Role of megalin in renal handling of aminoglycosides

2001 ◽  
Vol 281 (2) ◽  
pp. F337-F344 ◽  
Author(s):  
Junya Nagai ◽  
Hiroaki Tanaka ◽  
Naoki Nakanishi ◽  
Teruo Murakami ◽  
Mikihisa Takano
Keyword(s):  
Brush Border Membrane ◽  
Renal Cortex ◽  
Renal Medulla ◽  
Bolus Administration ◽  
Renal Tubules ◽  
Vitamin D Binding Protein ◽  
Renal Handling ◽  
Renal Brush Border Membrane

The role of megalin in tissue distribution of aminoglycosides was examined in normal rats and maleate-treated rats that shed megalin from the renal brush-border membrane. In normal rats, amikacin administered intravenously accumulated most abundantly in the renal cortex, followed by the renal medulla. No amikacin was detected in other tissues. Tissue distributions of amikacin were well correlated with megalin levels in each tissue. Bolus administration of gentamicin increased urinary excretion of megalin ligands (vitamin D binding protein and calcium), suggesting the competition between gentamicin and these megalin ligands in renal tubules. Ligand blotting showed that binding of45Ca2+ to megalin was inhibited by aminoglycosides. Both megalin levels and amikacin accumulation in renal cortex were decreased by maleate injection. Then, amikacin accumulation recovered proportionate to megalin levels. These findings suggest that megalin is involved in the renal cortical accumulation of aminoglycosides in vivo. In addition, the interaction between aminoglycosides and calcium in the kidney may be due to the competition among these compounds to bind to megalin.

scholarly journals Role of antennary structure of N-linked sugar chains in renal handling of recombinant human erythropoietin

Blood ◽  
1995 ◽  
Vol 86 (11) ◽  
pp. 4097-4104 ◽  
Author(s):  
T Misaizu ◽  
S Matsuki ◽  
TW Strickland ◽  
M Takeuchi ◽  
A Kobata ◽  
...  
Keyword(s):  
Whole Body ◽  
Renal Handling ◽  
Sugar Chain ◽  
Erythroid Progenitor ◽  
Human Erythropoietin ◽  
Sugar Chains ◽  
Effective Transfer ◽  
Branched Structure

To elucidate the role of the branched structure of sugar chains of human erythropoietin (EPO) in the expression of in vivo activity, the pharmacokinetic profile of a less active recombinant human EPO sample (EPO-bi) enriched with biantennary sugar chains was compared with that of a highly active control EPO sample enriched with tetraantennary sugar chains. After an intravenous injection in rats, 125I-EPO-bi disappeared from the plasma with 3.2 times greater total body clearance (Cltot) than control 125I-EPO. Whole-body autoradiography after 20 minutes of administration indicated that the overall distribution of radioactivity is similar, but 125I-EPO-bi showed a higher level of radioactivity in the kidneys than control 125I-EPO. Quantitative determination of radioactivity in the tissues also indicated that radioactivity of 125I-EPO-bi in the kidneys was two times higher than that of control 125I-EPO. The difference in plasma disappearance between 125I-EPO-bi and control 125I-EPO was not observed in bilaterally nephrectomized rats. The distribution of 125I-EPO-bi to bone marrow and spleen was similarly inhibited by simultaneous injection of excess amounts of either the nonlabeled EPO-bi or control EPO. These results indicate that the low in vivo biologic activity of EPO-bi results from rapid clearance from the systemic circulation by renal handling. Thus, the well-branched structure of the N-linked sugar chain of EPO is suggested to play an important role in maintaining its higher plasma level, which guarantees an effective transfer to target organs and stimulation of erythroid progenitor cells.

scholarly journals Differential regulation of the renal sodium-phosphate cotransporters NaPi-IIa, NaPi-IIc, and PiT-2 in dietary potassium deficiency

