scholarly journals Sat1 is dispensable for active oxalate secretion in mouse duodenum

2012 ◽  
Vol 303 (1) ◽  
pp. C52-C57 ◽  
Author(s):  
Narae Ko ◽  
Felix Knauf ◽  
Zhirong Jiang ◽  
Daniel Markovich ◽  
Peter S. Aronson
Keyword(s):  
Calcium Oxalate ◽  
Basolateral Membrane ◽  
Complete Removal ◽  
Calcium Oxalate Stones ◽  
Anion Transporter ◽  
Oxalate Secretion ◽  
In Series ◽  
Disulfonic Stilbene ◽  
Oxalate Transport

Mice deficient for the apical membrane oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium oxalate stones due to a defect in intestinal oxalate secretion. However, the nature of the basolateral membrane oxalate transport process that operates in series with SLC26A6 to mediate active oxalate secretion in the intestine remains unknown. Sulfate anion transporter-1 (Sat1 or SLC26A1) is a basolateral membrane anion exchanger that mediates intestinal oxalate transport. Moreover, Sat1-deficient mice also have a phenotype of hyperoxalemia, hyperoxaluria, and calcium oxalate stones. We, therefore, tested the role of Sat1 in mouse duodenum, a tissue with Sat1 expression and SLC26A6-dependent oxalate secretion. Although the active secretory flux of oxalate across mouse duodenum was strongly inhibited (>90%) by addition of the disulfonic stilbene DIDS to the basolateral solution, secretion was unaffected by changes in medium concentrations of sulfate and bicarbonate, key substrates for Sat1-mediated anion exchange. Inhibition of intracellular bicarbonate production by acetazolamide and complete removal of bicarbonate from the buffer also produced no change in oxalate secretion. Finally, active oxalate secretion was not reduced in Sat1-null mice. We conclude that a DIDS-sensitive basolateral transporter is involved in mediating oxalate secretion across mouse duodenum, but Sat1 itself is dispensable for this process.

Role of Fluoride in Formation of Calcium Oxalate Stones

1985 ◽  
pp. 383-386 ◽  
Author(s):  
F. Hering ◽  
T. Briellmann ◽  
H. Seiler ◽  
G. Rutishauser
Keyword(s):  
Calcium Oxalate ◽  
Calcium Oxalate Stones

scholarly journals Oxalate: From the Environment to Kidney Stones

2013 ◽  
Vol 64 (4) ◽  
pp. 609-630 ◽  
Author(s):  
Hrvoje Brzica ◽  
Davorka Breljak ◽  
Birgitta C Burckhardt ◽  
Gerhard Burckhardt ◽  
Ivan Sabolić
Keyword(s):  
Underlying Mechanism ◽  
Stone Disease ◽  
Sulfate Anion ◽  
Intestinal Excretion ◽  
Oxalate Absorption ◽  
Anion Transporter ◽  
Solute Carrier ◽  
Sat 1 ◽  
Oxalate Transport

Abstract Oxalate urolithiasis (nephrolithiasis) is the most frequent type of kidney stone disease. Epidemiological research has shown that urolithiasis is approximately twice as common in men as in women, but the underlying mechanism of this sex-related prevalence is unclear. Oxalate in the organism partially originate from food (exogenous oxalate) and largely as a metabolic end-product from numerous precursors generated mainly in the liver (endogenous oxalate). Oxalate concentrations in plasma and urine can be modified by various foodstuffs, which can interact in positively or negatively by affecting oxalate absorption, excretion, and/or its metabolic pathways. Oxalate is mostly removed from blood by kidneys and partially via bile and intestinal excretion. In the kidneys, after reaching certain conditions, such as high tubular concentration and damaged integrity of the tubule epithelium, oxalate can precipitate and initiate the formation of stones. Recent studies have indicated the importance of the SoLute Carrier 26 (SLC26) family of membrane transporters for handling oxalate. Two members of this family [Sulfate Anion Transporter 1 (SAT-1; SLC26A1) and Chloride/Formate EXchanger (CFEX; SLC26A6)] may contribute to oxalate transport in the intestine, liver, and kidneys. Malfunction or absence of SAT-1 or CFEX has been associated with hyperoxaluria and urolithiasis. However, numerous questions regarding their roles in oxalate transport in the respective organs and male-prevalent urolithiasis, as well as the role of sex hormones in the expression of these transporters at the level of mRNA and protein, still remain to be answered.

scholarly journals Extracellular nucleotides inhibit oxalate transport by human intestinal Caco-2-BBe cells through PKC-δ activation

