Faculty Profiles - SAITO Akihiko

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

Tanuma A, Sato H, Takeda T, Hosojima M, Obayashi H, Hama H, Iino N, Hosaka K, Kaseda R, Imai N, Ueno M, Yamazaki M, Sakimura K, Gejyo F, Saito A

Nephron. Physiology 107 ( 4 ) p87 - 97 2007

Current clinical aspects of dialysis-related amyloidosis in chronic dialysis patients Reviewed

Akihiko Saito, Fumitake Gejyo

THERAPEUTIC APHERESIS AND DIALYSIS 10 ( 4 ) 316 - 320 2006.8

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

The current understanding of dialysis-related amyloidosis has evolved over the past two decades. In the early 1980s, several researchers found amyloid deposits in the synovia of carpal tunnel syndrome (CTS), which have been recognized as a complication of chronic hemodialysis. The enigma was resolved in 1985, when beta(2)-microglobulin (beta(2)-m) with a molecular weight of 12 000 Da was identified as the major constitutional protein of this amyloid. Amyloid fibrils of this type that contain the sub-unit protein of human leukocyte antigens (HLA), beta(2)-m, deposit predominantly in osteoarticular tissues, inducing musculoskeletal symptoms such as CTS, polyarthralgia, bone cyst showing radiolucency at X-ray examination and destructive spondyloarthropathy. In addition, extra articular symptoms such as ischemic colitis, megaloglossia, and heart failure, that is, systemic involvement occasionally occur. We confirmed that the prevalence of CTS increases with duration of dialysis. Most patients with CTS associated with beta(2)-m amyloid deposits have undergone hemodialysis for 10 years or more. Up to 50% of patients had developed this complication after 20 years and the percentage was even higher after 25 years. General categories of therapeutic approaches for amyloidosis include prevention of onset or progression, symptomatic therapy (conservative treatment, orthopedic procedures, and physiotherapy), and renal transplantation. It is critical to elucidate the detail mechanisms of the amyloid fibril formation, and establish its radical treatment. It is also important to develop novel therapies such as cell implantation to compensate for normal kidney functions of uremic toxin protein metabolism.

DOI： 10.1111/j.1744-9987.2006.00383.x

[Megalin and cubilin: protein reabsorption in proximal tubule]. Reviewed

Takeda T, Saito A, Gejyo F

Nihon rinsho. Japanese journal of clinical medicine 64 Suppl 2 332 - 338 2006.2

Lymphoplasmacytic infiltration of multiple organs with immunoreactivity for IgG4: IgG4-related systemic disease Reviewed

Takako Saeki, Akihiko Saito, Tohru Hiura, Hajime Yamazaki, Iwao Emura, Mitsuhiro Ueno, Syoji Miyamura, Fumitake Gejyo

INTERNAL MEDICINE 45 ( 3 ) 163 - 167 2006

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

We report three elderly men with high serum IgG4 concentrations and multiple lymphoplasmacytic inflammation of the salivary glands, lymph nodes, pancreas, and renal interstitium. The infiltrating plasma cells had strong immunoreactivity for IgG4, even in patients without pancreatic lesions. These cases show that IgG4 is associated not only with autoimmune pancreatitis, but also with other systemic lymphoplasmacytic disease.

DOI： 10.2169/internalmedicine.45.1431

Role of megalin, a proximal tubular endocytic receptor, in the pathogenesis of diabetic and metabolic syndrome-related nephropathies: protein metabolic overload hypothesis Reviewed

A Saito, T Takeda, H Hama, Y Oyama, K Hosaka, A Tanuma, R Kaseda, M Ueno, S Nishi, S Ogasawara, F Gondaira, Y Suzuki, F Gejyo

