Effect of Experimental Fanconi Syndrome on Tubular Reabsorption of Lithium in Rats

Pharmacology ◽  
2021 ◽  
pp. 1-5
Author(s):  
Yuichi Uwai ◽  
Tomohiro Nabekura
Keyword(s):  
Proximal Tubule ◽  
Lithium Chloride ◽  
Maleic Acid ◽  
Fanconi Syndrome ◽  
Collecting Duct ◽  
Bipolar Disorders ◽  
Fractional Excretion ◽  
Tubular Reabsorption ◽  
Pharmacokinetic Parameters ◽  
Renal Handling

Lithium, administered to patients of bipolar disorders, is mainly excreted into urine, and tubular reabsorption at the proximal tubule is involved in the renal handling of lithium. In this study, we examined the renal excretion of lithium in rats with Fanconi syndrome, characterized by defects of transports of various compounds at the proximal tubules, induced by maleic acid. After maleic acid was intravenously injected, mannitol and lithium chloride were infused in turn. Using samples of plasma and bladder urine during the mannitol infusion, renal parameters were determined. Pharmacokinetic parameters of lithium were obtained using samples during the lithium chloride infusion. Maleic acid decreased creatinine clearance and increased the fractional excretion of glucose and phosphate, suggesting the induction of Fanconi syndrome. In rats with Fanconi syndrome, plasma concentration of lithium was increased, and its renal clearance was decreased. No effect on the fractional excretion of lithium was exhibited. This study represents that the tubular reabsorption of lithium was impaired to the same degree with glomerular filtration in rats with experimental Fanconi syndrome and that the dysfunction of the tubular reabsorption of glucose and phosphate was more severe. It is possible that Fanconi syndrome inhibited the reabsorption of lithium at the proximal tubule and facilitated the reabsorption of lithium from the loop of Henle to the collecting duct.

scholarly journals Potent inhibition of biphasic tubular reabsorption of lithium by acetazolamide and foscarnet in rats

2020 ◽  
pp. 645-651
Author(s):  
Y Uwai ◽  
R Kondo ◽  
T Suzuki ◽  
T Kawasaki ◽  
T Nabekura
Keyword(s):  
Urinary Excretion ◽  
Proximal Tubule ◽  
Lithium Chloride ◽  
Renal Excretion ◽  
Large Fraction ◽  
Fractional Excretion ◽  
Tubular Reabsorption ◽  
High Affinity ◽  
Maximum Value ◽  
Potent Inhibition

Lithium is mainly excreted into urine, and a large fraction of lithium filtered through glomeruli is reabsorbed in the proximal tubule. However, the mechanisms responsible for lithium reabsorption remain unclear. We previously reported that the reabsorption of lithium was biphasic in rats, and that foscarnet inhibited lithium reabsorption with a high affinity type. We herein evaluated the effects of acetazolamide and foscarnet on the renal excretion of lithium in rats treated with lithium chloride at 2 doses. In rats intravenously injected with a bolus of 25 mg/kg lithium chloride, acetazolamide facilitated the urinary excretion of lithium, and increased the fractional excretion of lithium from 0.446 to 0.953, near the theoretically maximum value. At a dose of 2.5 mg/kg lithium chloride, the fractional excretion of lithium was 0.241 in control rats, 0.420 in rats administered acetazolamide, and 0.976 in rats administered acetazolamide and foscarnet. These results showed the potent inhibition of lithium reabsorption by acetazolamide and foscarnet in rats. And, it was exhibited that the effects of acetazolamide on lithium reabsorption differed with the dosages of lithium administered.

