Physiological roles of renal anion transporters NaS1 and Sat1

This review will briefly summarize current knowledge on the renal anion transporters sodium-sulfate cotransporter-1 (NaS1; Slc13a1) and sulfate-anion transporter-1 (Sat1; Slc26a1). NaS1 and Sat1 mediate renal proximal tubular sulfate reabsorption and thereby regulate blood sulfate levels. Sat1 also mediates renal oxalate transport and controls blood oxalate levels. Targeted disruption of murine NaS1 and Sat1 leads to hyposulfatemia and hypersulfaturia. Sat1 null mice also exhibit hyperoxalemia, hyperoxaluria, and calcium oxalate urolithiasis. NaS1 and Sat1 null mice also have other phenotypes that result due to changes in blood sulfate and oxalate levels. Experimental data indicate that NaS1 is essential for maintaining sulfate homeostasis, whereas Sat1 controls both sulfate and oxalate homeostasis in vivo.

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In Vitro and In Vivo Evaluation of Amphiphilic Chitosan Derivatives for Inhibition of Organic Cation Transport Function

Key Engineering Materials ◽

10.4028/www.scientific.net/kem.859.45 ◽

2020 ◽

Vol 859 ◽

pp. 45-50

Author(s):

Sirima Soodvilai ◽

Sunhapas Soodvila ◽

Warayuth Sajomsang ◽

Theerasak Rojanarata ◽

Prasopchai Patrojanasophon ◽

...

Keyword(s):

Organic Cation ◽

Drug Disposition ◽

Organic Cation Transporter ◽

Transport Function ◽

Chitosan Derivatives ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular ◽

Renal Proximal Tubular

This study explored the interaction of amphiphilic chitosan derivatives, N-benzyl-N,O-succinyl chitosan (BSCS), N-naphthyl-N,O-succinyl chitosan (NSCS) and N-octyl-N,O-succinyl chitosan (OSCS), with renal organic cation transporter 2 (OCT2). The influence of amphiphilic chitosan derivatives on renal OCT2 transport function was determined by monitoring the transport of a positively charged substrate into human renal proximal tubular epithelial cells (RPTEC/TERT1 cells), and murine kidney. Amphiphilic chitosan derivatives inhibited 3H-MPP (a substrate of OCT2) transport in the renal cells in a concentration-reliance characteristic. OSCS reduced the accumulation of the cationic drug, cisplatin, in RPTEC/TERT1 cells. This effect was more pronounced than that of other chitosan derivatives. In addition, co-administration of cisplatin and OSCS significantly reduced cisplatin accumulation compared with receiving cisplatin alone. This result was accompanied by the decrease in nephrotoxicity induced by cisplatin. In conclusion, OSCS inhibited OCT2 function and reduced cationic drug disposition in human renal proximal tubular cells and murine kidney.

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Renoprotective Effects of Nobiletin on High Glucose-Induced Loss of Proximal Tubular Microvilli

Current Developments in Nutrition ◽

10.1093/cdn/nzaa045_045 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 412-412

Author(s):

Min kyung Kang ◽

Dongyeon Kim ◽

Young-Hee Kang

Keyword(s):

Proximal Tubule ◽

High Glucose ◽

Citrus Fruit ◽

Cellular Polarity ◽

Funding Sources ◽

In Vivo Animal Model ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular ◽

Renal Proximal Tubular

Abstract Objectives Kidney proximal tubular epithelium has microvillar brush borders, which is critical to renal reabsorption. Hyperglycemia induce change the loss of brush border and cellular polarity, tight junction disruption. Nobiletin is a polymethoxyflavone present in citrus fruit and peels, and has anti-inflammatory effects. This study investigated the renoprotective effects of nobiletin on proximal tubule microvillar ultrastructure and reabsorption under diabetic condition. Methods Human renal proximal tubular epithelial cells (RPTEC) were incubated in a media exposed to 33 mM glucose in the absence and presence of 1–20 μM nobiletin up to 6 days. Antibodies F-actin, villin, cubulin, megalin, SGLT2 and GLUT2 were used for Western blot analysis. The in vivo animal model employed db/db mice orally administrated with 10 mg/kg of nobiletin. Extracts of tissues were subjected to Western blotting or immunohistochemical staining. Results High glucose declined expression of F-actin and villin required for the assembly of proximal tubule microvilli. In addition, the expression of glucose uptake proteins of GLUT2 and SGLT2 was prompted in hyperglycemia. However, nontoxic nobiletin enhanced the expression of F-actin reduced by high glucose, while the elevated expression of the GLUT2 and SGLT2 was attenuated by nobiletin. In the in vivo study, oral administration of 10 mg/kg nobiletin inhibited loss of tubular microvilli through restoring expression of F-actin and villin in diabetic kidneys. Furthermore, nobiletin reduced expressions of GLUT2 and the albumin uptake receptors of cubulin and megalin in db/db mouse kidneys. Conclusions These results demonstrated that nobiletin curtailed loss of the proximal tubular microvillar proteins responsible for tubular reabsorption. Nobiletin may be a potent renoprotective agent counteracting diabetes-associated proximal tubular dysfunctions leading to kidney failure. Funding Sources This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (2017R1A6A3A04011473).

