Oxalate transport and calcium oxalate renal stone disease

Verkoelen, Carl F.; Romijn, Johannes C.

doi:10.1007/bf00295891

Cited by 22 publications

(13 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Oxalate undergoes bidirectional transport in the proximal tubule with overall net secretion (78). Perfusion studies demonstrate net absorption of oxalate by the S1 and S2 segments of the rat proximal tubule and net secretion by the S3 segment (34,51).…”

Section: Discussionmentioning

confidence: 99%

Cholinergic signaling inhibits oxalate transport by human intestinal T84 cells

Hassan

Cheng

Aronson

2012

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

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 M(3) 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 M(3) muscarinic receptor, phospholipase C, PKC-δ, and c-Src.

show abstract

Section: Discussionmentioning

confidence: 99%

Cholinergic signaling inhibits oxalate transport by human intestinal T84 cells

Hassan

Cheng

Aronson

2012

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

show abstract

“…A temporal and significant increase of serum Cr and UN levels was observed in Groups B and C compared to values obtained for Groups A and D (P < 0.05). Ox levels in serum and urine were significantly higher in Groups A and B than in the other two groups from day 7 urinary stones [8,9], although this notion was challenged by others [10] proposing hypercalciuria to be the prime metabolic ailment involved in stone formation.…”

Section: Introductionmentioning

confidence: 92%

“…As proposed previously, hyperoxaluria is considered a major risk factor for urinary stone, and experimental induction of hyperoxaluria can lead to crystalluria and CaOx crystal deposition in the kidney [6,7]. In addition, recurrent idiopathic stone formers always show mild hyperoxaluria; meanwhile, amount and size of CaOx crystals, alongside disease severity, are highly related to urinary excretion of oxalate (Ox) [8]. Many studies suggested a more pronounced role for hyperoxaluria than that of hypercalciuria in the formation of Abstract Hyperoxaluria and cell injury are key factors in urolithiasis.…”

Section: Introductionmentioning

confidence: 98%

Renal tubular injury induced by ischemia promotes the formation of calcium oxalate crystals in rats with hyperoxaluria

et al. 2016

View full text Add to dashboard Cite

Hyperoxaluria and cell injury are key factors in urolithiasis. Oxalate metabolism may be altered by renal dysfunction and therefore, impact the deposition of calcium oxalate (CaOx) crystals. We investigated the relationship of renal function, oxalate metabolism and CaOx crystal deposition in renal ischemia. One hundred male Sprague-Dawley rats were randomly divided into four groups. Hyperoxaluria model (Group A and B) was established by feeding rats with 0.75 % ethylene glycol (EG). The left renal pedicle was clamped for 30 min to establish renal ischemia Groups (B and C), while Groups A and D underwent sham operation. Then, serum and urine oxalate (Ox), creatinine (Cr) and urea nitrogen (UN) levels were evaluated by liquid chromatography mass spectrometry (LCMS) and ion mass spectrum (IMS) at days 0, 2, 4, 7, and 14. CaOx crystallization was assessed by transmission electron microscope (TEM). A temporal and significant increase of serum Cr and UN levels was observed in Groups B and C compared to values obtained for Groups A and D (P < 0.05). Ox levels in serum and urine were significantly higher in Groups A and B than in the other two groups from day 7 (P < 0.05). In addition, CaOx crystallization was observed in both Groups A and B, but Group B showed earlier and more pronounced crystal deposition in the renal tissue. Our results indicated that renal tubular injury induced by renal ischemia might not affect Ox levels but could promote CaOx crystal retention under hyperoxaluria.

show abstract

“…20 The effective radius of oxalate has been estimated to be around 3 to 4 Å on the basis of its structure and negative charge size. 21 In addition, oxalate forms soluble complexes with Na ϩ , Ca ϩϩ , and Mg ϩϩ that can increase its calculated size. 22 Mannitol has an estimated size of 4.2 Å 18 and has been demonstrated to traverse the size-independent "leak" pathway.…”

Section: Effect Of Inducing Claudin-10a Expression On Tight Junction mentioning

confidence: 99%

Net Intestinal Transport of Oxalate Reflects Passive Absorption and SLC26A6-mediated Secretion

Knauf

Ko²,

Jiang³

et al. 2011

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Mice lacking the oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calciumoxalate stones as a result of a defect in intestinal oxalate secretion, but what accounts for the absorptive oxalate flux remains unknown. We measured transepithelial absorption of [14 C]oxalate simultaneously with the flux of [ 3 H]mannitol, a marker of the paracellular pathway, across intestine from wild-type and Slc26a6-null mice. We used the anion transport inhibitor DIDS to investigate other members of the SLC26 family that may mediate transcellular oxalate absorption. Absorptive flux of oxalate in duodenum was similar to mannitol, insensitive to DIDS, and nonsaturable, indicating that it is predominantly passive and paracellular. In contrast, in wild-type mice, secretory flux of oxalate in duodenum exceeded that of mannitol, was sensitive to DIDS, and saturable, indicating transcellular secretion of oxalate. In Slc26a6-null mice, secretory flux of oxalate was similar to mannitol, and no net flux of oxalate occurred. Absorptive fluxes of both oxalate and mannitol varied in parallel in different segments of small and large intestine. In epithelial cell lines, modulation of the charge selectivity of the claudin-based pore pathway did not affect oxalate permeability, but knockdown of the tight-junction protein ZO-1 enhanced permeability to oxalate and mannitol in parallel. Moreover, formation of soluble complexes with cations did not affect oxalate absorption. In conclusion, absorptive oxalate flux occurs through the paracellular "leak" pathway, and net absorption of dietary oxalate depends on the relative balance between absorption and SLC26A6-dependent transcellular secretion. 22: 224722: -225522: , 201122: . doi: 10.1681 Nephrolithiasis is the second most common chronic kidney condition after hypertension and demonstrates a rising prevalence and association with chronic kidney disease. 1 Calcium oxalate (CaOx) is the predominant component of most stones, and the level of urinary oxalate is an important risk factor for CaOx nephrolithiasis. 2,3 The amount of urinary oxalate depends on the net effect of metabolic production, intestinal absorption, and renal excretion. 4 The integral role of the intestine in oxalate homeostasis becomes most evident in diseases of intestine. Inflammatory bowel disease and small-bowel resections are conditions that are strongly associated with hyperoxaluria and CaOx nephrolithiasis. 5 New insight into the importance of the intestine in the pathogenesis of CaOx nephrolithiasis has come from studies of anion transporter SLC26A6. Slc26a6-null mice have a defect in in- J Am Soc Nephrol

show abstract

Oxalate transport and calcium oxalate renal stone disease

Cited by 22 publications

References 64 publications

Cholinergic signaling inhibits oxalate transport by human intestinal T84 cells

Cholinergic signaling inhibits oxalate transport by human intestinal T84 cells

Renal tubular injury induced by ischemia promotes the formation of calcium oxalate crystals in rats with hyperoxaluria

Net Intestinal Transport of Oxalate Reflects Passive Absorption and SLC26A6-mediated Secretion

Contact Info

Product

Resources

About