scholarly journals A model of uric acid transport in the rat proximal tubule

2019 ◽  
Vol 316 (5) ◽  
pp. F934-F947 ◽  
Author(s):  
Aurélie Edwards ◽  
Muriel Auberson ◽  
Suresh K. Ramakrishnan ◽  
Olivier Bonny
Keyword(s):  
Uric Acid ◽  
Parathyroid Hormone ◽  
Proximal Tubule ◽  
Glucose Transporter ◽  
Transport Model ◽  
Ang Ii ◽  
Acid Transport ◽  
Secretion Pathways ◽  
Experimental Findings ◽  
Urate Reabsorption

The objective of the present study was to theoretically investigate the mechanisms underlying uric acid transport in the proximal tubule (PT) of rat kidneys, and their modulation by factors, including Na+, parathyroid hormone, ANG II, and Na+-glucose cotransporter-2 inhibitors. To that end, we incorporated the transport of uric acid and its conjugate anion urate in our mathematical model of water and solute transport in the rat PT. The model accounts for parallel urate reabsorption and secretion pathways on apical and basolateral membranes and their coupling to lactate and α-ketoglutarate transport. Model results agree with experimental findings at the segment level. Net reabsorption of urate by the rat PT is predicted to be ~70% of the filtered load, with a rate of urate removal from the lumen that is 50% higher than the rate of urate secretion. The model suggests that apical URAT1 deletion significantly reduces net urate reabsorption across the PT, whereas ATP-binding cassette subfamily G member 2 dysfunction affects it only slightly. Inactivation of basolateral glucose transporter-9 raises fractional urate excretion above 100%, as observed in patients with renal familial hypouricemia. Furthermore, our results suggest that reducing Na+ reabsorption across Na+/H+ exchangers or Na+-glucose cotransporters augments net urate reabsorption. The model predicts that parathyroid hormone reduces urate excretion, whereas ANG II increases it. In conclusion, we have developed the first model of uric acid transport in the rat PT; this model provides a framework to gain greater insight into the numerous solutes and coupling mechanisms that affect the renal handing of uric acid.

Micropuncture study of uric acid transport in rat kidney

1975 ◽  
Vol 228 (5) ◽  
pp. 1597-1605 ◽  
Author(s):  
RG Abramson ◽  
MF Levitt
Keyword(s):  
Uric Acid ◽  
Proximal Tubule ◽  
Rat Kidney ◽  
Chromatographic Technique ◽  
Acid Transport ◽  
Cent Sodium ◽  
Micropuncture Study ◽  
Nephron Segment ◽  
Fluid Collections ◽  
Column Chromatographic

Free-flow micropuncture studies were perfromed to evaluated uric acid transport in the rat kidney. In all studies (a-minus 14C) uric acid and (methoxy-3H) inulin wereadministered. A simple two-step, column-chromatographic technique was utilized to separate (2-minus 14C) uric acid from its labeled oxidation product in plasma, urine, and tubular fluid. Tubular fluid collections were obtained from the early-and late-proximal tubule under control conditions and during subsequent volume expansion induced with 0.9 per-cent sodium chloride. These studies indicate bidirectional, possible active, uric acidtransport in the proximal tubule undr control conditions, with net reabsorption evident early and net decretion apparent late in this nephron segment. In association with volumeexpansion net uric acid reabsorption and secretion both decreased. No significant nettransport was evident beyond the accessible portion of the late-proximal tubule in either experimental state.

