High expression of SLC26A6 in the kidney may contribute to renal calcification via an SLC26A6-dependent mechanism

Jiang, Hongyang; Pokhrel, Gaurab; Chen, Yinwei; Wang, Tao; Yin, Chang; Liu, Jihong; Wang, Shaogang; Liu, Zhuo

doi:10.7717/peerj.5192

Cited by 21 publications

(27 citation statements)

References 42 publications

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“…These results clearly indicated that there was a renal effect for the compensatory elimination of plasma oxalate if there was a deficiency in the intestinal oxalate secretions. Increased renal Slc26a6 expression contributes to hyperoxaluria [ 30 ]. Our results showed consistent results for a significant increase in Slc26a6 expression not only in the EG kidneys but also in the SB+EG kidneys ( Figure 6 A).…”

Section: Discussionmentioning

confidence: 99%

Small intestine resection increases oxalate and citrate transporter expression and calcium oxalate crystal formation in rat hyperoxaluric kidneys

Tseng

Chen

et al. 2020

Clinical Science

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Short bowel (SB) increases the risk of kidney stones. However, the underlying mechanism is unclear. Here, we examined how SB affected renal oxalate and citrate handlings for in vivo hyperoxaluric rats and in vitro tubular cells. SB was induced by small intestine resection in male Wistar rats. Sham-operated controls had no resection. After 7 days of recovery, the rats were divided into control, SB (both fed with distilled water), EG, and SB+EG (both fed with 0.75% ethylene glycol (EG) for hyperoxaluric induction) groups for 28 days. We collected the plasma, 24 h of urine, kidney, and intestine tissues for analysis. Hypocitraturia were found and persisted to 28 days for the SB group. Hypocalcemia and high plasma parathyroid hormone (PTH) levels were found in the 28-day SB rats. SB aggravated EG-mediated oxalate nephropathy by fostering hyperoxaluria and hypocitraturia, and increasing the degree of supersaturation and calcium oxalate (CaOx) crystal deposition. These effects were associated with renal upregulations of the oxalate transporter solute carrier family 26 (Slc26)a6 and citrate transporter sodium-dependent dicarboxylate cotransporter-1 (NaDC-1) but not Slc26a2. The effects of PTH on the SB kidneys were then examined in NRK-52E tubular cells. Recombinant PTH attenuated oxalate-mediated cell injury and upregulated NaDC-1 via protein kinase A activation. PTH, however, showed no additive effects on oxalate-induced Slc26a6 and NaDC-1 upregulation. Together, these results demonstrated that renal NaDC-1 upregulation-induced hypocitraturia weakened the defense against Slc26a6-mediated hyperoxaluria in SB kidneys for excess CaOx crystal formation. Increased tubular NaDC-1 expression caused by SB relied on PTH.

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Section: Discussionmentioning

confidence: 99%

Small intestine resection increases oxalate and citrate transporter expression and calcium oxalate crystal formation in rat hyperoxaluric kidneys

Tseng

Chen

et al. 2020

Clinical Science

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“…The Slc26a6 sequence (gene ID: 301010) was chosen according to the National Center for Biotechnology Information (NCBI) GenBank. To knock down Slc26a6 expression, lentiviral vector piLenti-siRNA-red fluorescent protein- (RFP-) based short hairpin RNA (shRNA) against Slc26a6 was constructed, and the targeting sequence of shSlc26a6 was 5′-GGGAACTACTCAAGCTAAT-3′ [ 17 ]. The sequences with red fluorescent protein (RFP) were synthesized and inserted into the vector pWSLV and pilentivirus as pWSLV-05-Slc26a6 and piLenti-siRNA (Slc26a6), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Solute carrier family 26 member 6 (Slc26a6) is an important protein that mediates oxalate transport, and it is expressed mainly in the apical membrane of the intestine and kidneys. In the intestine, Slc26a6 on the apical membrane of intestinal epithelial cells can transport Ox 2− from the blood to the intestinal lumen (oxalate secretion) through Cl/Ox 2− exchange [ 17 ]. In the kidneys, Slc26a6 is located in the proximal tubular epithelial cell side of the renal tubular cell and can transfer oxalate from the blood to the urine through the Cl − /Ox 2− exchange (oxalate secretion) [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Downregulated Expression of Solute Carrier Family 26 Member 6 in NRK‐52E Cells Attenuates Oxalate‐Induced Intracellular Oxidative Stress

