scholarly journals Claudin-12 Knockout Mice Demonstrate Reduced Proximal Tubule Calcium Permeability

2020 ◽  
Vol 21 (6) ◽  
pp. 2074
Author(s):  
Allein Plain ◽  
Wanling Pan ◽  
Deborah O’Neill ◽  
Megan Ure ◽  
Megan R. Beggs ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Ex Vivo ◽  
Protein S ◽  
Urinary Calcium ◽  
Calcium Excretion ◽  
Thick Ascending Limb ◽  
Calcium Reabsorption ◽  
Calcium Permeability ◽  
Claudin 14 ◽  
Junction Proteins

The renal proximal tubule (PT) is responsible for the reabsorption of approximately 65% of filtered calcium, primarily via a paracellular pathway. However, which protein(s) contribute this paracellular calcium pore is not known. The claudin family of tight junction proteins confers permeability properties to an epithelium. Claudin-12 is expressed in the kidney and when overexpressed in cell culture contributes paracellular calcium permeability (PCa). We therefore examined claudin-12 renal localization and its contribution to tubular paracellular calcium permeability. Claudin-12 null mice (KO) were generated by replacing the single coding exon with β-galactosidase from Escherichia coli. X-gal staining revealed that claudin-12 promoter activity colocalized with aquaporin-1, consistent with the expression in the PT. PTs were microperfused ex vivo and PCa was measured. PCa in PTs from KO mice was significantly reduced compared with WT mice. However, urinary calcium excretion was not different between genotypes, including those on different calcium containing diets. To assess downstream compensation, we examined renal mRNA expression. Claudin-14 expression, a blocker of PCa in the thick ascending limb (TAL), was reduced in the kidney of KO animals. Thus, claudin-12 is expressed in the PT, where it confers paracellular calcium permeability. In the absence of claudin-12, reduced claudin-14 expression in the TAL may compensate for reduced PT calcium reabsorption.

scholarly journals Primary Hyperparathyroidism in Homozygous Sickle Cell Patients: A Hemolysis-Mediated Hypocalciuric Hypercalcemia Phenotype?

2021 ◽  
Vol 10 (21) ◽  
pp. 5179
Author(s):  
Edmat Akhtar Khan ◽  
Lynda Cheddani ◽  
Camille Saint-Jacques ◽  
Rosa Vargas-Poussou ◽  
Vincent Frochot ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
Sickle Cell ◽  
Fractional Excretion ◽  
Urinary Calcium ◽  
High Rate ◽  
Calcium Handling ◽  
Control Group ◽  
Calcium Excretion ◽  
Calcium Reabsorption ◽  
Chronic Hemolysis

Primary hyperparathyroidism (pHPT) has been reported to have a higher prevalence in sickle cell disease (SCD) patients, including a high rate of recurrence following surgery. However, most patients are asymptomatic at the time of diagnosis, with surprisingly infrequent hypercalciuria, raising the issue of renal calcium handling in SCD patients. We conducted a retrospective study including (1) 64 hypercalcemic pHPT non-SCD patients; (2) 177 SCD patients, divided into two groups of 12 hypercalcemic pHPT and 165 non-pHPT; (3) eight patients with a diagnosis of familial hypocalciuric hypercalcemia (FHH). Demographic and biological parameters at the time of diagnosis were collected and compared between the different groups. Determinants of fasting fractional excretion of calcium (FeCa2+) were also analyzed in non-pHPT SCD patients. Compared to non-SCD pHPT patients, our data show a similar ionized calcium and PTH concentration, with a lower plasmatic calcitriol concentration and a lower daily urinary calcium excretion in pHPT SCD patients (p < 0.0001 in both cases). Fasting FeCa2+ is also surprisingly low in pHPT SCD patients, and thus inadequate to be considered hypercalcemia, recalling the FHH phenotype. FeCa2+ is also low in the non-pHPT SCD control group, and negatively associated with PTH and hemolytic biomarkers such as LDH and low hemoglobin. Our data suggest that the pHPT biochemical phenotype in SCD patients resembles the FHH phenotype, and the fasting FeCa2+ association with chronic hemolysis biomarkers strengthens the view of a potential pharmacological link between hemolytic by-products and calcium reabsorption, potentially through a decreased calcium-sensing receptor (CaSR) activity.

