Cisplatin-induced inhibition of receptor-mediated endocytosis of protein in the kidney

Takano, Mikihisa; Nakanishi, Naoki; Kitahara, Yasumi; Sasaki, Yuki; Murakami, Teruo; Nagai, Junya

doi:10.1046/j.1523-1755.2002.00623.x

Cited by 37 publications

(21 citation statements)

References 26 publications

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“…The particular cells used in these experiments took up FITC-BSA at rates similar to those reported in previously published work (28,32,33). Simvastatin, used as an example of the statin class, inhibited the uptake of FITC-BSA and FITC--␤ 2 -microglobulin but not of FITC-inulin-a marker of fluidphase fluid endocytosis.…”

Section: Discussionsupporting

confidence: 69%

Inhibitors of 3-Hydroxy-3-Methylglutaryl–CoA Reductase Reduce Receptor-Mediated Endocytosis in Opossum Kidney Cells

Sidaway¹,

Davidson

McTaggart

et al. 2004

Journal of the American Society of Nephrology

143

105

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Abstract. Renal proximal tubule cells are responsible for the reabsorption of proteins that are present in the tubular lumen. This occurs by receptor-mediated endocytosis, a process that has a requirement for some GTP-binding proteins. Statins are inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase used for the therapeutic reduction of cholesterol-containing plasma lipoproteins. However, they can also reduce intracellular levels of isoprenoid pyrophosphates that are derived from the product of the enzyme, mevalonate, and are required for the prenylation and normal function of GTP-binding proteins. The hypothesis that inhibition of HMG-CoA reductase in renal proximal tubule cells could reduce receptor mediated-endocytosis was therefore tested. Five different statins inhibited the uptake of FITC-labeled albumin by the proximal tubule-derived opossum kidney cell line in a dose-dependent manner and in the absence of cytotoxicity. The reduction in albumin uptake was related to the degree of inhibition of HMG-CoA reductase. Simvastatin (e.g., statin) inhibited receptor-mediated endocytosis of both FITC-albumin and FITC-␤ 2 -microglobulin to similar extents but without altering the binding of albumin to the cell surface. The effect on albumin endocytosis was prevented by mevalonate and by the isoprenoid geranylgeranyl pyrophosphate but not by cholesterol. Finally, evidence that the inhibitory effect of statins on endocytosis of proteins may be caused by reduced prenylation and thereby decreased function of one or more GTP-binding proteins is provided. These data establish the possibility in principle that inhibition of HMG-CoA reductase by statins in proximal tubule cells may reduce tubular protein reabsorption.Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, the major rate-limiting step of the sterol pathway (1). The statins are widely used for the therapeutic reduction of cholesterol-containing atherogenic lipoproteins (2-4). This is brought about as a result of depletion of intracellular mevalonate leading to reduction of the regulatory sterol pool, which in turn causes upregulation of HMGCoA reductase and other enzymes of the sterol pathway, most importantly the LDL receptors principally in the liver (5-7). However, a range of additional effects of statins on cells that are independent of cholesterol homeostasis has been described; these include, proliferation (8), signal transduction (9), and apoptosis (10). Many of these cholesterol-independent effects of statins have been shown to result from depletion of mevalonate and its nonsterol metabolites, particularly the isoprenoid pyrophosphates, such as farnesol pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), that are required for the posttranslation modification of a variety of cell proteins, including the superfamily of small GTP-binding proteins (11)(12)(13). Endocytosis is one cell function that requires multiple GTP-binding proteins (14,15) a...

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Section: Discussionsupporting

confidence: 69%

Inhibitors of 3-Hydroxy-3-Methylglutaryl–CoA Reductase Reduce Receptor-Mediated Endocytosis in Opossum Kidney Cells

Sidaway¹,

Davidson

McTaggart

et al. 2004

Journal of the American Society of Nephrology

143

105

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“…Uptake experiments were performed as described previously (39). RLE-6TN cells grown on 35-mm culture dishes were used.…”

Section: Methodsmentioning

confidence: 99%

Clathrin-mediated endocytosis of FITC-albumin in alveolar type II epithelial cell line RLE-6TN