Jiang

Gao

Gong

et al. 2018

Oxidative Medicine and Cellular Longevity

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Solute carrier family 26 member 6 (Slc26a6), which is mainly expressed in the intestines and kidneys, is a multifunctional anion transporter that is crucial in the transport of oxalate anions. This study is aimed at investigating the effect of Slc26a6 expression on oxalate-induced cell oxidation and crystal formation. Lentivirus transfection was used to upregulate or downregulate Slc26a6 expression in NRK cells. Cell viability and apoptosis, reactive oxygen species (ROS) and malondialdehyde (MDA) generation, and superoxide dismutase (SOD) activity were measured. Crystal adhesion and the cell ultrastructure were observed using light and transmission electron microscopy (TEM). Three groups of rats, normal control, lentivirus-vector, and lentivirus-small interfering RNA (lv-siRNA) groups, were used, and after lentivirus transfection, they were fed 1% ethylene glycol (EG) and 0.5% ammonium chloride (NH4Cl) for 2 weeks. Dihydroethidium (DHE), terminal deoxynucleotidyl transferase (TdT) deoxyuridine dUTP nick-end labeling (TUNEL), and von Kossa staining were performed, and nuclear factor κB (NFκB) and osteopontin (OPN) expression were measured. In the vitro study, compared to the control group, downregulated Slc26a6 NRK cells showed alleviation of the cell viability decrease, cell apoptosis rate, ROS generation, and SOD activity decrease after oxalate treatment. Crystal adhesion and vesicles were significantly less after oxalate exposure than in the untreated controls. Rats infected with lentivirus-siRNA exhibited attenuated SOD generation, cell apoptosis, and crystal formation in the kidneys. Increased phosphorylation of NFκB and OPN was involved in the pathological process. In conclusion, the results of the present study indicate that reducing the expression of Slc26a6 in the kidney may be a potential strategy for preventing stone formation.

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“…As Slc26A6-null mice have been reported to be hyperoxaluric and to develop calcium oxalate kidney stones, SLC26A6, which encodes an oxalate transporter, was investigated in a casecontrol study 161,163 . The case-control study identified a SLC26A6 variant to be associated with kidney stone disease 161 , and this variant paradoxically was associated with increased SLC26A6 expression in the kidneys of stone-forming patients 164 . Case control studies have also identified that a TRPV6 haplotype might] increase the risk of absorptive hypercalciuria via increased permeability of the TRPV6 calcium channel 162 .…”

Section: [H2] Genome-wide Association Studiesmentioning

confidence: 99%

Genetics of kidney stone disease

2020

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Kidney stone disease (nephrolithiasis) is a common problem that can be associated with alterations in urinary solute composition including hypercalciuria. Studies suggest that the prevalence of monogenic kidney stone disorders, including renal tubular acidosis with deafness, Bartter syndrome, primary hyperoxaluria, and cystinuria, in patients attending kidney stone clinics is 15%. However, for the majority of individuals, nephrolithiasis has a multifactorial aetiology involving genetic and environmental factors. Nonetheless, the genetic influence on stone formation in these idiopathic stone formers remains considerable and twin studies estimate a heritability of >45% for nephrolithiasis and >50% for hypercalciuria. The contribution of polygenic influences from multiple loci have been investigated by genome-wide association and candidate gene studies, which indicate that a number of genes and molecular pathways contribute to the risk of stone formation. Genetic approaches, studying both monogenic and polygenic factors in nephrolithiasis, have revealed that the following have important roles in the aetiology of kidney stones: transporters and channels; ions, protons and amino acids; the calcium-sensing receptor (a G-protein-coupled receptor) signalling pathway; and the metabolic pathways for vitamin D, oxalate, cysteine, purines and uric acid. These advances, which have increased our understanding of the pathogenesis of nephrolithiasis, will hopefully facilitate the future development of targeted therapies for precision medicine approaches in patients with nephrolithiasis.

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High expression of SLC26A6 in the kidney may contribute to renal calcification via an SLC26A6-dependent mechanism

Cited by 21 publications

References 42 publications

Small intestine resection increases oxalate and citrate transporter expression and calcium oxalate crystal formation in rat hyperoxaluric kidneys

Small intestine resection increases oxalate and citrate transporter expression and calcium oxalate crystal formation in rat hyperoxaluric kidneys

Downregulated Expression of Solute Carrier Family 26 Member 6 in NRK‐52E Cells Attenuates Oxalate‐Induced Intracellular Oxidative Stress

Genetics of kidney stone disease

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