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Oxalate: From the Environment to Kidney Stones

Archives of Industrial Hygiene and Toxicology ◽

10.2478/10004-1254-64-2013-2428 ◽

2013 ◽

Vol 64 (4) ◽

pp. 609-630 ◽

Cited By ~ 11

Author(s):

Hrvoje Brzica ◽

Davorka Breljak ◽

Birgitta C Burckhardt ◽

Gerhard Burckhardt ◽

Ivan Sabolić

Keyword(s):

Underlying Mechanism ◽

Stone Disease ◽

Sulfate Anion ◽

Intestinal Excretion ◽

Oxalate Absorption ◽

Anion Transporter ◽

Solute Carrier ◽

Sat 1 ◽

Oxalate Transport

Abstract Oxalate urolithiasis (nephrolithiasis) is the most frequent type of kidney stone disease. Epidemiological research has shown that urolithiasis is approximately twice as common in men as in women, but the underlying mechanism of this sex-related prevalence is unclear. Oxalate in the organism partially originate from food (exogenous oxalate) and largely as a metabolic end-product from numerous precursors generated mainly in the liver (endogenous oxalate). Oxalate concentrations in plasma and urine can be modified by various foodstuffs, which can interact in positively or negatively by affecting oxalate absorption, excretion, and/or its metabolic pathways. Oxalate is mostly removed from blood by kidneys and partially via bile and intestinal excretion. In the kidneys, after reaching certain conditions, such as high tubular concentration and damaged integrity of the tubule epithelium, oxalate can precipitate and initiate the formation of stones. Recent studies have indicated the importance of the SoLute Carrier 26 (SLC26) family of membrane transporters for handling oxalate. Two members of this family [Sulfate Anion Transporter 1 (SAT-1; SLC26A1) and Chloride/Formate EXchanger (CFEX; SLC26A6)] may contribute to oxalate transport in the intestine, liver, and kidneys. Malfunction or absence of SAT-1 or CFEX has been associated with hyperoxaluria and urolithiasis. However, numerous questions regarding their roles in oxalate transport in the respective organs and male-prevalent urolithiasis, as well as the role of sex hormones in the expression of these transporters at the level of mRNA and protein, still remain to be answered.

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Mitochondria transfer from mesenchymal stem cells structurally and functionally repairs renal proximal tubular epithelial cells in diabetic nephropathy in vivo

Scientific Reports ◽

10.1038/s41598-019-40163-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 20

Author(s):

Naoto Konari ◽

Kanna Nagaishi ◽

Shin Kikuchi ◽

Mineko Fujimiya

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Diabetic Nephropathy ◽

Epithelial Cells ◽

Tubular Epithelial Cells ◽

Mitochondria Transfer ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular ◽

Renal Proximal Tubular

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

AJP Renal Physiology ◽

10.1152/ajprenal.00290.2002 ◽

2003 ◽

Vol 284 (3) ◽

pp. F503-F509 ◽

Cited By ~ 30

Author(s):

Birgitta C. Burckhardt ◽

Stefan Brai ◽

Sönke Wallis ◽

Wolfgang Krick ◽

Natascha A. Wolff ◽

...

Keyword(s):

Organic Anion ◽

Human Kidney ◽

Organic Anion Transporter ◽

In Vivo Studies ◽

Xenopus Laevis Oocytes ◽

Organic Anion Transporters ◽

Anion Transporters ◽

Anion Transporter ◽

Inward Currents

The H2-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 [3H]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 [3H]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.

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The soluble intracellular domain of megalin does not affect renal proximal tubular function in vivo

Kidney International ◽

10.1038/ki.2010.169 ◽

2010 ◽

Vol 78 (5) ◽

pp. 473-477 ◽

Cited By ~ 16

Author(s):

Annabel Christ ◽

Sara Terryn ◽

Vanessa Schmidt ◽

Erik I. Christensen ◽

Matthew R. Huska ◽

...

