Birgitta C. Burckhardt

University of Göttingen

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Gerhard Burckhardt

University of Göttingen

Yohannes Hagos

University of Göttingen

Ivan Sabolić

University Hospital Centre Zagreb

Davorka Breljak

Institute for Medical Research and Occupational Health

Vedran Micek

Institute for Medical Research and Occupational Health

Ivana Vrhovac

University of Split

Hrvoje Brzica

University of Arizona

Maja Henjakovic

Danube Private University

Wolfgang Krick

Universitätsmedizin Göttingen

Marija Ljubojević

Institute for Medical Research and Occupational Health

Cooperative Institutions

Therapeutic Guidelines

Evidence Based Research (United States)

Association for Research and Industrial Development of Natural Resources

University of Göttingen

Universitätsmedizin Göttingen

Harvard University

Institute for Medical Research and Occupational Health

RELX Group (United States)

Nephrologisches Zentrum Goettingen

University of Zagreb

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Identification of a New Urate and High Affinity Nicotinate Transporter, hOAT10 (SLC22A13)

Journal of Biological Chemistry (2008)

Andrew Bahn Yohannes Hagos Stefan Reuter Daniela Balen Hrvoje Brzica

The orphan transporter hORCTL3 (human organic cation transporter like 3; SLC22A13) is highly expressed in kidneys and to a weaker extent in brain, heart, and intestine. hORCTL3-expressing Xenopus laevis oocytes showed uptake of [³H]nicotinate, [³H]p-aminohippurate, and [¹⁴C]urate. Hence, hORCTL3 is an organic anion transporter, and we renamed it hOAT10. [³H]Nicotinate transport by hOAT10 into X. laevis oocytes and into Caco-2 cells was saturable with Michaelis constants (K_m) of 22 and 44 μm, respectively, suggesting that hOAT10 may be the molecular equivalent of the postulated high affinity nicotinate transporter in kidneys and intestine. The pH dependence of hOAT10 suggests p-aminohippurate^–/OH^–, urate^–/OH^–, and nicotinate^–/OH^– exchange as possible transport modes. Urate inhibited [³H]nicotinate transport by hOAT10 with an IC₅₀ value of 759 μm, assuming that hOAT10 represents a low affinity urate transporter. hOAT10-mediated [¹⁴C]urate uptake was elevated by an exchange with l -lactate, pyrazinoate, and nicotinate. Surprisingly, we have detected urate^–/glutathione exchange by hOAT10, consistent with an involvement of hOAT10 in the renal glutathione cycle. Uricosurics, diuretics, and cyclosporine A showed substantial interactions with hOAT10, of which cyclosporine A enhanced [¹⁴C]urate uptake, providing the first molecular evidence for cyclosporine A-induced hyperuricemia.

Identification

10.1074/jbc.m800737200

Cite

Citations (207)

Ability of sat-1 to transport sulfate, bicarbonate, or oxalate under physiological conditions

AJP Renal Physiology (2009)

Wolfgang Krick Nina Schnedler Gerhard Burckhardt Birgitta C. Burckhardt

Tubular reabsorption of sulfate is achieved by the sodium-dependent sulfate transporter, NaSi-1, located at the apical membrane, and the sulfate-anion exchanger, sat-1, located at the basolateral membrane. To delineate the physiological role of rat sat-1, [(35)S]sulfate and [(14)C]oxalate uptake into sat-1-expressing oocytes was determined under various experimental conditions. Influx of [(35)S]sulfate was inhibited by bicarbonate, thiosulfate, sulfite, and oxalate, but not by sulfamate and sulfide, in a competitive manner with K(i) values of 2.7 +/- 1.3 mM, 101.7 +/- 9.7 microM, 53.8 +/- 10.9 microM, and 63.5 +/- 38.7 microM, respectively. Vice versa, [(14)C]oxalate uptake was inhibited by sulfate with a K(i) of 85.9 +/- 9.5 microM. The competitive type of inhibition indicates that these compounds are most likely substrates of sat-1. Physiological plasma bicarbonate concentrations (25 mM) reduced sulfate and oxalate uptake by more than 75%. Simultaneous application of sulfate, bicarbonate, and oxalate abolished sulfate as well as oxalate uptake. These data and electrophysiological studies using a two-electrode voltage-clamp device provide evidence that sat-1 preferentially works as an electroneutral sulfate-bicarbonate or oxalate-bicarbonate exchanger. In kidney proximal tubule cells, sat-1 likely completes sulfate reabsorption from the ultrafiltrate across the basolateral membrane in exchange for bicarbonate. In hepatocytes, oxalate extrusion is most probably mediated either by an exchange for sulfate or bicarbonate.