Juxtamedullary nephrons during acute metabolic alkalosis in the rat

1985 ◽  
Vol 249 (1) ◽  
pp. F107-F116
Author(s):  
J. P. Frommer ◽  
D. E. Wesson ◽  
M. E. Laski ◽  
N. A. Kurtzman
Keyword(s):  
Metabolic Alkalosis ◽  
Collecting Duct ◽  
Distal Tubule ◽  
Fractional Excretion ◽  
Group Iv ◽  
Renal Handling ◽  
Group Iii ◽  
Contralateral Kidney ◽  
Group I ◽  
Papillary Collecting Duct

The renal handling of bicarbonate during acute metabolic alkalosis was examined in Munich-Wistar rats using micropuncture techniques. Group I received an acute bicarbonate load, and fractional delivery of total CO2 (tCO2) (FDtCO2) to the superficial late distal tubule (LD) was significantly lower than to the base of the papillary collecting duct (B) (18.4 +/- 1.7 vs. 22.9 +/- 1.5%; P less than 0.01), indicating net addition of bicarbonate between LD and B. When acutely bicarbonate-loaded rats had their deep nephrons destroyed with bromoethylamine hydrobromide (BEA) (group II), net addition of tCO2 between LD and B was abolished and net reabsorption uncovered (FDtCO2 LD: 28.0 +/- 3.6 vs. B: 17.5 +/- 2.5%; P less than 0.01). The infusion of amiloride (2.5 mg/kg body wt) to alkalotic rats treated with BEA (group III) completely inhibited distal bicarbonate reabsorption but did not reestablish addition (FDtCO2 LD: 27.6 +/- 1.6 vs. B: 26.1 +/- 3.7%; P = NS). The values obtained for sham-operated animals (group IV) were the same for group I. The patterns that were observed between LD and B were reproduced for the four groups of animals when FDtCO2 LD was compared with the fractional excretion of bicarbonate in the urine of the intact contralateral kidney. These studies suggest that juxtamedullary nephrons contribute a higher load of bicarbonate than superficial nephrons to the final urine during acute metabolic alkalosis in the rat.

Renal concentrating defect in mice lacking group IV cytosolic phospholipase A2

2001 ◽  
Vol 280 (4) ◽  
pp. F607-F618 ◽  
Author(s):  
Patricio Downey ◽  
Adam Sapirstein ◽  
Eileen O'Leary ◽  
Tian-Xiao Sun ◽  
Dennis Brown ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Collecting Duct ◽  
Plasma Osmolality ◽  
Fractional Excretion ◽  
Group Iv ◽  
Urinary Concentration ◽  
Prostaglandin E ◽  
Age Related ◽  
Aqp1 Expression ◽  
Concentrating Defect

Eicosanoids regulate various cellular functions that are important in physiological and pathophysiological processes. Arachidonic acid is released from membranes by phospholipase A2 (PLA2) activity. Activated macrophages derived from mice lacking the 85-kDa group IV cytosolic PLA2 (cPLA2) have a markedly reduced release of prostaglandin E2 and leukotrienes B4and C4. Under basal conditions and after furosemide, urinary prostaglandin E2 excretion is reduced in cPLA2-knockout (cPLA2 −/−) mice. Serum creatinine, Na+, K+, and Ca2+concentrations, glomerular filtration rate, and fractional excretion of Na+ and K+ are not different in cPLA2 −/− and cPLA2 +/+mice. Maximal urinary concentration is lower in 48-h water-deprived cPLA2 −/− mice compared with cPLA2 +/+ animals (1,934 ± 324 vs. 3,541 ± 251 mmol/kgH2O). Plasma osmolality is higher (337 ± 5 vs. 319 ± 3 mmol/kgH2O) in cPLA2 −/− mice that lose a greater percentage of their body weight (20 ± 2 vs. 13 ± 1%) compared with cPLA2 +/+ mice after water deprivation. Vasopressin does not correct the concentrating defect. There is progressive reduction in urinary osmolality with age in cPLA2 −/− mice. Membrane-associated aquaporin-1 (AQP1) expression, identified by immunocytochemical techniques, is reduced markedly in proximal tubules of older cPLA2 −/− animals but is normal in thin descending limbs. However, Western blot analysis of kidney cortical samples revealed an equivalent AQP1 signal intensity in cPLA2 +/+ and cPLA2 −/−animals. Young cPLA2 −/− mice have normal proximal tubule AQP1 staining. Collecting duct AQP2, -3, and -4 were normally expressed in the cPLA2 −/− mice. Thus mice lacking cPLA2 develop an age-related defect in renal concentration that may be related to abnormal trafficking and/or folding of AQP1 in the proximal tubule, implicating cPLA2in these processes.

