SLC26A6-selective inhibitor identified in a small-molecule screen blocks fluid absorption in small intestine

Çil, Onur; Haggie, Peter M.; Tan, Joseph-Anthony; Rivera, Amber A.

doi:10.1172/jci.insight.147699

Cited by 12 publications

(6 citation statements)

References 30 publications

(66 reference statements)

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“…To investigate DRA inh -A270 inhibition of intestinal oxalate transport, experiments were done using closed distal colonic loops in which SLC26A3 is the major apical membrane anion transporter ( 18 , 22 ). Colonic loops were injected with the solution containing 500 μM sodium oxalate and loop fluid was removed at 60 minutes to quantify remaining oxalate concentration.…”

Section: Resultsmentioning

confidence: 99%

“…The deidentified slides were read and scored by the same person blindly. The same kidney sections were imaged using polarization microscopy ( 22 ) (Nikon TI microscope with ×10 0.3 NA objective, Nikon Inc.) in which whole sections were scanned, and images were stitched using ImageJ software (NIH). Initial studies showed that pixel intensity thresholding using 1600 arbitrary intensity units captured more than 95% of crystals with minimal background, allowing automated determination of the total number and area of crystals, as defined as spots with 4 or more adjacent bright pixels above threshold.…”

Section: Methodsmentioning

confidence: 99%

“…The effect of DRA inh -A270 on anion transport by slc26a1 (murine), slc26a2 (murine), and SLC26A3 (human) was measured in HEK293 cells that were either transiently transfected with a plasmid to coexpress halide-sensitive YFP and slc26a1 or slc26a2 as described previously ( 22 ) or infected to express SLC26A3 and halide-sensitive YFP ( 18 ). hERG activity, CYP450 inhibition, and microsomal stability studies were performed by ChemPartner Inc. hERG activity ( n ≥ 2 per condition) was measured by manual patch-clamp in Chinese hamster ovary cells stably transfected with hERG, and cisapride (0.1 μM) was used as positive control.…”

Section: Methodsmentioning

confidence: 99%

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Small-molecule inhibitor of intestinal anion exchanger SLC26A3 for treatment of hyperoxaluria and nephrolithiasis

Çil¹,

Chu²,

Haggie³

2022

JCI Insight

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Nephrolithiasis is a common and recurrent disease affecting 9% of the US population. Hyperoxaluria is major risk factor for calcium oxalate kidney stones, which constitute two-thirds of all kidney stones. SLC26A3 (DRA, downregulated in adenoma) is an anion exchanger of chloride, bicarbonate, and oxalate thought to facilitate intestinal oxalate absorption, as evidenced by approximately 70% reduced urine oxalate excretion in knockout mice. We previously identified a small-molecule SLC26A3 inhibitor (DRA inh -A270) that selectively inhibited SLC26A3-mediated chloride/bicarbonate exchange (IC 50 ~ 35 nM) and, as found here, oxalate/chloride exchange (IC 50 ~ 60 nM). In colonic closed loops in mice, luminal DRA inh -A270 inhibited oxalate absorption by 70%. Following oral sodium oxalate loading in mice, DRA inh -A270 largely prevented the 2.5-fold increase in urine oxalate/creatinine ratio. In a mouse model of oxalate nephropathy produced by a high-oxalate low-calcium diet, vehicle-treated mice developed marked hyperoxaluria with elevated serum creatinine, renal calcium oxalate crystal deposition, and renal injury, which were largely prevented by DRA inh -A270 (10 mg/kg twice daily). DRA inh -A270 administered over 7 days to healthy mice did not show significant toxicity. Our findings support a major role of SLC26A3 in intestinal oxalate absorption and suggest the therapeutic utility of SLC26A3 inhibition for treatment of hyperoxaluria and prevention of calcium oxalate nephrolithiasis.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Small-molecule inhibitor of intestinal anion exchanger SLC26A3 for treatment of hyperoxaluria and nephrolithiasis

Çil¹,

Chu²,

Haggie³

2022

JCI Insight

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“…Indeed, several FDA-approved agents were identified that increased the luminal alkalinity and reduced small and in part also large intestinal fluid absorptive rate [166,167] or reduced the CF-associated delayed small intestinal transit time [111]. Other experimental drugs also carry the potential to increase gut fluidity, but have not yet been tested in CFTR-deficient mice [28,59]. Two agents, one of them a TMEM16a/SLC26A3 inhibitor [181] and the other one an intestine-specific, selective, and FDA-approved NHE3 inhibitor [167], were able to significantly reduce the frequency of intestinal obstructions in CFTR null mice.…”

Section: Cystic Fibrosismentioning

confidence: 99%

Bicarbonate secretion and acid/base sensing by the intestine

Becker,

Seidler

2024

Pflugers Arch - Eur J Physiol

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The transport of bicarbonate across the enterocyte cell membrane regulates the intracellular as well as the luminal pH and is an essential part of directional fluid movement in the gut. Since the first description of “active” transport of HCO3− ions against a concentration gradient in the 1970s, the fundamental role of HCO3− transport for multiple intestinal functions has been recognized. The ion transport proteins have been identified and molecularly characterized, and knockout mouse models have given insight into their individual role in a variety of functions. This review describes the progress made in the last decade regarding novel techniques and new findings in the molecular regulation of intestinal HCO3− transport in the different segments of the gut. We discuss human diseases with defects in intestinal HCO3− secretion and potential treatment strategies to increase luminal alkalinity. In the last part of the review, the cellular and organismal mechanisms for acid/base sensing in the intestinal tract are highlighted.

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“…5 Thus, SLC26 anion exchangers are novel drug targets for gastrointestinal, kidney and pulmonary diseases. [6][7][8][9][10][11] In intestinal epithelia, SLC26A3 (down-regulated in adenoma, DRA) and SLC26A6 (putative anion transporter 1, PAT1) are the major Cl − /HCO 3 − exchangers expressed in the luminal plasma membrane where they facilitate Cl − and fluid absorption. 12 DRA is primarily expressed in the colon, whereas PAT1 is expressed in the small intestine.…”

Section: Introductionmentioning

confidence: 99%

Selective isoxazolopyrimidine PAT1 (SLC26A6) inhibitors for therapy of intestinal disorders

Chu,

Karmakar,

Haggie

et al. 2023

RSC Med. Chem.

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SLC26A6-selective inhibitor identified in a small-molecule screen blocks fluid absorption in small intestine

Cited by 12 publications

References 30 publications

Small-molecule inhibitor of intestinal anion exchanger SLC26A3 for treatment of hyperoxaluria and nephrolithiasis

Small-molecule inhibitor of intestinal anion exchanger SLC26A3 for treatment of hyperoxaluria and nephrolithiasis

Bicarbonate secretion and acid/base sensing by the intestine

Selective isoxazolopyrimidine PAT1 (SLC26A6) inhibitors for therapy of intestinal disorders

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