2009 ◽  
Vol 297 (2) ◽  
pp. F350-F361 ◽  
Author(s):  
Sophia Y. Breusegem ◽  
Hideaki Takahashi ◽  
Hector Giral-Arnal ◽  
Xiaoxin Wang ◽  
Tao Jiang ◽  
...  
Keyword(s):  
Brush Border Membrane ◽  
Protein Abundance ◽  
Transport Activity ◽  
Renal Brush Border Membrane ◽  
Cytoplasmic Vesicles ◽  
Dietary Potassium ◽  
Proximal Tubular ◽  
K Deficiency ◽  
Altered Lipid

Dietary potassium (K) deficiency is accompanied by phosphaturia and decreased renal brush border membrane (BBM) vesicle sodium (Na)-dependent phosphate (Pi) transport activity. Our laboratory previously showed that K deficiency in rats leads to increased abundance in the proximal tubule BBM of the apical Na-Pi cotransporter NaPi-IIa, but that the activity, diffusion, and clustering of NaPi-IIa could be modulated by the altered lipid composition of the K-deficient BBM (Zajicek HK, Wang H, Puttaparthi K, Halaihel N, Markovich D, Shayman J, Beliveau R, Wilson P, Rogers T, Levi M. Kidney Int 60: 694–704, 2001; Inoue M, Digman MA, Cheng M, Breusegem SY, Halaihel N, Sorribas V, Mantulin WW, Gratton E, Barry NP, Levi M. J Biol Chem 279: 49160–49171, 2004). Here we investigated the role of the renal Na-Pi cotransporters NaPi-IIc and PiT-2 in K deficiency. Using Western blotting, immunofluorescence, and quantitative real-time PCR, we found that, in rats and in mice, K deficiency is associated with a dramatic decrease in the NaPi-IIc protein abundance in proximal tubular BBM and in NaPi-IIc mRNA. In addition, we documented the presence of a third Na-coupled Pi transporter in the renal BBM, PiT-2, whose abundance is also decreased by dietary K deficiency in rats and in mice. Finally, electron microscopy showed subcellular redistribution of NaPi-IIc in K deficiency: in control rats, NaPi-IIc immunolabel was primarily in BBM microvilli, whereas, in K-deficient rats, NaPi-IIc BBM label was reduced, and immunolabel was prevalent in cytoplasmic vesicles. In summary, our results demonstrate that decreases in BBM abundance of the phosphate transporter NaPi-IIc and also PiT-2 might contribute to the phosphaturia of dietary K deficiency, and that the three renal BBM phosphate transporters characterized so far can be differentially regulated by dietary perturbations.

Renal sugar transport in the winter flounder: V. secretion of 2-deoxy-D-galactose

1978 ◽  
Vol 234 (5) ◽  
pp. F424-F431
Author(s):  
J. B. Pritchard ◽  
G. Booz ◽  
A. Kleinzeller
Keyword(s):  
Sugar Transport ◽  
Winter Flounder ◽  
Free Sugar ◽  
Renal Tubules ◽  
Pseudopleuronectes Americanus ◽  
Clearance Ratio ◽  
Renal Handling ◽  
Cell Clearance

Isolated renal tubules and renal clearance techniques were used to characterize the renal handling of 2-deoxy-D-galactose (2-d-Gal) by the winter flounder (Pseudopleuronectes americanus). In vitro, energy-dependent, pH-sensitive uptake of 2-d-Gal (2–100 micron) was seen at the antiluminal face of the cell. Clearance measurements showed net secretion of 2-d-Gal in vivo. The mean clearance of 2-d-Gal in 18 fish was 0.98 +/- 0.16 ml/h while the glomerular filtration rate (GFR) was only 0.37 +/- 0.10 ml/h. Secretion was associated with marked renal accumulation of both 2-d-Gal and phosphorylated derivatives (2-d-Gal-1-phosphate). Tissue-to-plasma ratios (T/P) averaged 19 for free sugar and 59 for total sugar. Both clearance ratio and T/P were reduced to approximately 1 by injection of galactose (2.5 mmol/kg) simultaneously with 2-d-Gal (25 mumol/kg). Phlorizin (2.5 mumol/kg) increased net 2-d-Gal secretion, whereas glucose (2.5 mmol/kg) produced no change in secretion. Both compounds depressed 2-d-Gal T/P. This result suggests the presence of readsorptive transport at the brush border, sensitive to glucose and phlorizin.