Renal sodium handling in patients with normal pressure glaucoma

2007 ◽  
Vol 112 (6) ◽  
pp. 337-344 ◽  
Author(s):  
Antoinette Pechere-Bertschi ◽  
Gordana Sunaric-Megevand ◽  
Ivan Haefliger ◽  
Francesca Panarello ◽  
Marc Maillard ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Fractional Excretion ◽  
Normal Pressure ◽  
Sodium Reabsorption ◽  
Orthostatic Test ◽  
Renal Handling ◽  
Normal Pressure Glaucoma ◽  
Renal Sodium Handling ◽  
Orthostatic Symptoms ◽  
Sodium Handling

Low BP (blood pressure) is a recognized risk factor for some patients with NPG (normal pressure glaucoma). We have shown previously that patients with orthostasis have impaired circadian renal handling of sodium, which may contribute to the low BP. Therefore the aim of the present study was to examine the renal handling of sodium, the circadian variations in BP and the neurohormonal response to an orthostatic test in a selected subpopulation of 18 patients with NPG with vasospastic and orthostatic symptoms, and in 24 healthy control subjects. The variations in BP and renal tubular sodium handling were evaluated using 24 h ambulatory BP recordings, 24 h urine collections and determination of endogenous lithium clearance as a marker of proximal sodium reabsorption. The neurohormonal and BP responses to changes in posture were also determined in a 30 min orthostatic test. This selected group of patients with NPG had lower 24 h ambulatory BPs (P<0.001), and a more pronounced fall in BP when assuming an upright position (P<0.001) compared with controls. FELi (fractional excretion of lithium) was higher in patients with NPG than controls during the day (36.6±21.8 compared with 20.4±8.7% respectively; P<0.01; values are means±S.D.) as well as during the night (38.8±41.9 compared with 19.7±10.8% respectively; P<0.02), suggesting a reduced reabsorption of sodium in the proximal tubule. This was compensated for by an increased distal reabsorption of sodium in patients with NPG (P<0.01). These data demonstrate that patients with vasospastic NPG have a high excretion of lithium, suggesting reduced sodium reabsorption in the proximal tubule, in spite of a low BP. The abnormal renal sodium handling might contribute to the maintenance of arterial hypotension and progression of the optic nerve damage in these patients.

Antiphosphaturic action of 25 (OH) vitamin D3 in experimental Fanconi syndrome.

1979 ◽  
Vol 236 (2) ◽  
pp. E90
Author(s):  
M M Popovtzer ◽  
S K Mehandru ◽  
D Saghafi ◽  
M S Blum
Keyword(s):  
Parathyroid Hormone ◽  
Urinary Excretion ◽  
Vitamin D3 ◽  
Volume Expansion ◽  
Fanconi Syndrome ◽  
Extracellular Volume ◽  
Fractional Excretion ◽  
Renal Handling ◽  
Phosphate Depletion ◽  
Extracellular Volume Expansion