NEPHROLOGY 10 S26 - S31 2005.10

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

Megalin is an endocytic receptor on the apical membranes of proximal tubule cells (PTC) in the kidney, and is involved in the reabsorption and metabolism of various proteins that have been filtered by glomeruli. Patients with diabetes, especially type 2 diabetes, or metabolic syndrome are likely to have elevated serum levels of advanced glycation end products, liver-type fatty acid binding protein, angiotensin 11, insulin and leptin, and renal metabolism of these proteins is potentially overloaded. Some of these proteins are themselves nephrotoxic, while others are carriers of nephrotoxic molecules. Megalin is involved in the proximal tubular uptake of these proteins. We hypothesize that megalin-mediated metabolic overload in PTC leads to compensatory cellular hypertrophy and sustained Na(+) reabsorption, causing systemic hypertension and glomerular hyperfiltration via tubuloglomerular feedback, and named this as 'protein metabolic overload hypothesis'. Impaired metabolism of bioactive proteins such as angiotensin 11 and insulin in PTC may enhance hypertrophy of PTC and/or Na(+) reabsorption. Sleep apnoea syndrome, a frequent complication of diabetes and metabolic syndrome, may cause renal hypoxia and result in relative overload of protein metabolism in the kidneys. The development of strategies to identify patients with diabetes or metabolic syndrome who are at high risk for renal metabolic overload would allow intensive treatment of these patients in an effort to prevent the development of nephropathy. Further studies on the intracellular molecular signalling associated with megalin-mediated metabolic pathways may lead to the development of novel strategies for the treatment of nephropathies related to diabetes and metabolic syndrome.

DOI： 10.1111/j.1440-1797.2005.00453.x

Evidence for megalin-mediated proximal tubular uptake of L-FABP, a carrier of potentially nephrotoxic molecules Reviewed

Y Oyama, T Takeda, H Hama, A Tanuma, N Iino, K Sato, R Kaseda, ML Ma, T Yamamoto, H Fujii, JJ Kazama, S Odani, Y Terada, K Mizuta, F Gejyo, A Saito

LABORATORY INVESTIGATION 85 ( 4 ) 522 - 531 2005.4

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

Liver-type fatty acid binding protein (L-FABP) binds with high affinity to hydrophobic molecules including free fatty acid, bile acid and bilirubin, which are potentially nephrotoxic, and is involved in their metabolism mainly in hepatocytes. L-FABP is released into the circulation, and patients with liver damage have an elevated plasma L-FABP level. L-FABP is also present in renal tubules; however, the precise localization of L-FABP and its potential role in the renal tubules are not known. In this study, we examined the cellular and subcellular localization of L-FABP in the rat kidney and tried to determine from where the L-FABP in kidney tissues had originated. Immunohistochemical studies of kidney sections localized L-FABP in the lysosomes of proximal tubule cells (PTC). In rats with carbon tetrachloride (CCl(4))-induced acute liver injury, we detected high levels of L-FABP in the circulation and in the kidney compared with those in the control rat by immunoblotting, while reverse transcription-polymerase chain reaction showed that the level of L-FABP mRNA expression in the kidney of CCl(4)-treated rats was low and did not differ from that in the control rat. When (35)S-L-FABP was intravenously administered to rats, the kidneys took up (35)S-L-FABP more preferentially than the liver and heart, and histoautoradiography of kidney sections revealed that (35)S-L-FABP was internalized via the apical domains of PTC. Quartz-crystal microbalance analysis revealed that L-FABP bound to megalin, a multiligand endocytotic receptor on PTC, in a Ca(2+)-dependent manner. Degradation assays using megalin-expressing rat yolk sac tumor-derived L2 cells demonstrated that megalin mediated the cellular uptake and catabolism of (125)I-L-FABP. In conclusion, circulatory L-FABP was found to be filtered by glomeruli and internalized by PTC probably via megalin-mediated endocytosis. These results suggest a novel renal uptake pathway for L-FABP, a carrier of hydrophobic molecules, some of which may exert nephrotoxic effects.