Use of pyrazinamide to assess renal uric acid transport in the rat: a micropuncture study

1976 ◽  
Vol 230 (5) ◽  
pp. 1276-1283 ◽  
Author(s):  
RG Abramson ◽  
MF Levitt
Keyword(s):  
Uric Acid ◽  
Proximal Tubule ◽  
Volume Expansion ◽  
Acid Transport ◽  
Sodium Dependent ◽  
Micropuncture Study ◽  
Bidirectional Transport ◽  
Fluid Collections ◽  
Uniform Reduction ◽  
Column Chromatographic

Free-flow micropuncture studies were performed to evaluate renal uric acid transport in control and pyrazinamide-treated rats. In all studies [2-14C]uric acid and [methoxy-3H]inulin were administered. [2-14C]uric acid was determined after column chromatographic separation from its labeled oxidation product in tubular fluid, plasma, and urine. Tubular fluid collections were obtained from the early and late proximal tubule under hydropenic conditions and from the early proximal tubule during volume expansion induced with 0.9% sodium chloride. These studies indicate that pyrazinamide, in the dose employed, provokes a uniform reduction in fractional uric acid excretion but simultaneously inhibits both net uric acid reabsorption and secretion in the early and late proximal tubule, respectively. In addition, these experiments unmasked uric acid reabsorption within the late proximal tubule and bidirectional transport beyond this nephron site. These studies also suggest at least two mechanisms for uric acid reabsorption; one sodium dependent, the other independent of sodium and water transport.

scholarly journals Functional role of sodium glucose transporter in high glucose-mediated angiotensin type 1 receptor downregulation in human proximal tubule cells

2012 ◽  
Vol 303 (5) ◽  
pp. F766-F774 ◽  
Author(s):  
Rekha Yesudas ◽  
Russell Snyder ◽  
Thomas Abbruscato ◽  
Thomas Thekkumkara
Keyword(s):  
Proximal Tubule ◽  
Glucose Uptake ◽  
High Glucose ◽  
Glucose Transporter ◽  
Glucose Transporters ◽  
Ang Ii ◽  
Angiotensin Type ◽  
Human Proximal Tubule

Previously, we have demonstrated human angiotensin type 1 receptor (hAT1R) promoter architecture with regard to the effect of high glucose (25 mM)-mediated transcriptional repression in human proximal tubule epithelial cells (hPTEC; Thomas BE, Thekkumkara TJ. Mol Biol Cell 15: 4347–4355, 2004). In the present study, we investigated the role of glucose transporters in high glucose-mediated hAT1R repression in primary hPTEC. Cells were exposed to normal glucose (5.5 mM) and high glucose (25 mM), followed by determination of hyperglycemia-mediated changes in receptor expression and glucose transporter activity. Exposure of cells to high glucose resulted in downregulation of ANG II binding (4,034 ± 163.3 to 1,360 ± 154.3 dpm/mg protein) and hAT1R mRNA expression (reduced 60.6 ± 4.643%) at 48 h. Under similar conditions, we observed a significant increase in glucose uptake (influx) in cells exposed to hyperglycemia. Our data indicated that the magnitude of glucose influx is concentration and time dependent. In euglycemic cells, inhibiting sodium-glucose cotransporters (SGLTs) with phlorizin and facilitative glucose transporters (GLUTs) with phloretin decreased glucose influx by 28.57 ± 0.9123 and 54.33 ± 1.202%, respectively. However, inhibiting SGLTs in cells under hyperglycemic conditions decreased glucose influx by 53.67 ± 2.906%, while GLUT-mediated glucose uptake remained unaltered (57.67 ± 3.180%). Furthermore, pretreating cells with an SGLT inhibitor reversed high glucose-mediated downregulation of the hAT1R, suggesting an involvement of SGLT in high glucose-mediated hAT1R repression. Our results suggest that in hPTEC, hyperglycemia-induced hAT1R downregulation is largely mediated through SGLT-dependent glucose influx. As ANG II is an important modulator of hPTEC transcellular sodium reabsorption and function, glucose-mediated changes in hAT1R gene expression may participate in the pathogenesis of diabetic renal disease.