Renal handling of phosphorus was studied in the following groups of parathyroidectomized rats with maleate-induced Fanconi syndrome: 1) 6 rats receiving intravenous parathyroid hormone, 2) 6 rats receiving intravenous dibutyryl cyclic AMP (DBcAMP), 3) 6 rats undergoing volume expansion with saline, 4) 12 rats receiving intravenous 25 (OH)vitamin D3, 5) 12 rats with acute hypercalcemia induced by intravenous CaCl2, 6) 6 rats with phosphate deprivation, and 7) 6 rats receiving intravenous calcitonin. Parathyroid hormone and calcitonin failed to increase the urinary excretion of both cAMP and phosphorus. Likewise, DBcAMP failed to increase the urinary excretion of phosphorus. Extracellular volume expansion and hypercalcemia (serum calcium 12.9 +/- 0.7 mg/100 ml) did not alter the tubular reabsorption of phosphorus. In phosphate-deprived animals, the fractional excretion 0.16 +/- 0.05 (mean +/- SE) was lower than that in the control animals (maleate-treated without phosphate depletion), 0.46 +/- 0.04 (P less than 0.001). 25 (OH)vitamin D3 decreased the fractional excretion of phosphorus from 0.39 +/- 0.03 in the control (maleate-treated not receiving 25 (OH)vitamin D3) to 0.23 +/- 0.02 (P less than 0.001) in the experimental animals. The present study demonstrated an antiphosphaturic effect of 25(OH)vitamin D3 in experimental Fanconi syndrome; the mechanism of this action is not well understood.

Renal Handling of Beta2-Microglobulin in Patients with Cystic Fibrosis

DICP ◽  
1989 ◽  
Vol 23 (12) ◽  
pp. 1013-1017 ◽  
Author(s):  
Gregory L. Kearns ◽  
Phillip L. Berry ◽  
Joseph A. Bocchini ◽  
Bettina C. Hilman ◽  
John T. Wilson
Keyword(s):  
Cystic Fibrosis ◽  
Creatinine Clearance ◽  
Fractional Excretion ◽  
Tubular Reabsorption ◽  
Hospitalized Patients ◽  
Normal Children ◽  
Renal Handling ◽  
Renal Tubular Reabsorption ◽  
Proximal Tubular ◽  
Renal Tubular

We evaluated the renal handling of beta2-microglobulin (β2-M) and creatinine in healthy outpatients (n = 6), normal children hospitalized for infections treated with antibiotics (not including an aminoglycoside) (n = 4); outpatients with cystic fibrosis (CF; n = 12), and hospitalized patients with CF (n = 6) who received a 10- to 14-day course of antibiotic treatment that included an aminoglycoside. The serum β2-M concentrations in the normal outpatients (2020.1 ± 276.6 μg/L) were significantly lower (p <0.05) than those observed for outpatients (2833.3 ± 202.6 μg/L) or patients with CF (2861.8 ± 340.5 μg/L. There were no significant differences found for creatinine clearance or fractional excretion of β2-M when subjects without CF were compared with those with the disease. Furthermore, no significant differences were observed in hospitalized patients with CF when creatinine clearance and fractional excretion of β2-M were compared between the initiation and conclusion of aminoglycoside treatment. Glomerular filtration and proximal tubular reabsorption of β2-M were not altered in patients with CF. These findings do not support a global defect in proximal renal tubular reabsorption as the underlying cause for altered aminoglycoside clearance in patients with CF.

Tubular reabsorption of α-aminoisobutyric acid in the pre-steady-state. Evidence for a cell-to-lumen flux

1980 ◽  
Vol 58 (5) ◽  
pp. 557-563 ◽  
Author(s):  
Roderick R. McInnes ◽  
Fazl Mohyuddin ◽  
Charles R. Scriver
Keyword(s):  
Steady State ◽  
Fractional Excretion ◽  
Renal Tissue ◽  
Tubular Reabsorption ◽  
Time Dependent ◽  
Renal Handling ◽  
Aminoisobutyric Acid ◽  
A Cell ◽  
Venous Infusion ◽  
Sufficient Magnitude