Bicarbonate

10.1152/ajprenal.90401.2008

Cite

Citations (36)

Role of hepatic and renal sat-1 in ethylene glycol-induced urolithiasis in rat

Ivan Sabolić Hrvoje Brzica Davorka Breljak Mila Lovrić Ivana Vrhovac

INTRODUCTION. Sodium-independent sulfate anion transporter (sat-1 ; Slc26a1) plays a major role in transport of oxalate (OX) across the cell membrane by exchanging OX for sulfate or bicarbonate. Sat-1 mRNA has been detected strongly in liver and kidney and weakly in few other organs in rats, mice, and humans. By immunocytochemistry (IC), the protein has been localized in rats to the sinusoidal membrane of hepatocytes and basolateral membrane of proximal tubules (PT) in the kidney cortex, with the male (M)-dominant expression. In liver, which is a major OX producer, sat-1 mediates the extrusion of OX and uptake of sulfate, whereas in PT, it mediates the OX uptake, mainly in exchange for intracellular sulfate. In middle-aged humans, OX is a major cause of sex-related urolithiasis ; men excrete more OX and have higher incidence of OX stones then women. Accordingly, in studies of experimental urolithiasis in ethylene glycol (EG)-treated rats, testosterone stimulated, whereas female (F) sex hormones inhibited the urine excretion of OX and formation of OX stones. The role of OX transporters that in liver and kidneys exhibit the sex-related expression, such as sat-1, in the development of OX urolithiasis is not known. In the present study, we tested the expression of sat-1 at the protein and mRNA levels in the liver and kidneys of EG-treated rats. METHODS. Adult M and female (F) Wistar strain rats were treated with EG (0, 75% v/v in drinking water) for one month. Controls drunk water without EG. 24-h urine was collected in metabolic cages a day before sacrificing. OX in the blood plasma and urine were determined by ion-chromatography. Tissue morphology and OX crystals in the urine sediment were checked by light microscopy. Sat-1 protein expression was studied using a polyclonal antibody by IC in p-formaldehyde-fixed tissue cryosections, and by Western blotting of total cell membranes isolated from tissue homogenates. Tissue expression of sat-1 mRNA was studied by real time RT-PCR. RESULTS. In control M and F animals, the M-dominant sex differences in the urine excretion of OX, in the number and size of urine OX crystals, and in the expression of sat-1 protein (but not mRNA) in liver and kidneys, were confirmed. Compared to controls, the EG-treated animals exhibited: a) in plasma, 100% (F) and 4-fold (M) higher concentration of OX, b) in urine, 100% (F) and 17-fold (M) higher OX excretion, c) in urine sediment, similar and low abundance of small OX crystals in F, and increased abundance of large OX crystals in M, d) in tissues of both sexes, un-affected morphology in liver, and dilatated PT and distended peritubular spaces in kidneys, e) upregulated expression of sat-1 protein in the F liver and kidneys to the level in M organs, f) unchanged expression of sat-1 protein in the M liver and kidneys, and g) unchanged expression of sat-1 mRNA in both organs of F and M animals. CONCLUSION. Whereas the blood and urinary parameters in EG-treated rats indicate the low and high oxaluric state in F and M rats, respectively, the EG-induced elevated expression of sat-1 protein in the F liver and kidneys, and unchanged expression of this protein in M organs, indicate that sat-1 plays no significant role in generation of OX urolithiasis in EG-treated animals.

