Urolithiasis and hepatotoxicity are linked to the anion transporter Sat1 in mice
Paul A. Dawson, … , Lorne A. Clarke, Daniel Markovich
Paul A. Dawson, … , Lorne A. Clarke, Daniel Markovich
Published February 15, 2010
Citation Information: J Clin Invest. 2010;120(3):706-712. https://doi.org/10.1172/JCI31474.
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Research Article Nephrology

Urolithiasis and hepatotoxicity are linked to the anion transporter Sat1 in mice

Abstract

Urolithiasis, a condition in which stones are present in the urinary system, including the kidneys and bladder, is a poorly understood yet common disorder worldwide that leads to significant health care costs, morbidity, and work loss. Acetaminophen-induced liver damage is a major cause of death in patients with acute liver failure. Kidney and urinary stones and liver toxicity are disturbances linked to alterations in oxalate and sulfate homeostasis, respectively. The sulfate anion transporter–1 (Sat1; also known as Slc26a1) mediates epithelial transport of oxalate and sulfate, and its localization in the kidney, liver, and intestine suggests that it may play a role in oxalate and sulfate homeostasis. To determine the physiological roles of Sat1, we created Sat1–/– mice by gene disruption. These mice exhibited hyperoxaluria with hyperoxalemia, nephrocalcinosis, and calcium oxalate stones in their renal tubules and bladder. Sat1–/– mice also displayed hypersulfaturia, hyposulfatemia, and enhanced acetaminophen-induced liver toxicity. These data suggest that Sat1 regulates both oxalate and sulfate homeostasis and may be critical to the development of calcium oxalate urolithiasis and hepatotoxicity.

Authors

Paul A. Dawson, Christopher S. Russell, Soohyun Lee, Sarah C. McLeay, Jacobus M. van Dongen, David M. Cowley, Lorne A. Clarke, Daniel Markovich

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Figure 2

Analysis of Sat1 protein and mRNA.

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Analysis of Sat1 protein and mRNA. (A) Schematic of Sat1 cDNA and the pr...
(A) Schematic of Sat1 cDNA and the predicted knockout cDNA lacking exon 3. Exons 1–4 (boxes), protein coding sequences (shading) of wild-type (3,821 nucleotides) and Sat1 knockout (3,201 nucleotides) cDNA, and primers P8 and P9 are shown. (B) Northern analysis of RNA from liver (L), kidney (K), and ileum (I) of Sat1+/+, Sat1+/–, and Sat1–/– mice. RNA was hybridized with a 32P-labeled Sat1 cDNA (top), showing the 3.8-kb transcript, and GAPDH cDNA (bottom). (C) Total RNA from kidney was RT-PCR amplified. A 1,716-bp wild-type product and a 1,096-bp knockout Sat1 cDNA product (top) were amplified using primers P8 and P9. A 983-bp product (bottom) was amplified using GAPDH primers. (D) Total RNA from Sat1+/+ intestinal segments was RT-PCR amplified. A 1,716-bp product was amplified using primers P8 and P9. A 983-bp product (bottom) was amplified using GAPDH primers. (E) Western analysis of protein from intestinal BLMVs and apical BBMVs. The Sat1 antibody detected a 75.4-kDa protein in Sat1+/+ BLMVs, but not in Sat1+/+ BBMVs or in Sat1–/– mice.