2013 ◽  
Vol 305 (1) ◽  
pp. C78-C89 ◽  
Author(s):  
Ruhul Amin ◽  
Sapna Sharma ◽  
Sireesha Ratakonda ◽  
Hatim A. Hassan
Keyword(s):  
Calcium Oxalate ◽  
Purinergic Receptor ◽  
Purinergic Signaling ◽  
Stone Formation ◽  
Surface Expression ◽  
Extracellular Nucleotides ◽  
Major Health Problem ◽  
Oxalate Secretion ◽  
Inflammatory Bowel ◽  
Oxalate Transport

Nephrolithiasis remains a major health problem in Western countries. Seventy to 80% of kidney stones are composed of calcium oxalate, and small changes in urinary oxalate affect risk of kidney stone formation. Intestinal oxalate secretion mediated by the anion exchanger SLC26A6 plays an essential role in preventing hyperoxaluria and calcium oxalate nephrolithiasis, indicating that understanding the mechanisms regulating intestinal oxalate transport is critical for management of hyperoxaluria. Purinergic signaling modulates several intestinal processes through pathways including PKC activation, which we previously found to inhibit Slc26a6 activity in mouse duodenal tissue. We therefore examined whether purinergic stimulation with ATP and UTP affects oxalate transport by human intestinal Caco-2-BBe (C2) cells. We measured [14C]oxalate uptake in the presence of an outward Cl−gradient as an assay of Cl−/oxalate exchange activity, ≥50% of which is mediated by SLC26A6. We found that ATP and UTP significantly inhibited oxalate transport by C2 cells, an effect blocked by the PKC inhibitor Gö-6983. Utilizing pharmacological agonists and antagonists, as well as PKC-δ knockdown studies, we observed that ATP inhibits oxalate transport through the P2Y2receptor, PLC, and PKC-δ. Biotinylation studies showed that ATP inhibits oxalate transport by lowering SLC26A6 surface expression. These findings are of potential relevance to pathophysiology of inflammatory bowel disease-associated hyperoxaluria, where supraphysiological levels of ATP/UTP are expected and overexpression of the P2Y2receptor has been reported. We conclude that ATP and UTP inhibit oxalate transport by lowering SLC26A6 surface expression in C2 cells through signaling pathways including the P2Y2purinergic receptor, PLC, and PKC-δ.

scholarly journals Contribution of the Na+-K+-2Cl− Cotransporter (NKCC1) to Transepithelial Transport of H+, NH4+, K+, and Na+ in Rat Outer Medullary Collecting Duct

2002 ◽  
Vol 13 (4) ◽  
pp. 827-835
Author(s):  
Susan M. Wall ◽  
Michael P. Fischer
Keyword(s):  
Collecting Duct ◽  
Rat Kidney ◽  
Basolateral Membrane ◽  
Transepithelial Transport ◽  
In Series ◽  
Acid Secreting ◽  
Medullary Collecting Duct ◽  
Nacl Secretion

ABSTRACT. In rat kidney, the “secretory” isoform of the Na-K-Cl cotransporter, NKCC1 (BSC-2), localizes to the basolateral membrane of the α intercalated cell, the acid secreting cell of the outer medullary collecting duct (OMCD). This laboratory has reported that NKCC1 mediates Cl− uptake across the basolateral membrane in series with Cl− secretion across the apical membrane in rat OMCD. NKCC1 transports NH4+, K+, and Na+ as well as Cl−; therefore, a role for the cotransporter in the process of HCl, NH4Cl, KCl, and NaCl secretion has been suggested. Thus, it was determined if bumetanide, an inhibitor of NKCC1, alters transepithelial cation transport in rat OMCD. OMCD tubules from deoxycorticosterone pivalate (DOCP)–treated rats were perfused in vitro. Hydration of CO2, rather than NH4+, provides the principle source of H+ for net acid secretion. In HCO3−/CO2-buffered solutions, no effect of bumetanide on net K+ flux was detected. Under some conditions, bumetanide addition resulted in a small reduction in secretion of net H+ equivalents. Transepithelial Na+ flux, JNa, was −1.5 ± 1.7 pmol/mm per min, values not different from zero. However, with the application of bumetanide to the bath, JNa was +5.2 ± 1.3 pmol/mm per min (P < 0.05), which indicates net Na+ absorption. In conclusion, inhibition of NKCC1 in rat OMCD changes transepithelial movement of Na+ and Cl−. The role of NKCC1 in the secretion of net H+ equivalents is small.

scholarly journals Cholinergic signaling inhibits oxalate transport by human intestinal T84 cells

2012 ◽  
Vol 302 (1) ◽  
pp. C46-C58 ◽  
Author(s):  
Hatim A. Hassan ◽  
Ming Cheng ◽  
Peter S. Aronson
Keyword(s):  
Calcium Oxalate ◽  
Signaling Pathways ◽  
Phospholipase C ◽  
Muscarinic Receptor ◽  
Surface Expression ◽  
Intestinal Cell ◽  
Common Disease ◽  
T84 Cells ◽  
Oxalate Secretion ◽  
Oxalate Transport