Effect of glucocorticoids on renal cortical NHE-3 and NHE-1 mRNA

1994 ◽  
Vol 267 (3) ◽  
pp. F437-F442 ◽  
Author(s):  
M. Baum ◽  
O. W. Moe ◽  
D. L. Gentry ◽  
R. J. Alpern
Keyword(s):  
Proximal Tubule ◽  
Mammalian Cells ◽  
Brush Border Membrane ◽  
Renal Cortex ◽  
Membrane Vesicles ◽  
Mrna Abundance ◽  
Renal Brush Border Membrane ◽  
Acute Increase ◽  
Glucocorticoid Deficiency ◽  
Convoluted Tubules

Glucocorticoids play an important role in modulating proximal tubule acidification. Chronic systemic administration of dexamethasone increases the rate of bicarbonate absorption in isolated perfused proximal convoluted tubules and Na+/H+ antiporter activity in renal brush-border membrane vesicles. The proximal tubule expresses mRNA corresponding to two known Na+/H+ antiporter isoforms: NHE-3, an amiloride-resistant apical membrane Na+/H+ antiporter; and NHE-1, an amiloride-sensitive Na+/H+ antiporter found on most mammalian cells. Administration of dexamethasone for 1 and 2 days (600 micrograms/kg twice daily and 2 h before animals were killed) increased NHE-3 mRNA abundance 1.3- and 2.5-fold, respectively, but had no effect on NHE-1 mRNA abundance. Aminoglutethimide-induced glucocorticoid deficiency had no effect on NHE-1 or NHE-3 mRNA abundance. Incubation of proximal tubules for 3 h with 10(-5) M dexamethasone increased proximal tubule Na+/H+ antiporter activity from 0.69 +/- 0.04 to 0.92 +/- 0.03 pH units/min (P < 0.01); however, there was no increase in NHE-3 or NHE-1 mRNA abundance. Similarly, there was no effect on NHE-3 or NHE-1 mRNA abundance in rabbit renal cortex 4 h after intravenous administration of 600 micrograms/kg dexamethasone. Thus chronic dexamethasone increases NHE-3 but not NHE-1 mRNA abundance. The acute increase in Na+/H+ antiporter activity induced by dexamethasone occurs by mechanisms independent of changes in NHE-1 and NHE-3 mRNA abundance.

scholarly journals Renal handling of phosphate in vivo and in vitro by the X-linked hypophosphatemic male mouse: Evidence for a defect in the brush border membrane

1978 ◽  
Vol 14 (3) ◽  
pp. 236-244 ◽  
Author(s):  
Harriet S. Tenenhouse ◽  
Charles R. Scriver ◽  
Roderick McInnes ◽  
Francis H. Glorieux
Keyword(s):  
Brush Border ◽  
Male Mouse ◽  
Brush Border Membrane ◽  
Renal Handling

scholarly journals THE ROLE OF PENICILLIN-INDUCED BACTERIAL VARIANTS IN EXPERIMENTAL PYELONEPHRITIS

1967 ◽  
Vol 125 (4) ◽  
pp. 607-618 ◽  
Author(s):  
Richard H. Winterbauer ◽  
Laura T. Gutman ◽  
Marvin Turck ◽  
Ralph J. Wedgwood ◽  
Robert G. Petersdorf
Keyword(s):  
Escherichia Coli ◽  
Renal Medulla ◽  
Round Cell ◽  
Histologic Response ◽  
E Coli ◽  
Round Cell Infiltration ◽  
Kidney Liver

1. After injection into the renal medulla of rats Escherichia coli 06 variants reverted rapidly in vivo in the absence of penicillin. These variants had previously been shown to be stable in vitro. 2. Variants failed to survive following intramedullary injection when animals were receiving penicillin. 3. Late reversion of variants also failed to occur in animals treated with penicillin for only 1 or 2 days. 4. Variants survived and reverted more readily when injected in the renal medulla, compared with liver and spleen. Classical bacteria injected into the kidney, liver, and spleen were recovered in approximately equal numbers. 5. The histologic response to nonreverting variants, medium not containing variants, and killed variants was similar and was characterized by a fibrotic reaction with moderate round cell infiltration. 6. In contrast, the histologic response to reverting variants and to classical E. coli was characterized by an intense, acute, polymorphonuclear leukocytosis typical of acute pyelonephritis.