We investigated time-dependent and concentration-dependent renal handling of α-aminoisobutyric acid (AIB) in the rat during seven consecutive 30-min clearance periods after onset of AIB infusion. Following low-level rapid venous infusion of AIB (9.75 μmol/kg in 30 s), plasma [AIB] fell exponentially in the initial three periods and in linear fashion (−0.00158 μM/min) thereafter. Although filtered AIB fell in proportion to plasma [AIB] during the early clearance periods (5–125 min), fractional excretion of AIB (FEAIB) rose (Δ FEAIB = +0.077 ± 0.010, mean ± SD) and stabilized only in later clearance periods (125–215 min). Saturable intrarenal binding does not explain rising FEAIB with falling plasma [AIB] because sequential infusions of AIB, 120 min apart, also elicited the phenomenon after each infusion. During continuous infusions of AIB, time dependence of FEAIB was also observed, in the early interval (5–95 min), after onset of AIB infusion at various concentrations of plasma [AIB] below 3 mM approximately. Measurement of concentration-dependent net tubular reabsorption of AIB in the fourth through seventh clearance periods (near the steady state) revealed progressive saturation over the whole range of plasma [AIB] (0–12 mM), yet with a collapse of net reabsorption in the plasma [AIB] range 2–4 mM. Measurements of renal tissue AIB in these experiments revealed that cellular AIB is of sufficient magnitude and bears such a relationship to plasma AIB and FEAIB that it could contribute to an observable cell-to-lumen movement of amino acid in the "pre-steady-state" situation and could account for the rise in FEAIB following AIB infusion and the collapse in tubular reabsorption of AIB at 2–4 mM plasma [AIB].

scholarly journals Analysis of sex difference in the tubular reabsorption of lithium in rats

2021 ◽  
Vol 70 (4) ◽  
pp. 655-659
Author(s):  
Yuichi Uwai ◽  
Riku Yamaguchi ◽  
Tomohiro Nabekura
Keyword(s):  
Sex Differences ◽  
Lithium Chloride ◽  
Tubular Reabsorption ◽  
Female Rats ◽  
Pharmacokinetic Parameters ◽  
Phosphate Transporters ◽  
High Affinity ◽  
Male And Female Rats ◽  
Sodium Dependent ◽  
Low Rate

Lithium is used in the treatment of bipolar disorder. We previously demonstrated that two types of transporters mediate the tubular reabsorption of lithium in rats, and suggested that sodium-dependent phosphate transporters play a role in lithium reabsorption with high affinity. In the present study, we examined sex differences in lithium reabsorption in rats. When lithium chloride was infused at 60 µg/min, creatinine clearance and the renal clearance of lithium were lower, and the plasma concentration of lithium was higher in female rats. These values reflected the higher fractional reabsorption of lithium in female rats. In rats infused with lithium chloride at 6 µg/min, the pharmacokinetic parameters of lithium examined were all similar in both sexes. The fractional reabsorption of lithium was decreased by foscarnet, a representative inhibitor of sodium-dependent phosphate transporters, in male and female rats when lithium chloride was infused at the low rate. Among the candidate transporters mediating lithium reabsorption examined herein, the mRNA expression of only PiT2, a sodium-dependent phosphate transporter, exhibited sexual dimorphism. The present results demonstrated sex differences in the tubular reabsorption of lithium with low affinity in rats.

Dysfunction of the proximal tubule underlies maleic acid-induced type II renal tubular acidosis

1982 ◽  
Vol 243 (6) ◽  
pp. F604-F611 ◽  
Author(s):  
H. A. Al-Bander ◽  
R. A. Weiss ◽  
M. H. Humphreys ◽  
R. C. Morris
Keyword(s):  
Proximal Tubule ◽  
Renal Tubular Acidosis ◽  
Maleic Acid ◽  
Free Water ◽  
Fractional Excretion ◽  
Thick Ascending Limb ◽  
Type Ii ◽  
Free Water Clearance ◽  
Plasma Bicarbonate ◽  
Renal Tubular

