Kinetics, competition, and selectivity of tubular absorption of proteins

1982 ◽  
Vol 243 (4) ◽  
pp. F379-F392 ◽  
Author(s):  
B. E. Sumpio ◽  
T. Maack
Keyword(s):  
Rat Kidney ◽  
High Capacity ◽  
Human Growth ◽  
Protein Molecule ◽  
Structural Features ◽  
Cyt C ◽  
Tubular Absorption ◽  
Beta 2 ◽  
Beta 2 Microglobulin ◽  
Endocytic Vesicles

Tubular absorption (T) of two cationic proteins, lysozyme (LZM) and cytochrome c (CYT c), and two anionic proteins, beta 2-microglobulin (beta 2M) and 125I-labeled human growth hormone (hGH), was studied in the isolated perfused rat kidney. All four proteins are extensively filtered and, at low loads, almost completely absorbed by the tubular epithelium. TLZM and TCYT c is a saturable process of high capacity (Tm) and low apparent affinity. (Tm)LZM was two orders of magnitude larger than (Tm)CYT c. LZM inhibited TCYT c in a dose-dependent and reversible manner. Saturating loads of CYT c failed to inhibit T beta 2M and ThGH. Saturation, selectivity, and competition is explained on the basis of a model that incorporates adsorption of protein to microvilli as well as geometric and electrical constraints on the access of filtered proteins to endocytic sites at the base of the microvilli. Tubular absorption of all proteins is decreased by inhibitors of the formation and/or internalization of endocytic vesicles (iodoacetate and cytochalasin B). However, lysine (5 mM) and low perfusate calcium concentration (0.5 mM) inhibited T beta 2M but not TCYT c and ThGH. The selective effect of 5 mM lysine, which causes morphologic damage in initial portions of the proximal convoluted tubule, may be due to preferential or exclusive absorption of beta 2 M in this portion of the nephron. The results as a whole demonstrate that in addition to net charge other structural features of the protein molecule and of the luminal wall of proximal tubules may be important determinants of the efficiency and capacity of the tubular absorption of filtered proteins.

Renal hydrolysis of absorbed protein: influence of load and lysosomal pH

1984 ◽  
Vol 247 (4) ◽  
pp. F656-F664 ◽  
Author(s):  
M. J. Camargo ◽  
B. E. Sumpio ◽  
T. Maack
Keyword(s):  
Rat Kidney ◽  
High Capacity ◽  
Lysosomal Ph ◽  
Renal Tubular Cells ◽  
Weak Bases ◽  
Uptake Rates ◽  
Cyt C ◽  
Renal Tubular ◽  
Hydrolysis Of

The kinetics of intracellular hydrolysis of administered protein and the effect of alkalinization of lysosomal pH on this process were studied in the isolated perfused rat kidney (IPK). Cytochrome c (CYT c) was used as a probe protein, and its hydrolysis was determined by measuring the efflux of radioactivity from IPK preloaded in vivo with [14CH3]CYT c and various doses of unlabeled CYT c. The nature of radioactivity absorbed by the kidney and released to the perfusate was analyzed by Sephadex chromatography. Administered CYT c is absorbed and hydrolyzed by the kidney, and the resulting amino acids are returned to the perfusate. At low uptake rates, the half time of hydrolysis of absorbed CYT c is about 20 min. The disposal of absorbed CYT c is a saturable function of its concentration in kidney with a Vmax = 0.60 mg CYT c X h-1 X g kidney-1 and an apparent Km = 0.55 mg CYT c/g kidney. To alkalinize the lysosomal pH, IPK were perfused in the presence of NH4Cl (10 mM) or chloroquine (0.1 mM). These lysosomotropic weak bases almost completely inhibit in a reversible manner the hydrolysis of absorbed CYT c. The results demonstrate that renal catabolism of absorbed protein is a saturable process of high capacity compared with the normal filtered loads of protein. The data are consistent with the view that normal lysosomal function is required for an adequate disposal of absorbed proteins in the kidney. It is postulated that abnormal deposition of protein absorption droplets within renal tubular cells may result from high absorbed loads and/or a deficient acidification of lysosomes.