Epithelial polarity

Apical membrane

Source

Cite

Citations (0)

Contents Vol. 26, 2014

Nephron Physiology (2014)

Geoffrey A. Block Colo Denver Philip A. Kalra Southampton Roderick Minn Foley

10.1159/000365804

Cite

Citations (0)

Transport of cimetidine by flounder and human renal organic anion transporter 1

AJP Renal Physiology (2003)

Birgitta C. Burckhardt Stefan Brai Sönke Wallis Wolfgang Krick Natascha A. Wolff

The H 2 -receptor antagonist cimetidine is efficiently excreted by the kidneys. In vivo studies indicated an interaction of cimetidine not only with transporters for basolateral uptake of organic cations but also with those involved in excretion of organic anions. We therefore tested cimetidine as a possible substrate of the organic anion transporters cloned from winter flounder (fROAT) and from human kidney (hOAT1). Uptake of [ 3 H]cimetidine into fROAT-expressing Xenopus laevis oocytes exceeded uptake into control oocytes. At −60-mV clamp potential, 1 mM cimetidine induced an inward current, which was smaller than that elicited by 0.1 mM PAH. Cimetidine concentrations exceeding 0.1 mM decreased PAH-induced inward currents, indicating interaction with the same transporter. At pH 6.6, no current was seen with 0.1 mM cimetidine, whereas at pH 8.6 a current was readily detectable, suggesting preferential translocation of uncharged cimetidine by fROAT. Oocytes expressing hOAT1 also showed [ 3 H]cimetidine uptake. These data reveal cimetidine as a substrate for fROAT/hOAT1 and suggest that organic anion transporters contribute to cimetidine excretion in proximal tubules.

Cimetidine

Organic anion

10.1152/ajprenal.00290.2002

Cite

Citations (44)

The orphan drug carbaglu is a substrate of the sodium dicarboxylate transporter 3 (896.8)

The FASEB Journal (2014)

Birgitta C. Burckhardt Elisabeth Schwob Yohannes Hagos Gerhard Burckhardt

Inborn defects in the carbamoylphosphate synthase 1 (CPS1) cause a reduction of N ‐acetylglutamate (NAG), an essential cofactor for the function of the urea cycle, and consequently elevated blood levels of the neurotoxic ammonia. N ‐carbamoylglutamate (carglumic acid, carbaglu®, NCG) is a structural analog of NAG that can substitute for NAG on CPS1, thereby reactivating the urea cycle and finally reducing blood ammonia levels. The renal clearance of NCG exceeds the glomerular filtration rate suggesting an active secretion process in kidney proximal tubules. The kidneys are known to express organic anion transporting polypeptides (OATPs) and organic anion transporters (OATs). OATs work in cooperation with sodium‐dicarboxylate transporters (NaDCs) thereby mediating the exit of many drugs. The impact of NCG on several human OATPs, OATs, and NaDCs stably transfected in HEK293 cells was tested. From the transporters tested, OAT1, OATP1B3, and NaDC3 interacted with NCG. Sodium‐ and concentration‐dependent NCG‐mediated currents were measured in Xenopus laevis oocytes expressing NaDC3. NCG was identified as a high affinity substrate of NaDC3 with a K M of 27.5 µM. This value equals the plasma concentration of succinate, the lead substance of NaDC3 and as well as the plasma concentration of patients treated with NCG. Competition of succinate and NCG on NaDC3 may result in reduced renal clearance of drugs.