scholarly journals Evidence for increased postprandial distal nephron calcium delivery in hypercalciuric stone-forming patients

2008 ◽  
Vol 295 (5) ◽  
pp. F1286-F1294 ◽  
Author(s):  
Elaine M. Worcester ◽  
Fredric L. Coe ◽  
Andrew P. Evan ◽  
Kristin J. Bergsland ◽  
Joan H. Parks ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Stone Formation ◽  
Selective Reduction ◽  
Normal Subjects ◽  
Idiopathic Hypercalciuria ◽  
Calcium Excretion ◽  
Distal Nephron ◽  
Clinical Research Center ◽  
Calcium Reabsorption ◽  
New Finding

A main mechanism of idiopathic hypercalciuria (IH) in calcium stone-forming patients (IHSF) is postprandial reduction of renal tubule calcium reabsorption that cannot be explained by selective reduction of serum parathyroid hormone levels; the nephron site(s) responsible are not as yet defined. Using fourteen 1-h measurements of the clearances of sodium, calcium, and endogenous lithium during a three-meal day in the University of Chicago General Clinical Research Center, we found reduced postprandial proximal tubule reabsorption of sodium and calcium in IHSF vs. normal subjects. The increased distal sodium delivery is matched by increased distal reabsorption so that urine sodium excretions do not differ, but distal calcium reabsorption does not increase enough to match increased calcium delivery, so hypercalciuria results. In fact, urine calcium excretion and overall renal fractional calcium reabsorption both are high in IHSF vs. normal when adjusted for distal calcium delivery, strongly suggesting a distal as well as proximal reduction of calcium reabsorption. The combination of reduced proximal tubule and distal nephron calcium reabsorption in IHSF is a new finding and indicates that IH involves a complex, presumably genetic, variation of nephron function. The increased calcium delivery into the later nephron may play a role in stone formation via deposition of papillary interstitial apatite plaque.

Divalent cation transport by the distal nephron: insights from Bartter's and Gitelman's syndromes

2000 ◽  
Vol 279 (4) ◽  
pp. F616-F625 ◽  
Author(s):  
David H. Ellison
Keyword(s):  
Ion Transport ◽  
Divalent Cation ◽  
Urinary Calcium ◽  
Distal Convoluted Tubule ◽  
Calcium Excretion ◽  
Thick Ascending Limb ◽  
Inherited Disease ◽  
Diuretic Drugs ◽  
Tubule Cells ◽  
Phenotypic Features

Elucidation of the gene defects responsible for many disorders of renal fluid and electrolyte homeostasis has provided new insights into normal and abnormal physiology. Identifying the causes of Gitelman's and Bartter's syndromes has greatly enhanced our understanding of ion transport by thick ascending limb and distal convoluted tubule cells. Despite this information, several phenotypic features of these diseases remain confusing, even in the face of molecular insight. Paramount among these are disorders of divalent cation homeostasis. Bartter's syndrome is caused by dysfunction of thick ascending limb cells. It is associated with calcium wasting, but magnesium wasting is usually mild. Loop diuretics, which inhibit ion transport by thick ascending limb cells, markedly increase urinary excretion of both calcium and magnesium. In contrast, Gitelman's syndrome is caused by dysfunction of the distal convoluted tubule. Hypocalciuria and hypomagnesemia are universal parts of this disorder. Yet although thiazide diuretics, which inhibit ion transport by distal convoluted tubule cells, reduce urinary calcium excretion, they have minimal effects on urinary magnesium excretion, when given acutely. This review proposes mechanisms that may account for the differences between the effects of diuretic drugs and the phenotypic features of Gitelman's and Bartter's syndromes. These mechanisms are based on recent insights from another inherited disease of ion transport, inherited magnesium wasting, and from a review of the chronic effects of diuretic drugs in animals and people.