To investigate whether dysfunction of the proximal tubule underlies maleic acid-(MA) induced type II (“proximal”) renal tubular acidosis (RTA II), we intravenously administered either MA or acetazolamide to eight conscious trained dogs undergoing water diuresis and examined the relationship between fractional solute-free water clearance (Ch2o/GFR), a measure of NaCl reabsorption in the post-proximal nephron, and either fractional urine flow (V/GFR), a measure of total solute rejected by the proximal tubule, or the sum of fractional excretion of Cl- and Ch2o/GFR [(Ccl + Ch2o)/GFR], a measure of proximally rejected solute that is potentially reabsorbable by the thick ascending limb. When MA or acetazolamide induced brisk bicarbonaturia at normal plasma bicarbonate concentrations: 1) V/GFR, (Ccl + Ch20)GFR, and Ch2o/GFR increased strikingly; 2) at any increment of Ch2o/GFR ws not; 3) the increments of V/GFR correlated positively with those of fractional excretion of bicarbonate (P less than 0.001); 4) during hyperchloremic acidosis, MA-induced bicarbonaturia was greatly attenuated; the increment in V/GFR was halved and approximated that in Ch20/GFR, which was unchanged; 5) when plasma bicarbonate was abruptly increased, bicarbonaturia increased strikingly and V/GFR increased further but Ch20/GFR and aminoaciduria did not. We conclude that MA induces a reduction in the net rate at which the proximal tubule reabsorbs HCO-3, Na+, and Cl-. This dysfunction underlies RTA II and evokes greatly increased reabsorption of Cl- and Na+ in the post-proximal tubule.

Microperfusion study of proximal tubule bicarbonate transport in maleic acid-induced renal tubular acidosis

1986 ◽  
Vol 250 (3) ◽  
pp. F476-F482
Author(s):  
N. Bank ◽  
H. S. Aynedjian ◽  
B. F. Mutz
Keyword(s):  
Proximal Tubule ◽  
Renal Tubular Acidosis ◽  
Maleic Acid ◽  
Basolateral Membrane ◽  
Bicarbonate Transport ◽  
Mitochondrial Energy Metabolism ◽  
Before And After ◽  
Renal Tubular ◽  
Blood Transport ◽  
Acid Administration

Microperfusion studies were carried out in rats to examine the abnormality in proximal tubule HCO3- transport caused by maleic acid administration. Permeability of the proximal tubule to HCO-3 was measured by perfusing proximal tubules with a HCO3- -free low-buffer isotonic equilibrium solution containing acetazolamide after plasma [HCO3-] had been raised by intravenous NaHCO3 infusion. Insulin recovery in the collected perfusate was approximately 100% in control and maleic acid-treated rats. CO2 influx measured by microcalorimetry was not significantly different in control vs. maleic acid-treated rats. Thus maleic acid did not cause increased permeability of the proximal tubule to either inulin or HCO3-. In a second group of experiments, proximal tubule fluid and HCO3- efflux were measured in paired-reperfusion experiments before and after maleic acid administration. The perfusion fluid contained 25 mM HCO3- and 120 mM Cl-. HCO3- absorption was inhibited 25% (79 pmol/min), Na+ was inhibited 22% (164 pmol/min), and Cl- absorption (calculated as the anion gap) by 85 pmol/min. [HCO3-] in the collected perfusate rose significantly after maleic acid, presumably accompanied by a fall in [Cl-]. The observations indicate that proximal renal tubular acidosis (RTA) induced by maleic acid is characterized by impaired lumen-to-blood transport of sodium bicarbonate and chloride but not by increased backflux. Based on previously demonstrated effects of maleic acid on mitochondrial energy metabolism and cellular ATP levels, we postulate that the principal transport abnormality is impaired basolateral membrane active sodium transport, leading to a secondary reduction in brush border Na+-H+ exchange.(ABSTRACT TRUNCATED AT 250 WORDS)

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