Organic anion-transporting polypeptide

10.1096/fasebj.28.1_supplement.896.8

Cite

Citations (0)

Transport of organic anions across the basolateral membrane of proximal tubule cells

Reviews of physiology, biochemistry and pharmacology (2003)

Birgitta C. Burckhardt Gerhard Burckhardt

Epithelial polarity

Probenecid

Estrone sulfate

Organic anion

10.1007/s10254-002-0003-8

Cite

Citations (298)

Potential-dependent steady-state kinetics of a dicarboxylate transporter cloned from winter flounder kidney

Pflügers Archiv - European Journal of Physiology (2000)

Birgitta C. Burckhardt Jürgen Steffgen Denis Langheit Gerhard A. Müller Gerhard Burckhardt

Hyperpolarization

10.1007/s004240000421

Cite

Citations (13)

Sex-independent expression of chloride/formate exchanger Cfex (Slc26a6) in rat pancreas, small intestine, and liver, and male-dominant expression in kidneys

Archives of Industrial Hygiene and Toxicology (2018)

Dean Karaica Davorka Breljak Jovica Lončar Mila Lovrić Vedran Micek

Abstract Chloride/formate exchanger (CFEX; SLC26A6) mediates oxalate transport in various mammalian organs. Studies in Cfex knockout mice indicated its possible role in development of male-dominant hyperoxaluria and oxalate urolithiasis. Rats provide an important model for studying this pathophysiological condition, but data on Cfex (rCfex) localisation and regulation in their organs are limited. Here we applied the RT-PCR and immunochemical methods to investigate rCfex mRNA and protein expression and regulation by sex hormones in the pancreas, small intestine, liver, and kidneys from intact prepubertal and adult as well as gonadectomised adult rats treated with sex hormones. rCfex cDNA-transfected HEK293 cells were used to confirm the specificity of the commercial anti-CFEX antibody. Various biochemical parameters were measured in 24-h urine collected in metabolic cages. rCfex mRNA and related protein expression varied in all tested organs. Sex-independent expression of the rCfex protein was detected in pancreatic intercalated ducts (apical domain), small intestinal enterocytes (brush-border membrane; duodenum > jejunum > ileum), and hepatocytes (canalicular membrane). In kidneys, the rCfex protein was immunolocalised to the proximal tubule brush-border with segment-specific pattern (S1=S2<S3), and both rCfex mRNA and protein expression exhibited male-dominant sex differences driven by stimulatory effects of androgens after puberty. However, urinary oxalate excretion was unrelated to renal rCfex protein expression. While the effect of male-dominant expression of rCfex in renal proximal tubules on urine oxalate excretion remains unknown, its expression in the hepatocyte canalicular membrane may be a pathway of oxalate elimination via bile.

Brush border

10.2478/aiht-2018-69-3157

Cite

Citations (6)

Glutathione Is a Low-Affinity Substrate of the Human Sodium-Dependent Dicarboxylate Transporter

Nephron Physiology (2013)

Lena Schorbach Wolfgang Krick Gerhard Burckhardt Birgitta C. Burckhardt

During a single pass through the kidneys, more than 80% of glutathione (GSH) is excreted, indicating not only glomerular filtration, but also tubular secretion. The first step in tubular secretion is the uptake of a substance across the basolateral membrane of proximal tubule cells by sodium-dependent and -independent transporters. Due to the dicarboxylate-like structure, we postulated that GSH uptake across the basolateral membrane is mediated by the sodium-dependent dicarboxylate transporter 3 (NaDC3).Tracer uptake and electrophysiologic measurements using a two-electrode voltage clamp device were performed in Xenopus laevis oocytes expressing the human (h)NaDC3.Uptake of succinate, the reference substrate of hNaDC3, was inhibited by GSH in a dose-dependent manner with an IC50 of 1.88 mM. GSH evoked potential-dependent inward currents, which were abolished under sodium-free conditions. At -60 mV, GSH currents showed saturation kinetics with a KM of 1.65 mM.hNaDC3 present at the basolateral membrane of proximal tubule cells mediates sodium-dependent GSH uptake. The kinetic data show that NaDC3 is a low-affinity GSH transporter.

10.1159/000356419

Cite

Citations (5)