytic machinery proteins, megalin, cubilin, and disabled-2 (Dab2) in proximal tubules. Results: Genomic analysis revealed a novel G-to-A transition at the first nucleotide of the 333rd codon of CLCN5, causing a substitution of glycine with arginine. Inefficient expression of the mutant gene in Xenopus oocytes resulted in abolished chloride currents. Impaired N-glycosylation of the mutant protein was evident in the DNA-transfected CHO cells. Proximal tubular expression of megalin, cubilin, and Dab2 was markedly reduced and irregular staining in some portions was observed in the patient compared with controls. Conclusions: A novel G333R CLCN5 mutation caused defective expression of megalin, cubilin, and Dab2 in a patient with Dent's disease. Copyright (c) 2007 S. Karger AG, Basel.

DOI： 10.1159/000111253

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