Urolithiasis remains a very common disease in Western countries. Seventy to eighty percent of kidney stones are composed of calcium oxalate, and minor changes in urinary oxalate affect stone risk. Intestinal oxalate secretion mediated by anion exchanger SLC26A6 plays a major constitutive role in limiting net absorption of ingested oxalate, thereby preventing hyperoxaluria and calcium oxalate urolithiasis. Using the relatively selective PKC-δ inhibitor rottlerin, we had previously found that PKC-δ activation inhibits Slc26a6 activity in mouse duodenal tissue. To identify a model system to study physiologic agonists upstream of PKC-δ, we characterized the human intestinal cell line T84. Knockdown studies demonstrated that endogenous SLC26A6 mediates most of the oxalate transport by T84 cells. Cholinergic stimulation with carbachol modulates intestinal ion transport through signaling pathways including PKC activation. We therefore examined whether carbachol affects oxalate transport in T84 cells. We found that carbachol significantly inhibited oxalate transport by T84 cells, an effect blocked by rottlerin. Carbachol also led to significant translocation of PKC-δ from the cytosol to the membrane of T84 cells. Using pharmacological inhibitors, we observed that carbachol inhibits oxalate transport through the M3 muscarinic receptor and phospholipase C. Utilizing the Src inhibitor PP2 and phosphorylation studies, we found that the observed regulation downstream of PKC-δ is partially mediated by c-Src. Biotinylation studies revealed that carbachol inhibits oxalate transport by reducing SLC26A6 surface expression. We conclude that carbachol negatively regulates oxalate transport by reducing SLC26A6 surface expression in T84 cells through signaling pathways including the M3 muscarinic receptor, phospholipase C, PKC-δ, and c-Src.

scholarly journals Absence of the sulfate transporter SAT-1 has no impact on oxalate handling by mouse intestine and does not cause hyperoxaluria or hyperoxalemia

2019 ◽  
Vol 316 (1) ◽  
pp. G82-G94 ◽  
Author(s):  
Jonathan M. Whittamore ◽  
Christine E. Stephens ◽  
Marguerite Hatch
Keyword(s):  
Calcium Oxalate ◽  
Stone Formation ◽  
Distal Colon ◽  
Toxic Waste ◽  
Oxalate Excretion ◽  
Anion Transporter ◽  
Oxalate Secretion ◽  
Mechanistic Basis ◽  
Urinary Oxalate Excretion ◽  
Sat 1

The anion exchanger SAT-1 [sulfate anion transporter 1 (Slc26a1)] is considered an important regulator of oxalate and sulfate homeostasis, but the mechanistic basis of these critical roles remain undetermined. Previously, characterization of the SAT-1-knockout (KO) mouse suggested that the loss of SAT-1-mediated oxalate secretion by the intestine was responsible for the hyperoxaluria, hyperoxalemia, and calcium oxalate urolithiasis reportedly displayed by this model. To test this hypothesis, we compared the transepithelial fluxes of 14C-oxalate, 35[Formula: see text], and 36Cl− across isolated, short-circuited segments of the distal ileum, cecum, and distal colon from wild-type (WT) and SAT-1-KO mice. The absence of SAT-1 did not impact the transport of these anions by any part of the intestine examined. Additionally, SAT-1-KO mice were neither hyperoxaluric nor hyperoxalemic. Instead, 24-h urinary oxalate excretion was almost 50% lower than in WT mice. With no contribution from the intestine, we suggest that this may reflect the loss of SAT-1-mediated oxalate efflux from the liver. SAT-1-KO mice were, however, profoundly hyposulfatemic, even though there were no changes to intestinal sulfate handling, and the renal clearances of sulfate and creatinine indicated diminished rates of sulfate reabsorption by the proximal tubule. Aside from this distinct sulfate phenotype, we were unable to reproduce the hyperoxaluria, hyperoxalemia, and urolithiasis of the original SAT-1-KO model. In conclusion, oxalate and sulfate transport by the intestine were not dependent on SAT-1, and we found no evidence supporting the long-standing hypothesis that intestinal SAT-1 contributes to oxalate and sulfate homeostasis. NEW & NOTEWORTHY SAT-1 is a membrane-bound transport protein expressed in the intestine, liver, and kidney, where it is widely considered essential for the excretion of oxalate, a potentially toxic waste metabolite. Previously, calcium oxalate kidney stone formation by the SAT-1-knockout mouse generated the hypothesis that SAT-1 has a major role in oxalate excretion via the intestine. We definitively tested this proposal and found no evidence for SAT-1 as an intestinal anion transporter contributing to oxalate homeostasis.

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