Keyword(s):

Tubular Function ◽

Intracellular Domain ◽

Proximal Tubular ◽

Proximal Tubular Function ◽

Renal Proximal Tubular ◽

Renal Proximal Tubular Function

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How big is the electrochemical potential difference of Na+ across rat renal proximal tubular cell membranes in vivo?

Pflügers Archiv - European Journal of Physiology ◽

10.1007/bf00581792 ◽

1985 ◽

Vol 405 (S1) ◽

pp. S121-S126 ◽

Cited By ~ 43

Author(s):

K. Yoshitomi ◽

E. Fr�mter

Keyword(s):

Cell Membranes ◽

Proximal Tubular Cell ◽

Electrochemical Potential ◽

Potential Difference ◽

Tubular Cell ◽

Renal Proximal Tubular Cell ◽

Proximal Tubular ◽

Renal Proximal Tubular

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Cell Spinpods: A Simple Inexpensive Device to Determine Suspension Culture and Toxicity Effects on Renal Proximal Tubular Cells

10.21203/rs.3.rs-625193/v1 ◽

2021 ◽

Author(s):

Timothy G. Hammond ◽

Corey Nislow ◽

Ivan C. Christov ◽

Vecihi Batuman ◽

Pranay P. Nagrani ◽

...

Keyword(s):

Suspension Culture ◽

Industrial Applications ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Proximal Tubular ◽

Injection Molded ◽

Renal Proximal Tubular Cells ◽

Renal Proximal Tubular

Abstract Rotating forms of suspension culture allow cells to aggregate into spheroids, prevent the de-differentiating influence of adherence to plastic surfaces, and, perhaps most importantly of all, provide physiologically relevant, in vivo levels of shear stress. Suspension culture technology has not, however, been widely implemented, in large part because the vessels are prohibitively expensive, labor-intensive to use, and are difficult to scale for industrial applications. Our solution addresses each of these challenges in a new vessel called a cell spinpod. These small 3.5 mL capacity vessels are constructed from injection molded thermoplastic polymer components. They contain self-sealing axial silicone rubber ports, and fluoropolymer, breathable membranes. Here we report the development of injection molded cell spinpods with two-fluid modeling of the flow and stresses. Their validation was accomplished using immortalized human renal proximal tubular cells for functional assays, renal damage marker release, and differential gene expression analysis via next-generation sequencing. During exposure to myeloma immunoglobulin light chains, rotation increased both toxin-induced cell death, and release of clinically validated nephrotoxicity cytokine markers in a toxin-specific pattern. Cell spinpods are a sensitive tool for detecting nephrotoxicity in vitro.

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Enhancement of in vitro human tubulogenesis by endothelial cell-derived factors: implications for in vivo tubular regeneration after injury

AJP Renal Physiology ◽

10.1152/ajprenal.00619.2010 ◽

2011 ◽

Vol 301 (2) ◽

pp. F387-F395 ◽

Cited By ~ 23

Author(s):

Masaaki Miya ◽

Akito Maeshima ◽

Keiichiro Mishima ◽

Noriyuki Sakurai ◽

Hidekazu Ikeuchi ◽

...

Keyword(s):

Endothelial Cell ◽

Critical Role ◽

Capillary Endothelium ◽

Renal Tubules ◽

Tubular Structures ◽

Peritubular Capillaries ◽

Proximal Tubular ◽

Renal Proximal Tubular

Renal proximal tubular epithelium can regenerate after various insults. To examine whether the tubular repair process is regulated by surrounding peritubular capillaries, we established an in vitro human tubulogenesis model that mimics in vivo tubular regeneration after injury. In this model, HGF, a potent renotropic factor, dose dependently induced tubular structures in human renal proximal tubular epithelial cells cultured in gels. Consistent with regenerating tubular cells after injury, HGF-induced tubular structures expressed a developmental gene, Pax-2, and a mesenchymal marker, vimentin, and formed a lumen with aquaporin-1 expression. Electron microscopic analysis showed the presence of microvilli on the apical site of the lumen, suggesting that these structures are morphologically equivalent to renal tubules in vivo. When cocultured with human umbilical vein endothelial cells (HUVEC), HGF-induced tubular formation was significantly enhanced. This could not be reproduced by the addition of VEGF, basic FGF, or PDGF. Protein array revealed that HUVEC produced various matrix metalloproteinases (MMPs). The stimulatory effects of coculture with HUVEC or HUVEC-derived conditional medium were almost completely abolished by addition of the tissue inhibitor of metalloproteinase (TIMP)-1 or TIMP-2. These data suggest that endothelial cell-derived factors including MMPs play a critical role in tubulogenesis and imply a potential role of peritubular capillary endothelium as a source of factor(s) required for tubular recovery after injury.

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