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

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          Abstract

          Background

          Solute-linked carrier 26 gene family 6 (SLC26A6), which is mainly expressed in intestines and kidneys, is a multifunctional anion transporter crucial in the transport of oxalate anions. This study aimed to investigate the role of kidney SLC26A6 in urolithiasis.

          Methods

          Patients were divided into two groups: stone formers and nonstone formers. Samples were collected from patients following nephrectomy. Lentivirus with Slc26a6 (lentivirus-Slc26a6) sequence and lentivirus with siRNA-Slc26a6 (lentivirus-siRNA-Slc26a6) sequence were transfected into rats’ kidneys respectively and Slc26a6 expression was detected using Western blot and immunohistochemical analyses. After administering ethylene glycol, oxalate concentration and prevalence of stone formation between the transgenic and control groups were measured using 24-h urine analysis and Von Kossa staining, respectively.

          Results

          Immunohistochemical and Western blot analyses indicated that stone formers had a significantly higher level of expression of SLC26A6 in the kidney compared with the control group. After lentivirus infection, the urinary oxalate concentration and rate of stone formation in lentivirus-Slc26a6-tranfected rats increased remarkably, while lentivirus-siRNA-Slc26a6-transfected rats showed few crystals.

          Conclusion

          The results showed that high expression levels of renal SLC26A6 may account for kidney stone formation. Downregulating the expression of SLC26A6 in the kidney may be a potential therapeutic target to prevent or treat urolithiasis.

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          Most cited references33

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          The SLC26 gene family of multifunctional anion exchangers.

          The ten-member SLC26 gene family encodes anion exchangers capable of transporting a wide variety of monovalent and divalent anions. The physiological role(s) of individual paralogs is evidently due to variation in both anion specificity and expression pattern. Three members of the gene family are involved in genetic disease; SLC26A2 in chondrodysplasias, SLC26A3 in chloride-losing diarrhea, and SLC26A4 in Pendred syndrome and hereditary deafness (DFNB4). The analysis of Slc26a4-null mice has significantly enhanced the understanding of the roles of this gene in both health and disease. Targeted deletion of Slc26a5 has in turn revealed that this paralog is essential for electromotor activity of cochlear outer hair cells and thus for cochlear amplification. Anions transported by the SLC26 family, with variable specificity, include the chloride, sulfate, bicarbonate, formate, oxalate and hydroxyl ions. The functional versatility of SLC26A6 identifies it as the primary candidate for the apical Cl(-)-formate/oxalate and Cl(-)-base exchanger of brush border membranes in the renal proximal tubule, with a central role in the reabsorption of Na(+)-Cl(-) from the glomerular ultrafiltrate. At least three of the SLC26 exchangers mediate electrogenic Cl(-)-HCO(3)(-) and Cl(-)-OH(-) exchange; the stoichiometry of Cl(-)-HCO(3)(-) exchange appears to differ between SLC26 paralogs, such that SLC26A3 transports >/=2 Cl(-) ions per HCO(3)(-) ion, whereas SLC26A6 transports >/=2 HCO(3)(-) ions per Cl(-) ion. SLC26 Cl(-)-HCO(3)(-) and Cl(-)-OH(-) exchange is activated by the cystic fibrosis transmembrane regulator (CFTR), implicating defective regulation of these exchangers in the reduced HCO(3)(-) transport seen in cystic fibrosis and related disorders; CFTR-independent activation of these exchangers is thus an important and novel goal for the future therapy of cystic fibrosis.
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            IL-36 Signaling Facilitates Activation of the NLRP3 Inflammasome and IL-23/IL-17 Axis in Renal Inflammation and Fibrosis.

            IL-36 cytokines are proinflammatory and have an important role in innate and adaptive immunity, but the role of IL-36 signaling in renal tubulointerstitial lesions (TILs), a major prognostic feature of renal inflammation and fibrosis, remains undetermined. In this study, increased IL-36α expression detected in renal biopsy specimens and urine samples from patients with renal TILs correlated with renal function impairment. We confirmed the increased expression of IL-36α in the renal tubular epithelial cells of a mouse model of unilateral ureteral obstruction (UUO) and related cell models using mechanically induced pressure, oxidative stress, or high mobility group box 1. In contrast, the kidneys of IL-36 receptor (IL-36R) knockout mice exhibit attenuated TILs after UUO. Compared with UUO-treated wild-type mice, UUO-treated IL-36 knockout mice exhibited markedly reduced NLRP3 inflammasome activation and macrophage/T cell infiltration in the kidney and T cell activation in the renal draining lymph nodes. In vitro, recombinant IL-36α facilitated NLRP3 inflammasome activation in renal tubular epithelial cells, macrophages, and dendritic cells and enhanced dendritic cell-induced T cell proliferation and Th17 differentiation. Furthermore, deficiency of IL-23, which was diminished in IL-36R knockout UUO mice, also reduced renal TIL formation in UUO mice. In wild-type mice, administration of an IL-36R antagonist after UUO reproduced the results obtained in UUO-treated IL-36R knockout mice. We propose that IL-36 signaling contributes to the pathogenesis of renal TILs through the activation of the NLRP3 inflammasome and IL-23/IL-17 axis.
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              A Method for Murine Islet Isolation and Subcapsular Kidney Transplantation

              Since the early pioneering work of Ballinger and Reckard demonstrating that transplantation of islets of Langerhans into diabetic rodents could normalize their blood glucose levels, islet transplantation has been proposed to be a potential treatment for type 1 diabetes 1,2. More recently, advances in human islet transplantation have further strengthened this view 1,3. However, two major limitations prevent islet transplantation from being a widespread clinical reality: (a) the requirement for large numbers of islets per patient, which severely reduces the number of potential recipients, and (b) the need for heavy immunosuppression, which significantly affects the pediatric population of patients due to their vulnerability to long-term immunosuppression. Strategies that can overcome these limitations have the potential to enhance the therapeutic utility of islet transplantation. Islet transplantation under the mouse kidney capsule is a widely accepted model to investigate various strategies to improve islet transplantation. This experiment requires the isolation of high quality islets and implantation of islets to the diabetic recipients. Both procedures require surgical steps that can be better demonstrated by video than by text. Here, we document the detailed steps for these procedures by both video and written protocol. We also briefly discuss different transplantation models: syngeneic, allogeneic, syngeneic autoimmune, and allogeneic autoimmune.
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                Author and article information

                Contributors
                Journal
                PeerJ
                PeerJ
                PeerJ
                PeerJ
                PeerJ
                PeerJ Inc. (San Francisco, USA )
                2167-8359
                3 July 2018
                2018
                : 6
                : e5192
                Affiliations
                [1 ] Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
                [2 ] Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
                [3 ] School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
                Author information
                http://orcid.org/0000-0002-6307-2859
                Article
                5192
                10.7717/peerj.5192
                6034601
                30002986
                930870c5-6585-40ed-9b8f-cc7e86ec31a9
                © 2018 Jiang et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                : 23 February 2018
                : 18 June 2018
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81400706
                The work was funded by the National Natural Science Foundation of China (grant no. 81400706). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Biotechnology
                Molecular Biology
                Urology

                slc26a6,oxalate,lentivirus,hyperoxaluria,urolithiasis
                slc26a6, oxalate, lentivirus, hyperoxaluria, urolithiasis

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