Evidence that postprandial reduction of renal calcium reabsorption mediates hypercalciuria of patients with calcium nephrolithiasis

2007 ◽  
Vol 292 (1) ◽  
pp. F66-F75 ◽  
Author(s):  
Elaine M. Worcester ◽  
Daniel L. Gillen ◽  
Andrew P. Evan ◽  
Joan H. Parks ◽  
Katrina Wright ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Serum Magnesium ◽  
Normal Subjects ◽  
Urinary Calcium ◽  
Idiopathic Hypercalciuria ◽  
Calcium Excretion ◽  
Stone Formers ◽  
Calcium Reabsorption ◽  
Renal Tubular ◽  
Filtered Load

Idiopathic hypercalciuria (IH) is common among calcium stone formers (IHSF). The increased urinary calcium arises from increased intestinal absorption of calcium, but it is unclear whether increased filtered load or decreased renal tubular reabsorption of calcium is the main mechanism for the increased renal excretion. To explore this question, 10 IHSF and 7 normal subjects (N) were studied for 1 day. Urine and blood samples were collected at 30- to 60-min intervals while subjects were fasting and after they ate three meals providing known amounts of calcium, phosphorus, sodium, protein, and calories. Fasting and fed, ultrafiltrable calcium levels, and filtered load of calcium did not differ between N and IHSF. Urine calcium rose with meals, and fractional reabsorption fell in all subjects, but the change was significantly higher in IHSF. The changes in calcium excretion were independent of sodium excretion. Serum parathyroid hormone levels did not differ between N and IHSF, and they could not account for the greater fall in calcium reabsorption in IHSF. Serum magnesium and phosphorus levels in IHSF were below N throughout the day, and tubule phosphate reabsorption was lower in IHSF than N after meals. The primary mechanism by which kidneys ferry absorbed calcium into the urine after meals is via reduced tubule calcium reabsorption, and IHSF differ from N in the magnitude of the response. Parathyroid hormone is not likely to be a sufficient explanation for this difference.

Mechanisms Underlying Calcium Nephrolithiasis

2021 ◽  
Vol 84 (1) ◽  
Author(s):  
R.T. Alexander ◽  
D.G. Fuster ◽  
H. Dimke
Keyword(s):  
Kidney Stones ◽  
Kidney Stone ◽  
Stone Formation ◽  
Urinary Calcium ◽  
Annual Review ◽  
Publication Date ◽  
Calcium Excretion ◽  
Thick Ascending Limb ◽  
Renal Tubular ◽  
Kidney Stone Formation

Nephrolithiasis is a worldwide problem with increasing prevalence, enormous costs, and significant morbidity. Calcium-containing kidney stones are by far the most common kidney stones encountered in clinical practice. Consequently, hypercalciuria is the greatest risk factor for kidney stone formation. Hypercalciuria can result from enhanced intestinal absorption, increased bone resorption, or altered renal tubular transport. Kidney stone formation is complex and driven by high concentrations of calcium-oxalate or calcium-phosphate in the urine. After discussing the mechanism mediating renal calcium salt precipitation, we review recent discoveries in renal tubular calcium transport from the proximal tubule, thick ascending limb, and distal convolution. Furthermore, we address how calcium is absorbed from the intestine and mobilized from bone. The effect of acidosis on bone calcium resorption and urinary calcium excretion is also considered. Although recent discoveries provide insight into these processes, much remains to be understood in order to provide improved therapies for hypercalciuria and prevent kidney stone formation. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Calcium sensitivity of dicarboxylate transport in cultured proximal tubule cells

2011 ◽  
Vol 300 (2) ◽  
pp. F425-F432 ◽  
Author(s):  
Kathleen S. Hering-Smith ◽  
Faith R. Schiro ◽  
Ana M. Pajor ◽  
L. Lee Hamm
Keyword(s):  
Proximal Tubule ◽  
Transport Process ◽  
Urinary Calcium ◽  
Extracellular Calcium ◽  
Calcium Excretion ◽  
Proximal Tubule Cells ◽  
Citrate Transport ◽  
Dicarboxylate Transport ◽  
Tubule Cells ◽  
Urinary Citrate