Expression of mRNA (D2) encoding a protein involved in amino acid transport in S3 proximal tubule

1992 ◽  
Vol 263 (6) ◽  
pp. F1087-F1092 ◽  
Author(s):  
Y. Kanai ◽  
M. G. Stelzner ◽  
W. S. Lee ◽  
R. G. Wells ◽  
D. Brown ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Proximal Tubule ◽  
Amino Acid Transport ◽  
Glucose Transporter ◽  
Rat Kidney ◽  
Expression Cloning ◽  
Acid Transport ◽  
Specific Expression ◽  
High Affinity

A rat kidney- and intestine-specific cDNA (D2) that induces high-affinity, Na(+)-independent uptake of cystine and dibasic and neutral amino acids into cRNA-injected Xenopus oocytes was recently isolated by expression cloning in our laboratory (R. G. Wells and M. A. Hediger. Proc. Natl. Acad. Sci. USA 89: 5596-5600, 1992). At present it is not known whether the D2-encoded protein functions as a transporter or as a transporter activator. To gain more insight into the role of D2 in renal amino acid transport, we studied the site of its expression in the kidney. This was determined by Northern blot analysis and by using a combination of in situ hybridization and immunocytochemistry with antibodies that recognize specific proximal tubule segments. D2 antisense RNA hybridized to the same tubular segments that were strongly positive for anti-ecto-adenosinetriphosphatase but negative for carbonic anhydrase type IV and the facilitated glucose transporter GLUT2. We conclude that D2 mRNA is strongly expressed in the rat kidney proximal tubule S3 segment, although there is weak hybridization to the S1 and S2 segments. The signal is absent in all other parts of the kidney. The S3 specific expression of D2 mRNA coincides with the site of high-affinity transport of cystine and other amino acids, consistent with the proposed involvement of D2 in these processes.

Influence of inorganic electrolytes and ouabain on uric acid transport

1965 ◽  
Vol 208 (4) ◽  
pp. 642-648 ◽  
Author(s):  
W. O. Berndt ◽  
E. C. Beechwood
Keyword(s):  
Uric Acid ◽  
Organic Acids ◽  
Potassium Concentration ◽  
Flow Analysis ◽  
Rabbit Kidney ◽  
Kidney Cortex ◽  
Acid Transport ◽  
Acid Accumulation ◽  
Stop Flow ◽  
Urate Reabsorption

The importance of certain inorganic electrolytes in the transport of some organic acids by the kidney has been demonstrated. The present study was undertaken to evaluate further the transport characteristics for uric acid. Slices of rabbit kidney cortex were found to accumulate urate with a dependency on the medium potassium concentration. At 5 mm potassium the urate uptake was about 50% of maximum, with optimal accumulation above 10–40 mm potassium. Rubidium or cesium were found to substitute successfully for potassium; both substances permitted better uric acid accumulation than did potassium. Removal of sodium from the medium to concentrations as low as 65 mm did not influence urate uptake. At 15 mm sodium the urate accumulation was markedly depressed. Ouabain was found to depress urate uptake. The inhibition produced by this substance could be reversed by elevation of the medium potassium. Stop-flow analysis on the rabbit indicated that ouabain increased the proximal secretory peak for uric acid. On the basis of experiments where ouabain and probenecid were administered together, it was possible to attribute the action of ouabain to blockade of urate reabsorption.

Placental uric acid transport system and its impact on fetal development

2018 ◽  
Author(s):  
B Lüscher ◽  
D Surbek ◽  
P Schneider ◽  
M Baumann
Keyword(s):  
Uric Acid ◽  
Transport System ◽  
Fetal Development ◽  
Acid Transport

scholarly journals Angiotensin II stimulates trafficking of NHE3, NaPi2, and associated proteins into the proximal tubule microvilli

2010 ◽  
Vol 298 (1) ◽  
pp. F177-F186 ◽  
Author(s):  
Anne D. M. Riquier-Brison ◽  
Patrick K. K. Leong ◽  
Kaarina Pihakaski-Maunsbach ◽  
Alicia A. McDonough
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Flow Rate ◽  
Enzyme Inhibitor ◽  
Volume Flow Rate ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Water Reabsorption ◽  
Associated Proteins ◽  
Gradient Fractionation