DOI： 10.1038/labinvest.3700240

Significance of proximal ribular metabolism of advanced glycation end products in kidney diseases Reviewed

A Saito, T Takeda, K Sato, H Hama, A Tanuma, R Kaseda, Y Suzuki, F Gejyo

MAILLARD REACTION: CHEMISTRY AT THE INTERFACE OF NUTRITION, AGING, AND DISEASE 1043 637 - 643 2005

Language：English Publishing type：Research paper (scientific journal) Publisher：NEW YORK ACAD SCIENCES

Advanced glycation end products (AGEs) are formed by the nonenzymatic Maillard reaction between sugars and proteins. Low-molecular weight AGES are filtered by renal glomeruli and then reabsorbed and metabolized by proximal tubule cells (PTCs). High-molecular weight AGES are also delivered to PTCs in proteinuric states. In patients with diabetes, AGE generation is increased, and the actions of AGES on PTCs are likely involved in the pathogenesis of diabetic nephropathy. In patients with chronic renal failure (CRF), reduced renal metabolism of AGEs likely accounts for the accumulation of AGEs in serum, leading to uremic complications including dialysis-related amyloidosis. AGE precursors such as reactive carbonyl compounds also accumulate in the sera of patients with CRF. It is likely that PTCs take up AGEs and AGE precursors via specific endocytotic receptors or transporters. Megalin is a multiligand endocytotic receptor that is abundantly expressed on PTCs. There is evidence that megalin is involved in the cellular uptake and degradation of AGES. We previously reported a cell therapy model involving implantation of megalin-expressing cells into experimental mice with renal failure for elimination of uremic toxin proteins. Further studies are needed to clarify the molecular mechanisms of the metabolism of AGEs and their precursors to develop a strategy

DOI： 10.1196/annals.1333.072

Evidence indicating that renal tubular metabolism of leptin is mediated by megalin but not by the leptin receptors

H Hama, A Saito, T Takeda, A Tanuma, YS Xie, K Sato, JJ Kazama, F Gejyo

ENDOCRINOLOGY 145 ( 8 ) 3935 - 3940 2004.8

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

Leptin is secreted by adipocytes and is a circulating factor that regulates food intake and energy expenditure. Its serum level is elevated in patients with renal failure and has been suggested to be associated with malnutritional factors in these patients. Leptin has been suggested to be primarily metabolized by the kidneys, although the precise molecular mechanisms are not known. The purpose of this study was to determine the nephron segments and potential receptors involved in renal leptin metabolism. To determine the segment involved in leptin uptake, we performed histoautoradiography of kidney sections obtained from rats that had been injected iv with I-125-leptin. The ability of megalin, a multiligand endocytic receptor in the proximal tubules, to bind and endocytose leptin was examined by ligand blotting analysis, quartz-crystal microbalance, and degradation assays using megalin-expressing rat yolk sac L2 cells. Immunohistochemistry was performed to localize leptin receptors (LEP-R) in the rat kidney using two antibodies that recognize different epitopes on the LEP-R proteins. Circulating I-125-leptin was filtered by glomeruli and internalized by proximal convoluted tubules. Megalin bound leptin in the presence of Ca2+ and mediated its cellular internalization and degradation. On immunohistochemistry, LEP-R were localized in the proximal straight tubules, loops of Henle, distal tubules, and collecting ducts. In conclusion, circulating leptin was filtered by glomeruli and taken up by proximal convoluted tubules, where megalin likely mediates its binding and uptake. The localization of LEP-R suggests that they are not primarily involved in leptin metabolism in the proximal tubules.

DOI： 10.1210/en.2004-0074

Differentiation-induced cultured podocytes express endocytically active megalin, a Heymann nephritis antigen

H Yamazaki, A Saito, H Ooi, N Kobayashi, P Mundel, F Gejyo

NEPHRON EXPERIMENTAL NEPHROLOGY 96 ( 2 ) E52 - E58 2004

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

Background/Aims: Megalin is a multiligand endocytic receptor expressed in a number of epithelia. In the Lewis rat kidney, podocytes, as well as proximal tubule cells, express megalin that acts as a pathogenic antigen for Heymann nephritis (HN), an experimental model of membranous nephropathy. To obtain a tool to investigate the molecular mechanisms of megalin-mediated endocytosis and the pathogenesis of HN, we examined whether a differentiation-inducible mouse podocyte cell line expressed endocytically active megalin. Methods: Immunofluorescence and immunoprecipitation analyses with an anti-rat megalin antibody were carried out to investigate whether megalin was expressed in the differentiated and undifferentiated podocytes. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed to elucidate whether the cells synthesize megalin mRNA. I-125-labeled receptor-associated protein (RAP), an endocytic ligand for megalin, was used for cellular internalization and degradation assays. Results: Immunofluorescence, immunoprecipitation and RT-PCR analyses revealed that megalin was synthesized in both differentiated and undifferentiated cells and localized to the cell surfaces. Effective endocytosis of RAP via megalin was shown under the differentiated condition. Conclusion: Endocytically active megalin is expressed in differentiation-induced cultured podocytes. This cell line could be a useful tool for studies on megalin-mediated endocytosis and the pathogenesis of HN. Copyright (C) 2004 S. Karger AG, Basel.