Urinary citrate is an important inhibitor of calcium nephrolithiasis and is primarily determined by proximal tubule reabsorption. The major transporter to reabsorb citrate is Na+-dicarboxylate cotransporter (NaDC1), which transports dicarboxylates, including the divalent form of citrate. We previously found that opossum kidney (OK) proximal tubule cells variably express either divalent or trivalent citrate transport, depending on extracellular calcium. The present studies were performed to delineate the mechanism of the effect of calcium on citrate and succinate transport in these cells. Transport was measured using isotope uptake assays. In some studies, NaDC1 transport was studied in Xenopus oocytes, expressing either the rabbit or opossum ortholog. In the OK cell culture model, lowering extracellular calcium increased both citrate and succinate transport by more than twofold; the effect was specific in that glucose transport was not altered. Citrate and succinate were found to reciprocally inhibit transport at low extracellular calcium (<60 μM), but not at normal calcium (1.2 mM); this mutual inhibition is consistent with dicarboxylate transport. The inhibition varied progressively at intermediate levels of extracellular calcium. In addition to changing the relative magnitude and interaction of citrate and succinate transport, decreasing calcium also increased the affinity of the transport process for various other dicarboxylates. Also, the affinity for succinate, at low concentrations of substrate, was increased by calcium removal. In contrast, in oocytes expressing NaDC1, calcium did not have a similar effect on transport, indicating that NaDC1 could not likely account for the findings in OK cells. In summary, extracellular calcium regulates constitutive citrate and succinate transport in OK proximal tubule cells, probably via a novel transport process that is not NaDC1. The calcium effect on citrate transport parallels in vivo studies that demonstrate the regulation of urinary citrate excretion with urinary calcium excretion, a process that may be important in decreasing urinary calcium stone formation.

The comparative effects of feeding ammonium carbonate, ammonium sulfate, and ammonium chloride on urinary calcium excretion in the rat

1987 ◽  
Vol 65 (11) ◽  
pp. 2202-2204 ◽  
Author(s):  
Susan J. Whiting ◽  
David E. C. Cole
Keyword(s):  
Urinary Calcium ◽  
Urinary Calcium Excretion ◽  
Male Rats ◽  
Calcium Excretion ◽  
Acid Excretion ◽  
Calcium Reabsorption ◽  
Acid Load ◽  
Feeding Trials ◽  
Renal Tubular ◽  
Excretion Rates

When either sulfate or chloride is added to the diet, the resulting acid load causes a rise in urinary calcium excretion. There is, however, the possibility that sulfate, which has been shown to complex renal tubular calcium, will further decrease renal calcium reabsorption and thus produce a greater calciuria than chloride. Because addition of a fixed cation (e.g., sodium) to the diet may also stimulate calciuresis, experiments were conducted using metabolizable ammonium to minimize cation effects. Ammonium salts of sulfate, chloride, and carbonate (control) were added to the diets of male rats at 0.3 mequiv./g weight of diet. Twenty-four hour excretion rates of calcium, sulfate, chloride, and net acid were measured at various intervals up to 1 month. As expected, the chloride and sulfate diets were both associated with significantly elevated urine calcium and net acid excretion as compared with controls. However, those fed sulfate exhibited significantly less calcium and acid excretion and absorbed a smaller proportion of the anion load than those given chloride. In a second experiment, the amounts of supplemental sulfate and chloride were adjusted so that total absorptions were similar. At 2 weeks, both calcium and acid excretions in the fixed anion groups were no longer significantly different. Thus, in chronic feeding trials, there appears to be no measurable difference in the calciuretic properties of sulfate and chloride anions.

Hypercalcaemia of Malignancy: Evidence for a Non-Parathyroid Humoral Agent with An Effect on Renal Tubular Handling of Calcium

1984 ◽  
Vol 66 (2) ◽  
pp. 187-191 ◽  
Author(s):  
S. H. Ralston ◽  
I. Fogelman ◽  
M. D. Gardner ◽  
F. J. Dryburgh ◽  
R. A. Cowan ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
Urinary Calcium ◽  
Urinary Calcium Excretion ◽  
Calcium Excretion ◽  
Renal Handling ◽  
Calcium Reabsorption ◽  
Humoral Agent ◽  
Calcium Infusion ◽  
Calcium Load ◽  
Renal Tubular

