Role of Megalin in Endocytosis of Advanced Glycation End Products

Saito, Akihiko; Nagai, Ryoji; Tanuma, Atsuhito; Hama, Hitoshi; Cho, Kenji; Takeda, Takeshi; Yoshida, Yutaka; Toda, Tosifusa; Shimizu, Fujio; Horiuchi, Seikoh; Gejyo, Fumitake

doi:10.1097/01.asn.0000062962.51879.f8

Cited by 40 publications

(34 citation statements)

References 44 publications

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“…Increased urinary excretion in parallel with decreased circulating CML levels was also found in the long-term protocol in all age groups studied. It has been shown that AGE peptides are filtered across the glomerulus and are partially reabsorbed by the proximal convoluted tubule, while AGE-free adducts, which filter freely, are not well reabsorbed [18, 19]. Whether alagebrium itself has any direct effect on the AGE tubular transport system as well remains undetermined at present.…”

Section: Discussionmentioning

confidence: 99%

Prevention and Reversal of Diabetic Nephropathy in db/db Mice Treated with Alagebrium (ALT-711)

et al. 2006

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Background: Alagebrium (ALT-711) has been shown to improve renal dysfunction in animal models of diabetes. Methods: To test its effects in diabetic nephropathy (DN), ALT-711 was administered (1 mg/kg daily i.p.) to 9-week-old female db/db mice (n = 15, group A1) for 3 weeks and to 3-month-old (n = 15, group A2), 7-month-old (n = 7, group A3), and 12-month-old (n = 5, group A4) female db/db mice for 12 weeks, while a similar number of diabetic and nondiabetic mice were used as controls. The ΕN-carboxymethyllysine (CML) levels in serum, urine, skin, and kidney tissue were measured by enzyme-linked immunosorbent assay. The renal morphometric parameters were assessed by electron and light microscopy. Results: By the 3rd week of treatment, the serum CML level decreased by 41%, and the urinary CML concentration increased by 138% from baseline, while the urinary albumin/creatinine ratio was lower (p < 0.05) in diabetic and nondiabetic group A1 mice. After 3 months of treatment, serum, skin, and kidney CML levels and urinary albumin/creatinine ratio were lower (p < 0.05) and the urinary CML levels higher (p < 0.05) in treated group A2, A3, and A4 animals compared with groups which received phosphate-buffered saline, with a similar pattern observed in nondiabetic mice. The renal morphological parameters characteristic of DN decreased in treated compared with untreated mice. Conclusion: Alagebrium may prevent, delay, and/or reverse established DN in db/db mice by reducing the systemic advanced glycation end product pools and facilitating the urinary excretion of advanced glycation end products.

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Section: Discussionmentioning

confidence: 99%

Prevention and Reversal of Diabetic Nephropathy in db/db Mice Treated with Alagebrium (ALT-711)

et al. 2006

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“…Megalin is a multifactorial binding receptor for a number of molecules such as protein-associated vitamins, lipids, and hormones [33,36], vitamin D carrier protein [37,38] and advanced glycation end-products, which are up-regulated in diabetes [39], but also for insulin itself [34]. Therefore, megalin may also act as a scavenger for cytokine molecules in the endocytotic process.…”

Section: Discussionmentioning

confidence: 99%

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

et al. 2004

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Aims/hypothesis. Cytokines are important humoral mediators of beta cell destruction in autoimmune diabetes. The aim of this study was to identify novel cytokine-induced genes in insulin-producing RINm5F cells, which may contribute to beta cell death or survival. Methods. A global gene expression profile in cytokine-exposed insulin-producing RINm5F cells was achieved by automated restriction fragment differential display PCR. The expression of selected candidate genes was confirmed by real-time RT-PCR analysis. Results. Exposure of RINm5F cells to IL-1β or to a cytokine mixture (IL-1β, TNF-α, IFN-γ) for 6 h resulted in the differential expression of a functional gene cluster. Apart from the well-known up-regulation of the cytokine-responsive genes iNOS, NF-κB, MnSOD and Hsp70, several genes that belong to the functional cluster of the endocytotic pathway were identified. These endocytotic genes comprised: clathrin, megalin, synaptotagmin and calcineurin, which were up-regulated by IL-1β or the cytokine mixture.In contrast, the expression of the calcineurin inhibitor CAIN and of the GDP/GTP exchange protein Rab3 was down-regulated by cytokines. Other up-regulated cytokine-responsive genes were: agrin, murine adherent macrophage protein mRNA (MAMA) and transport-associated protein (TAP1/MTP), whereas the plasma membrane calcium ATPase (PMCA) 2 and PMCA 3 genes were down-regulated by cytokines. Conclusions/interpretation. Our results indicate that genes of the endocytotic pathway are regulated by pro-inflammatory cytokines. This might affect the density of cytokine receptors at the beta cell surface and concomitantly the sensitivity of the cells to cytokine toxicity. A better understanding of the functional cross-talk between endocytotic and cytokine signalling pathways could further the development of novel strategies to protect pancreatic beta cells against toxic effects of pro-inflammatory cytokines.

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“…Importantly, both transporters of albumin (megalin and cubilin) [1] and receptors for AGEs [27] recognize multiple ligands. Thus, AGE-modified albumin binds to megalin in a model using transfected hamster ovary cells [28]. In this work, MGO-BSA appears to be taken up and processed by more than one pathway.…”

Section: Discussionmentioning

confidence: 82%

Effects of Advanced Glycation End Product Modification on Proximal Tubule Epithelial Cell Processing of Albumin

Ozdemir¹,

Hopfer

Roșca³

et al. 2007

Am J Nephrol

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Aim: The goal of this work is to understand the cellular effects of advanced glycation end product (AGE)-modified protein on renal proximal tubule cells. Background: A major function of the proximal tubule is to reabsorb and process filtered proteins. Diabetes is characterized by increased quantities of tissue and circulating proteins modified by AGEs. Therefore in diabetes, plasma proteins filtered at the glomerulus and presented to the renal proximal tubule are likely to be highly modified by AGEs. Methods: The model system was electrically resistant polarized renal proximal tubular epithelial cells in monolayer culture. The model proteins comprise a well-characterized AGE, methylglyoxal-modified bovine serum albumin (MGO-BSA), and unmodified BSA. Results: Renal proximal tubular cells handle MGO-BSA and native BSA in markedly disparate ways, including differences in: (1) kinetics of binding, uptake, and intracellular accumulation, (2) processing and fragmentation, and (3) patterns of electrical conductance paralleling temporal changes in binding, uptake and processing. Conclusion: These differences support the idea that abnormal protein processing by the renal tubule can be caused by abnormal proteins, thereby forging a conceptual link between the pathogenic role of AGEs and early changes in tubular function that can lead to hypertrophy and nephropathy in diabetes.

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Role of Megalin in Endocytosis of Advanced Glycation End Products

Cited by 40 publications

References 44 publications

Prevention and Reversal of Diabetic Nephropathy in db/db Mice Treated with Alagebrium (ALT-711)

Prevention and Reversal of Diabetic Nephropathy in db/db Mice Treated with Alagebrium (ALT-711)

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

Effects of Advanced Glycation End Product Modification on Proximal Tubule Epithelial Cell Processing of Albumin

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