DOI： 10.1159/000076404

Different type and localization of CD44 on surface membrane of regenerative renal tubular epithelial cells in vivo

YS Xie, S Nishi, S Fukase, H Nakamura, XM Chen, N Imai, M Sakatsume, A Saito, M Ueno, Narita, I, T Yamamoto, F Gejyo

AMERICAN JOURNAL OF NEPHROLOGY 24 ( 2 ) 188 - 197 2004

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

Background: CD44 is a transmembrane glycoprotein comprising an extracellular domain, a transmembrane domain, and a cytoplasmic tail. Previous studies demonstrated that CD44 was generally restricted to lateral- basal plasma membrane ( PM) of epithelial cells, whether it localized on apical PM in vivo has not been clarified. Methods: In this study, we used a gentamicin-induced acute tubular necrosis (ATN) and spontaneous recovery model in rats and two distinct antibodies, an anti-rat distal extracellular domain (OX49) of standard CD44 ( CD44-OX49) and an anti-rat CD44 cytoplasmic tail (CD44CPT), to survey the localization of CD44-OX49 and CD44CPT on the PM in renal tubular epithelial cells in different recovery stages after ATN with immunohistochemistry and immunoelectron-microscopic examinations. Results: CD44-OX49 was localized not only on the lateral-basal PM in tubular epithelial cells, but also on the apical surface membrane in PCNA-positive newly regenerative tubular epithelial cells in early recovery stages after ATN. However, CD44CPT was only localized on the lateral-basal PM. The immunoelectron-microscopic results showed that CD44-OX49 localization was changed from the apical to lateral to basal surface membrane in renal tubular epithelial cells during the recovery process after ATN, finally disappearing from basal PM when normal polarized epithelial cells formed. Conclusions: These results suggest that there were two types of CD44 including CD44 without a cytoplasmic tail localizing on the apical surface membrane related to newly regenerative epithelial cells, and CD44 with a cytoplasmic tail localizing on the lateral-basal PM related to establishment of tubular epithelial cell polarity after ATN in vivo. Copyright (C) 2004 S. Karger AG, Basel.

DOI： 10.1159/000076758

Bioengineered implantation of megalin-expressing cells: A potential intracorporeal therapeutic model for uremic toxin protein clearance in renal failure Reviewed

A Saito, JJ Kazama, N Iino, KJ Cho, N Sato, H Yamazaki, Y Oyama, T Takeda, RA Orlando, F Shimizu, Y Tabata, F Gejyo

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 14 ( 8 ) 2025 - 2032 2003.8

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Patients who have renal failure and are on dialysis therapy experience serious complications caused by low-molecular-weight uremic toxin proteins normally filtered by glomeruli and metabolized by proximal tubule cells (PTC). Dialysis-related amyloidosis is one such complication induced by systemic deposition of amyloid proteins derived from 12-kD beta(2)-microglobulin (beta(2)-M). Despite the use of high-flux membrane hemodialysis devices and direct absorbent columns, the removal of beta(2)-M is suboptimal, because the effects are transient and insufficient. Megalin is expressed in the apical membranes of PTC and recognized as a multiligand endocytic receptor that binds numerous low-molecular-weight proteins, including, beta(2)-M. This study tested the feasibility of an intra corporeal therapeutic model of continuous beta(2)-m removal using megalin-expressing cell implantation. By cell association and degradation assays, rat yolk sac-derived L2 cells were identified to internalize and degrade beta(2)-M via megalin. The cells were effectively implanted within the subcutaneous tissues of nude mice using a type I collagen scaffold and a method inducing local angiogenesis. After nephrectomy and intraperitoneal injection with I-125-beta(2)-m, it was found that the implanted cells took up the labeled ligand, efficiently removing it from the blood. Bioengineered implantation of megalin-expressing cells may represent a new supportive therapy for dialysis patients to compensate for the loss of renal protein metabolism and remove uremic toxin proteins.