Yumoto¹,

Nishikawa²,

Okamoto³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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-We examined mechanisms of FITC-albumin uptake by alveolar type II epithelial cells using cultured RLE-6TN cells. Alkaline phosphatase activity and the expression of cytokeratin 19 mRNA, which are characteristic features of alveolar type II epithelial cells, were detected in RLE-6TN cells. The uptake of FITCalbumin by the cells was time and temperature dependent and showed the saturation kinetics of high-and low-affinity transport systems. FITC-albumin uptake was inhibited by native albumin, by chemically modified albumin, and by metabolic inhibitors and bafilomycin A 1, an inhibitor of vacuolar H ϩ -ATPase. Confocal laser scanning microscopic analysis after FITCalbumin uptake showed punctate localization of fluorescence in the cells, which was partly localized in lysosomes. FITC-albumin taken up by the cells gradually degraded over time, as shown by fluoroimage analyzer after SDS-PAGE. The uptake of FITC-albumin by RLE-6TN cells was not inhibited by nystatin, indomethacin, or methyl-␤-cyclodextrin (inhibitors of caveolae-mediated endocytosis) but was inhibited by phenylarsine oxide and chlorpromazine (inhibitors of clathrin-mediated endocytosis) in a concentration-dependent manner. Uptake was also inhibited by potassium depletion and hypertonicity, conditions known to inhibit clathrin-mediated endocytosis. These results indicate that the uptake of FITC-albumin in cultured alveolar type II epithelial cells, RLE-6TN, is mediated by clathrin-mediated but not by caveolae-mediated endocytosis, and intracellular FITC-albumin is gradually degraded in lysosomes. Possible receptors involved in this endocytic system are discussed. albumin clearance; caveolae-mediated endocytosis; endocytic receptor; modified albumin; protein transport THE DISTAL AIR SPACES OF THE lung (alveolar region) are lined with a continuous epithelium comprising two major types of epithelial cells, type I and type II. Type I epithelial cells have a squamous morphology and cover ϳ90 -95% of the alveolar surface area. Type II cells are cuboidal epithelial cells and cover ϳ5-10% of the surface area, although the number of type II cells in alveolar epithelia is similar to or more than that of type I cells. Type II cells also serve as progenitors of type I cells (13,40). Alveolar lining fluid contains various physiologically important proteins such as albumin, immunoglobulin G, and transferrin. The concentration of albumin in alveolar fluid is usually much lower than that in the blood, whereas the concentration would increase to 40 -65% of plasma level in hydrostatic pulmonary edema and to 75-95% in lung injury pulmonary edema. The clearance of serum proteins from the alveolar space is a critical process in recovery from pulmonary edema and in maintaining the normal alveolar milieu (17,22). Therefore, understanding the mechanisms of protein transport in alveolar epithelial cells is important for the development of better therapeutic approaches. In addition, such information could provide new insights into improved strategies for pulmonary delivery of ex...

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“…Intracellular FITC-albumin content was measured using a procedure adapted from Takano et al (Takano et al, 2002). RF/6A cells were plated at 0.75ϫ10 6 cells/ml on 35-mm culture dishes.…”

Section: Cellular Permeability Assay Analysesmentioning

confidence: 99%

Tubedown associates with cortactin and controls permeability of retinal endothelial cells to albumin

Paradis

Islam

Tucker

et al. 2008

Journal of Cell Science

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Tubedown (Narg1, Tbdn), a member of the Nat1 family of proteins, associates with the acetyltransferase Ard1 and exerts an angiostatic function in adult retinal-blood-vessel homeostasis. The purpose of the present study was to gain a better understanding of the nature of the Tbdn protein complex and how it might exert a homeostatic influence on blood vessels. Immunoprecipitation of Tbdn from endothelial cells followed by gel electrophoresis and liquid-chromatography–tandem-mass-spectrometry identified the actin-cytoskeleton-binding protein cortactin as a co-immunopurifying species. Western blotting confirmed the association between Tbdn and cortactin. Immunofluorescence confocal microscopy revealed that Tbdn colocalizes with cortactin and F-actin in cytoplasmic regions and at the cortex of cultured endothelial cells. Because cortactin is known to regulate cellular permeability through its interaction with the actin cytoskeleton, a process that is crucial for endothelial cell homeostasis, the role of Tbdn on endothelial cell permeability was examined. Knockdown of Tbdn expression in endothelial cells led to the co-suppression of Ard1 protein expression and to a significant increase in cellular permeability measured by the transit of FITC-albumin across the cellular monolayer. Furthermore, the proliferative retinal neovascularization and thickening resulting from induction of Tbdn knockdown in endothelium in transgenic mice was associated with a significant increase in extravasation or leakage of albumin from abnormal retinal blood vessels in vivo. These results provide evidence that an association occurs between Tbdn and cortactin, and that Tbdn is involved in the regulation of retinal-endothelial-cell permeability to albumin. This work implicates a functional role for Tbdn in blood-vessel permeability dynamics that are crucial for vascular homeostasis.

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Cisplatin-induced inhibition of receptor-mediated endocytosis of protein in the kidney

Abstract: These results suggest that CDDP decreases the receptor-mediated endocytosis of protein following the inhibition of vacuolar H+-ATPase in the renal proximal tubules, and the inhibition of receptor-mediated endocytosis would be the mechanisms underlying the proteinuria induced by CDDP.

Cited by 37 publications

References 26 publications

Inhibitors of 3-Hydroxy-3-Methylglutaryl–CoA Reductase Reduce Receptor-Mediated Endocytosis in Opossum Kidney Cells

Inhibitors of 3-Hydroxy-3-Methylglutaryl–CoA Reductase Reduce Receptor-Mediated Endocytosis in Opossum Kidney Cells

Clathrin-mediated endocytosis of FITC-albumin in alveolar type II epithelial cell line RLE-6TN

Tubedown associates with cortactin and controls permeability of retinal endothelial cells to albumin

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