1. The renal handling of calcium was examined in 31 patients with hypercalcaemia of malignancy. Results were compared with those from patients with primary hyperparathyroidism, and normal controls rendered hypercalcaemic by calcium infusion. 2. On relating the urinary calcium excretion indices to serum calcium values, inappropriately low rates of urinary calcium excretion were generally found in patients with malignancy associated hypercalcaemia. Further, the pattern of urinary calcium excretion in these subjects was similar to that found in patients with primary hyperparathyroidism. 3. These observations suggest that, in many solid tumours, the development of hypercalcaemia may be attributable to a humoral mediator with a parathyroid hormone-like effect on renal tubular calcium reabsorption. 4. The relatively frequent occurrence of hypercalcaemia in malignant disease thus may be partially explained by the presence of this humoral agent, which may impair the renal excretion of an increase in filtered calcium load, whether due to bone metastases, or humorally mediated osteolysis.

Acute decrease of urine calcium by amiloride in healthy volunteers under high sodium diet

2021 ◽  
Author(s):  
Dusan Harmacek ◽  
Anne Blanchard ◽  
Gregoire Wuerzner ◽  
Marc Maillard ◽  
Xavier Jeunemaitre ◽  
...  
Keyword(s):  
Animal Studies ◽  
Collecting Duct ◽  
Plasma Renin ◽  
Fractional Excretion ◽  
Urinary Calcium ◽  
Calcium Excretion ◽  
High Sodium ◽  
Calcium Reabsorption ◽  
Excretion Rates ◽  
Low K

Abstract Background Amiloride is a competitive blocker of the epithelial sodium channel (ENaC) in the renal collecting duct. It is a less potent diuretic than thiazides or loop diuretics, but is often used in association for its potassium-sparing profile. Whether amiloride has hypocalciuric effect similar to thiazides remains unclear. Animal studies and experiments on cell lines suggested that amiloride increases calcium reabsorption in the distal nephron, but human studies are scarce. Methods We performed a post hoc analysis of a study with 48 healthy males (age, 23.2 ± 3.9 years) who were assigned to a high sodium (Na)/low potassium (K) diet for 7 days before receiving 20 mg of amiloride p.o. Urinary excretions of electrolytes were measured at 3 and 6 hours afterward; we calculated the relative changes in urinary excretion rates after amiloride administration. Results The high Na/low K diet led to an expected suppression of plasma renin and aldosterone. Amiloride showed a mild natriuretic effect associated with a decreased kaliuresis. Urinary calcium excretion dropped substantially (by 80%) 3 hours after amiloride administration and remained low at the 6th hour. At the same time, fractional excretion of lithium decreased by a third, reflecting an increased proximal tubular reabsorption. Conclusion During a high Na/low K diet, amiloride had a strong acute hypocalciuric effect, most probably mediated by increased proximal calcium reabsorption, even though distal effect cannot be excluded. Further studies should establish if chronic amiloride or combined amiloride/thiazide treatment may decrease calciuria more efficiently and be useful in preventing kidney stones.

Renal tubular calcium transport: effects of changes in filtered calcium load

1983 ◽  
Vol 245 (4) ◽  
pp. F515-F520
Author(s):  
R. A. Sutton ◽  
N. L. Wong ◽  
G. A. Quamme ◽  
J. H. Dirks
Keyword(s):  
Urinary Calcium ◽  
Calcium Excretion ◽  
Reciprocal Effect ◽  
Group I ◽  
Calcium Reabsorption ◽  
Calcium Infusion ◽  
Transport Effects ◽  
Calcium Load ◽  
Renal Tubular ◽  
Filtered Load

Micropuncture experiments were performed in thyroparathyroidectomized dogs to examine the influence of changes in filtered calcium load on segmental tubular calcium reabsorption. Filtered calcium load was changed either by reducing glomerular filtration rate (GFR) by aortic clamping (group I) or by progressive calcium infusion (group II) to increase plasma ultrafilterable calcium concentration (UFCa). The results suggest that fractional proximal calcium reabsorption responds similarly to altered filtered load, whether produced by changes in GFR or UFCa. In contrast, fractional reabsorption by the loop segment is progressively reduced as UFCa is increased but is relatively unchanged by alterations in filtered load secondary to altered GFR. These data indicate a specific parathyroid hormone-independent reciprocal effect of UFCa on calcium reabsorption in the loop segment, which may be an important determinant of urinary calcium excretion.

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