A distal convoluted tubule‐specific isoform of murine SLC41A3 extrudes magnesium

Acta Physiologica, Год журнала: 2025, Номер 241(3)

Опубликована: Фев. 11, 2025

The distal convoluted tubule (DCT) plays an indispensable role in magnesium (Mg2+) reabsorption the kidney. Yet, extrusion mechanism of Mg2+ has not been identified. solute carrier 41A3 (SLC41A3) suggested to be involved extrusion, but this never conclusively demonstrated. Using available RNA-sequencing data and real-time quantitative PCR, expression two alternative Slc41a3 transcripts, encoding isoform (Iso) 1 or 2, were assessed kidney isolated DCT tubules. HEK293 HAP1 cells transfected with plasmids expressing either isoforms, followed by 25Mg2+ transport studies. Identification cis-regulatory elements (CRE) was achieved combining from publicly ATAC sequencing luciferase assays. Gene studies revealed a distinct transcript promoter, leading protein unique N-terminus; SLC41A3-Iso 2. overexpressing -Iso 1, exhibited 2.7-fold 1.6-fold higher uptake compared mock, respectively. independent Na+, channel TRPM7 transporters CNNM3 -4. We identified CRE accessible DCT, ±2.8kb upstream transcript. presence increased Slc41a3-Iso 2 promoter activity 3.8-fold following assays, indicating contains enhancer function. In conclusion, we transcripts mouse. is enriched within using specific gene regulatory elements. speculate that specifically orchestrates extrusion.

Язык: Английский

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“SLC-omics” of the kidney: solute transporters along the nephron

AJP Cell Physiology, Год журнала: 2021, Номер 321(3), С. C507 - C518

Опубликована: Июнь 30, 2021

The fluid in the 14 distinct segments of renal tubule undergoes sequential transport processes that gradually convert glomerular filtrate into final urine. solute carrier (SLC) family proteins is responsible for much ions and organic molecules along tubule. In addition, some SLC mediate housekeeping functions by transporting substrates metabolism. Here, we have developed a curated list proteins. We used to produce resource webpages map these their transcripts specific data were highlight interesting features expression including sex-specific proximal role accessory (β-subunit proteins) are thought be important polarized targeting epithelia. Also, as an example application resource, describe patterns acid-base transporter

Язык: Английский

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Mineralocorticoid Receptor Antagonists Cause Natriuresis in the Absence of Aldosterone

Hypertension, Год журнала: 2022, Номер 79(7), С. 1423 - 1434

Опубликована: Июнь 8, 2022

Background: MR (mineralocorticoid receptor) antagonists are recommended for patients with resistant hypertension even when circulating aldosterone levels not high. Although activates to increase epithelial sodium channel (ENaC) activity, glucocorticoids also activate but metabolized by 11βHSD2 (11β-hydroxysteroid dehydrogenase type 2). is expressed at increasing from distal convoluted tubule (DCT) through collecting duct. Here, we hypothesized that maintains ENaC activity in the DCT2 and early connecting absence of aldosterone. Methods: We studied AS (aldosterone synthase)-deficient (AS −/− ) mice, which were backcrossed onto same C57BL6/J strain as kidney-specific knockout (KS-MR mice. KS-MR mice used compare expression localization cleavage Results: was highly along cortical duct (CCD), whereas no observed DCT2. signal apical clearly reduced both CCD fully preserved partially Apical currents increased after low salt. exhibited transient Na + wasting under low-salt diet, administration antagonist eplerenone led hyperkalemia decreased body weight higher excretion, mimicking phenotype Conclusions: Our results provide evidence activated CCD, suggesting glucocorticoid binding preserves homeostasis

Язык: Английский

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Aristolochic acid-induced nephropathy is attenuated in mice lacking the neutral amino acid transporter B⁰AT1 (Slc6a19)

AJP Renal Physiology, Год журнала: 2022, Номер 323(4), С. F455 - F467

Опубликована: Авг. 18, 2022

B0AT1 (Slc6a19) mediates absorption of neutral amino acids in the small intestine and kidneys, where it is primarily expressed early proximal tubules (S1-S2). To determine role nephropathy induced by aristolochic acid (AA), which targets tubule, littermate female B0AT1-deficient (Slc6a19-/-), heterozygous (Slc6a19+/-), wild-type (WT) mice were administered AA (10 mg/kg ip) or vehicle every 3 days for wk, analyses performed after last injection wk later. Vehicle-treated lacking Slc6a19 showed normal body kidney weight plasma creatinine versus WT mice. The urinary glucose-to-creatinine ratio (UGCR) albumin-to-creatinine (UACR) two to four times higher vehicle-treated Slc6a19-/- mice, associated with lesser expression transporters Na+-glucose cotransporter 2 megalin, respectively. caused tubular injury independently B0AT1, including robust increases cortical mRNA p53, p21, hepatitis A virus cellular receptor 1 (Havcr1), downregulation related tubule B0AT2 (Slc6a15), B0AT3 (Slc6a18), Slc7a9, modest histological damage a rise creatinine. Absence however, attenuated AA-induced upregulation markers senescence (p16), inflammation [lipocalin (Lcn2), C-C motif chemokine ligand (Ccl2), (Ccr2)], fibrosis [tissue inhibitor metallopeptidase (Timp1), transforming growth factor-β1 (Tgfb1), collagen type I-α1 (Col1a1)], staining, suppression organic anion transporter 1, restoration expression, prevention fivefold increase observed data suggest that important physiology renal glucose albumin retention but potentially deleterious response following injury.NEW & NOTEWORTHY Based on insights from studies manipulating transport, hypothesis has been proposed inhibiting intestinal uptake reabsorption energy substrates unique therapeutic potential improve metabolic disease outcome injury. present study takes this idea major kidney, shows its absence attenuates acid-induced nephropathy.

Язык: Английский

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Impaired Endosome Maturation Mediates Tubular Proteinuria in Dent Disease Cell Culture and Mouse Models

Journal of the American Society of Nephrology, Год журнала: 2023, Номер 34(4), С. 619 - 640

Опубликована: Фев. 9, 2023

Significance Statement Loss of function the 2Cl − /H + antiporter ClC-5 in Dent disease causes an unknown impairment endocytic traffic, leading to tubular proteinuria. The authors integrated data from biochemical and quantitative imaging studies proximal tubule cells into a mathematical model determine that loss impairs endosome acidification delays early maturation cells, resulting reduced megalin recycling, surface expression, half-life. Studies mouse also revealed subsegment-specific differences effects knockout on subsegments. approach provides template dissect mutations or perturbations alter recovery filtered proteins level individual entire axis. Background uptake by kidney tubule, Reduced posttranslational stability cubilin, receptors bind recover proteins, is believed underlie defect. How leads receptor expression remains unknown. Methods We used adapt traffic control cells. mice were performed describe effect S1 segment along Results predicts have rates exit endosomes, decreased Early endosomes had lower [Cl ] higher pH. observed more profound expressing pathogenic E211G mutant. Alterations cellular distribution consistent with delayed recycling. Greater reductions S2 compared S1, consequences profile protein retrieval Conclusions Delayed due impaired accumulation primary mediator proteinuria disease. Rapid critical for efficient proteins.

Язык: Английский

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