scholarly journals COX-2 mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla

2014 ◽  
Vol 307 (1) ◽  
pp. F25-F32 ◽  
Author(s):  
Fei Wang ◽  
Xiaohan Lu ◽  
Kexin Peng ◽  
Li Zhou ◽  
Chunling Li ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Expression ◽  
Renal Medulla ◽  
Receptor Expression ◽  
Ang Ii ◽  
Cox 2 ◽  
Renin Content

(Pro)renin receptor (PRR) is predominantly expressed in the distal nephron where it is activated by angiotensin II (ANG II), resulting in increased renin activity in the renal medulla thereby amplifying the de novo generation and action of local ANG II. The goal of the present study was to test the role of cycloxygenase-2 (COX-2) in meditating ANG II-induced PRR expression in the renal medulla in vitro and in vivo. Exposure of primary rat inner medullary collecting duct cells to ANG II induced sequential increases in COX-2 and PRR protein expression. When the cells were pretreated with a COX-2 inhibitor NS-398, ANG II-induced upregulation of PRR protein expression was almost completely abolished, in parallel with the changes in medium active renin content. The inhibitory effect of NS-398 on the PRR expression was reversed by adding exogenous PGE2. A 14-day ANG II infusion elevated renal medullary PRR expression and active and total renin content in parallel with increased urinary renin, all of which were remarkably suppressed by the COX-2 inhibitor celecoxib. In contrast, plasma and renal cortical active and total renin content were suppressed by ANG II treatment, an effect that was unaffected by COX-2 inhibition. Systolic blood pressure was elevated with ANG II infusion, which was attenuated by the COX-2 inhibition. Overall, the results obtained from in vitro and in vivo studies established a crucial role of COX-2 in mediating upregulation of renal medullary PRR expression and renin content during ANG II hypertension.

Actions of NAD+ on renal brush border transport of phosphate in vivo and in vitro

1985 ◽  
Vol 249 (6) ◽  
pp. F948-F955 ◽  
Author(s):  
S. A. Kempson ◽  
S. T. Turner ◽  
A. N. Yusufi ◽  
T. P. Dousa
Keyword(s):  
Brush Border ◽  
Brush Border Membrane ◽  
Competitive Inhibition ◽  
Inhibitory Effect ◽  
Pi Transport ◽  
Renal Brush Border Membrane ◽  
Dependent Transport ◽  
Renal Brush Border

Previous studies showed that an increase in NAD+ content in renal cortex in vivo was accompanied by specific inhibition of Na+-dependent inorganic phosphate (Pi) transport across the renal brush border membrane (BBM). Further, in vitro addition of NAD+ to isolated renal BBM vesicles specifically inhibited Na+ gradient-dependent transport of Pi. The present study examined some aspects of the mechanism of this inhibition by NAD+ in vitro and in vivo. When NAD+ was increased in vivo by nicotinamide injection, the apparent Vmax was decreased, but the apparent Km was not different, indicating apparent noncompetitive inhibition. In the presence of 0.3 mM NAD+ added in vitro, the apparent Km for Na+-dependent Pi transport by BBM vesicles was increased, whereas the apparent Vmax was unchanged, indicating apparent competitive inhibition. These changes in apparent Km and apparent Vmax were identical when Pi uptake was measured either at 30-s or at 5-s (the initial rate) incubation times. Inhibition of Pi transport by BBM vesicles in vitro was due primarily to the action of intact added NAD+, although there may be some contribution by isotope dilution due to Pi released from NAD+ by enzymatic hydrolysis. Although in vitro inhibition of Pi transport by added NAD+ was reversed by washing the BBM, the inhibition due to increased NAD+ in vivo persisted after extensive washing of the isolated BBM. The specificity of the inhibitory effect of NAD+ in vivo was indicated by the finding that changes in renal cortical content of ATP or Pi, evoked by loading with glycerol or fructose, did not change BBM transport of Pi.(ABSTRACT TRUNCATED AT 250 WORDS)

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