DOI： 10.1097/01.ASN.0000078804.98322.4A

Infection-associated hemophagocytic syndrome in a diabetic patient undergoing chronic hemodialysis Reviewed

Yoko Wada, Maki Sato, Akihiko Saito, Fumitake Gejyo

Clinical and Experimental Nephrology 7 ( 2 ) 163 - 166 2003.6

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

Hemophagocytic syndrome (HPS) is an uncommon but severe illness associated with a variety of infections, malignant tumors, and autoimmune diseases. We report a case of infection-associated HPS in a patient receiving chronic hemodialysis. Peptostreptococcus-induced sepsis and abscess formation in the left iliopsoas muscle led to the onset of infection-associated HPS in this patient. The patient had diabetes mellitus and end-stage renal disease, and it is likely that immunological dysfunctions from these disorders played a part in the onset of both severe bacterial infections and HPS.

DOI： 10.1007/s10157-003-0230-6

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Role of megalin in endocytosis of advanced glycation end products: Implications for a novel protein binding to both megalin and advanced glycation end products Reviewed

A Saito, R Nagai, A Tanuma, H Hama, KJ Cho, T Takeda, Y Yoshida, T Toda, F Shimizu, S Horiuchi, F Gejyo

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 14 ( 5 ) 1123 - 1131 2003.5

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

Advanced glycation end products (AGE) are filtered by glomeruli and reabsorbed and metabolized by proximal tubule cells (PTC). In renal failure, decreased renal AGE metabolism likely accounts for the accumulation in serum that is related to uremic complications. In diabetes, AGE generation is increased, and the handling mechanisms in PTC are likely associated with the pathogenesis of tubulointerstitial injury. It is therefore important to clarify the mechanisms of the AGE metabolism to develop a strategy for removing AGE in uremia and to elucidate the pathogenesis of diabetic nephropathy. To this end, this study focused on the molecular analysis of megalin, a multi-ligand endocytic receptor, in PTC. AGE uptake analysis was performed using the rat yolk sac-derived L2 cell line system established for the analysis of megalin's endocytic functions. The cells mediated specific internalization and degradation of AGE, which were significantly blocked by anti-megalin IgG, indicating that megalin is involved in the cellular processes. However, cell surface AGE-binding assays and ligand blot analysis revealed no evidence that megalin is a direct AGE receptor. Affinity chromatography and ligand blot analysis originally revealed that 200-kD and 400-kD proteins in the cells bind to AGE and the 200-kD protein to megalin in a Ca2+-dependent manner. The binding of megalin with the 200-kD protein was suppressed by receptor-associated protein (RAP), a ligand for megalin. In conclusion, megalin functions for endocytosis of AGE via an indirect mechanism. L2 cells express novel AGE-binding proteins, one of which may interact with megalin.

DOI： 10.1097/01.ASN.0000062962.51879.F8

Association of Gene Polymorphism of Polymeric Immunoglobulin Receptor and IgA Nephropathy

IgA腎症の進展におけるACE及びAngiotensinogen(AGT)遺伝子多型の検討

後藤眞, 成田一衛, 斉藤徳子, 坂爪実, 飯野則昭, 斉藤亮彦, 西慎一, 上野光博, 下条文武

日本腎臓学会誌 43 ( 3 ) 270 - 270 2001.4

メサンギウム増殖性糸球体腎炎(MesPGN)におけるLRP遺伝子多型の検討

齋藤徳子, 成田一衛, 後藤眞, 坂爪実, 斎藤亮彦, 大森健太郎, 上野光博, 下条文武

日本腎臓学会誌 43 ( 3 ) 271 - 271 2001.4

IgA腎症の進展におけるレニン・アンギオテンシン系遺伝子多型の検討

後藤眞, 成田一衛, 斉藤徳子, 坂爪実, 飯野則昭, 斉藤亮彦, 西慎一, 上野光博, 今井直史, 下条文武

日本内科学会雑誌 90 ( 臨増 ) 211 - 211 2001.2

Ichiei Narita, Daisuke Kondo, Shin Goto, Noriko Saito, Yasuo Watanabe, Hajime Yamazaki, Minoru Sakatsume, Akihiko Saito, Fumitake Gejyo