Serial Quantification of Urinary Protein Biomarkers to Predict Drug-induced Acute Kidney Injury

2019 ◽  
Vol 20 (8) ◽  
pp. 656-664 ◽  
Author(s):  
Yi Da ◽  
K. Akalya ◽  
Tanusya Murali ◽  
Anantharaman Vathsala ◽  
Chuen-Seng Tan ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cystatin C ◽  
Calcineurin Inhibitors ◽  
Kidney Injury ◽  
Tubular Dysfunction ◽  
Renal Tubular Dysfunction ◽  
Protein Biomarkers ◽  
Drug Induced ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Background: : Drug-induced Acute Kidney Injury (AKI) develops in 10-15% of patients who receive nephrotoxic medications. Urinary biomarkers of renal tubular dysfunction may detect nephrotoxicity early and predict AKI. Methods:: We prospectively studied patients who received aminoglycosides, vancomycin, amphotericin, or calcineurin inhibitors, and collected their serial urine while on therapy. Patients who developed drug-induced AKI (fulfilling KDIGO criteria) were matched with non-AKI controls in a 1:2 ratio. Their urine samples were batch-analyzed at time-intervals leading up to AKI onset; the latter benchmarked against the final day of nephrotoxic therapy in non- AKI controls. Biomarkers examined include clusterin, beta-2-microglobulin, KIM1, MCP1, cystatin-C, trefoil-factor- 3, NGAL, interleukin-18, GST-Pi, calbindin, and osteopontin; biomarkers were normalized with corresponding urine creatinine. Results:: Nine of 84 (11%) patients developed drug-induced AKI. Biomarkers from 7 AKI cases with pre-AKI samples were compared with those from 14 non-AKI controls. Corresponding mean ages were 55(±17) and 52(±16) years; baseline eGFR were 99(±21) and 101(±24) mL/min/1.73m2 (all p=NS). Most biomarker levels peaked before the onset of AKI. Median levels of 5 biomarkers were significantly higher in AKI cases than controls at 1-3 days before AKI onset (all µg/mmol): clusterin [58(8-411) versus 7(3-17)], beta-2-microglobulin [1632(913-3823) versus 253(61-791)], KIM1 [0.16(0.13-0.76) versus 0.07(0.05-0.15)], MCP1 [0.40(0.16-1.90) versus 0.07(0.04-0.17)], and cystatin-C [33(27-2990) versus 11(7-19)], all p<0.05; their AUROC for AKI prediction were >0.80 (confidence intervals >0.50), with average accuracy highest for clusterin (86%), followed by beta-2-microglobulin, cystatin-C, MCP1, and KIM1 (57%) after cross-validation. Conclusion: : Serial surveillance of these biomarkers could improve the lead time for nephrotoxicity detection by days.

Theiler's virus infection of beta 2-microglobulin-deficient mice.

1993 ◽  
Vol 67 (1) ◽  
pp. 589-592 ◽  
Author(s):  
L Fiette ◽  
C Aubert ◽  
M Brahic ◽  
C P Rossi
Keyword(s):  
Virus Infection ◽  
Theiler's Virus ◽  
Beta 2 ◽  
Beta 2 Microglobulin ◽  
Deficient Mice

Time-resolved fluoroimmunoassay of beta 2-microglobulin in serum and cerebrospinal fluid

1993 ◽  
Vol 39 (3) ◽  
pp. 552-553 ◽  
Author(s):  
D Meillet ◽  
L Bélec ◽  
E Schuller ◽  
J Delattre
Keyword(s):  
Cerebrospinal Fluid ◽  
Time Resolved ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Evaluation of beta-2 microglobulin, erythropoietin and tobacco use in polycythemic cases

2021 ◽  
Author(s):  
Kristell Mahe ◽  
Francis Couturaud ◽  
Hélène Kerspern ◽  
Aurélie Chauveau ◽  
Jean-Christophe Ianotto
Keyword(s):  
Tobacco Use ◽  
Beta 2 ◽  
Beta 2 Microglobulin
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