Angiotensin II (ANG II) stimulates proximal tubule (PT) sodium and water reabsorption. We showed that treating rats acutely with the angiotensin-converting enzyme inhibitor captopril decreases PT salt and water reabsorption and provokes rapid redistribution of the Na+/H+ exchanger isoform 3 (NHE3), Na+/Pi cotransporter 2 (NaPi2), and associated proteins out of the microvilli. The aim of the present study was to determine whether acute ANG II infusion increases the abundance of PT NHE3, NaPi2, and associated proteins in the microvilli available for reabsorbing NaCl. Male Sprague-Dawley rats were infused with a dose of captopril (12 μg/min for 20 min) that increased PT flow rate ∼20% with no change in blood pressure (BP) or glomerular filtration rate (GFR). When ANG II (20 ng·kg−1·min−1 for 20 min) was added to the captopril infusate, PT volume flow rate returned to baseline without changing BP or GFR. After captopril, NHE3 was localized to the base of the microvilli and NaPi2 to subapical cytoplasmic vesicles; after 20 min ANG II, both NHE3 and NaPi2 redistributed into the microvilli, assayed by confocal microscopy and density gradient fractionation. Additional PT proteins that redistributed into low-density microvilli-enriched membranes in response to ANG II included myosin VI, DPPIV, NHERF-1, ezrin, megalin, vacuolar H+-ATPase, aminopeptidase N, and clathrin. In summary, in response to 20 min ANG II in the absence of a change in BP or GFR, multiple proteins traffic into the PT brush-border microvilli where they likely contribute to the rapid increase in PT salt and water reabsorption.

scholarly journals Serum uric acid, disease severity and outcomes in COVID-19

Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Inès Dufour ◽  
Alexis Werion ◽  
Leila Belkhir ◽  
Anastazja Wisniewska ◽  
Marie Perrot ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Uric Acid ◽  
Respiratory Failure ◽  
Confidence Interval ◽  
Proximal Tubule ◽  
Disease Severity ◽  
Serum Levels ◽  
Kidney Proximal Tubule ◽  
Urate Transporter ◽  
Low Serum

Abstract Background The severity of coronavirus disease 2019 (COVID-19) is highly variable between individuals, ranging from asymptomatic infection to critical disease with acute respiratory distress syndrome requiring mechanical ventilation. Such variability stresses the need for novel biomarkers associated with disease outcome. As SARS-CoV-2 infection causes a kidney proximal tubule dysfunction with urinary loss of uric acid, we hypothesized that low serum levels of uric acid (hypouricemia) may be associated with severity and outcome of COVID-19. Methods In a retrospective study using two independent cohorts, we investigated and validated the prevalence, kinetics and clinical correlates of hypouricemia among patients hospitalized with COVID-19 to a large academic hospital in Brussels, Belgium. Survival analyses using Cox regression and a competing risk approach assessed the time to mechanical ventilation and/or death. Confocal microscopy assessed the expression of urate transporter URAT1 in kidney proximal tubule cells from patients who died from COVID-19. Results The discovery and validation cohorts included 192 and 325 patients hospitalized with COVID-19, respectively. Out of the 517 patients, 274 (53%) had severe and 92 (18%) critical COVID-19. In both cohorts, the prevalence of hypouricemia increased from 6% upon admission to 20% within the first days of hospitalization for COVID-19, contrasting with a very rare occurrence (< 1%) before hospitalization for COVID-19. During a median (interquartile range) follow-up of 148 days (50–168), 61 (12%) patients required mechanical ventilation and 93 (18%) died. In both cohorts considered separately and in pooled analyses, low serum levels of uric acid were strongly associated with disease severity (linear trend, P < 0.001) and with progression to death and respiratory failure requiring mechanical ventilation in Cox (adjusted hazard ratio 5.3, 95% confidence interval 3.6–7.8, P < 0.001) or competing risks (adjusted hazard ratio 20.8, 95% confidence interval 10.4–41.4, P < 0.001) models. At the structural level, kidneys from patients with COVID-19 showed a major reduction in urate transporter URAT1 expression in the brush border of proximal tubules. Conclusions Among patients with COVID-19 requiring hospitalization, low serum levels of uric acid are common and associate with disease severity and with progression to respiratory failure requiring invasive mechanical ventilation.

Sign in / Sign up

Export Citation Format

Share Document