Internal Medicine 40 ( 9 ) 867 - 872 2001

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

Objective In order to explore the possibility that genetic predisposition to dysfunction of mucosal immunity and the IgA processing pathway plays a role in the pathogenesis of mesangial IgA1 deposition in IgAN, we examined the possible association of the gene polymorphism of plgR in the patients with and without IgAN. Subjects and Methods Genomic DNA of peripheral blood cells was isolated from 372 individuals including 172 histologically confirmed IgAN patients. Segments of the pIgR gene were PCR amplified and restriction fragment length polymorphism was determined as Al and A2 with and without Pvu II site, respectively. Results The pIgR genotype distribution was significantly different between the patients with IgAN and those without IgAN. Allele frequency of A2 was higher in IgAN than in other renal diseases (Al and A2
0.516 and 0.484 in IgAN, 0.641 and 0.359 in others, X2=9.84, P=0.0017, Odds ratio=1.71). Moreover, the subjects with A2A2 genotype were associated with a relatively low level of serum IgA only in the patients with IgAN but not in other renal diseases. The difference of allele frequencies was more remarkable in the patients with a serum IgA level of less than 300 mg/dl (Al and A2
0.439 and 0.561 in IgAN, 0.702 and 0.298 in others, X2=12.44, P=0.0004, Odds ratio=3.01). Conclusion This is the first demonstration of the pIgR gene polymorphisms in IgAN which are associated with its clinical phenotype. Gene polymorphisms of pIgR may be candidate genetic markers of susceptibility to IgAN. (Internal Medicine 40: 867-872, 2001). © 2001, The Japanese Society of Internal Medicine. All rights reserved.

DOI： 10.2169/internalmedicine.40.867

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Expression of osteopontin in gentamicin-induced acute tubular necrosis and its recovery process

Yuansheng Xie, Shinichi Nishi, Seitaro Iguchi, Naofumi Imai, Minoru Sakatsume, Akihiko Saito, Mika Ikegame, Noriaki Iino, Hisaki Shimada, Mitsuhiro Ueno, H. Kawashima, M. Arakawa, Fumitake Gejyo

Kidney International 59 ( 3 ) 959 - 974 2001

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

Background. There is controversy regarding the exact localization and roles of osteopontin (OPN), a multipotential chemokine, in renal injury. There is little information on the expression and role of OPN in gentamicin-induced acute tubular necrosis (ATN) and its recovery process. Methods. A severe ATN model was made using male Wistar rats by injecting gentamicin (150 mg/kg/day) for five days and limiting the provision of water. The expression and localization of OPN mRNA and protein, ED1 as a macrophage marker, proliferating cellular nuclear antigen (PCNA), CD44 as an OPN receptor, megalin as a proximal tubule marker, and their relationships to each other were examined from the early tubular necrotic period to the late recovery period by Northern blotting, in situ hybridization, and double immunohistochemical staining. Results. In the gentamicin group, OPN mRNA and protein were expressed in only the PCNA-positive proliferating cortical distal tubules, not in the necrotic proximal tubules, until day 6 after the first administration, but were found markedly in PCNA-positive regenerative proximal and distal tubules on days 10, 15, and 30. The localization of PCNA-positive cells was almost always accompanied with the up-regulated expression of OPN using quantitative analysis (P &lt
0.01). CD44 expression was markedly up-regulated in the renal cortical tubular epithelium from days 6 to 30. In the control group, no expression of OPN and CD44 in the cortical area was found throughout the experimental period. Conclusions. These results suggested that OPN is related to the proliferation and regeneration of tubular epithelial cells after tubular damage.

DOI： 10.1046/j.1523-1755.2001.059003959.x

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