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https://www.readbyqxmd.com/read/28210973/renal-drug-transporters-and-drug-interactions
#1
REVIEW
Anton Ivanyuk, Françoise Livio, Jérôme Biollaz, Thierry Buclin
Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side...
February 16, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28208054/high-glucose-induced-hypomethylation-promotes-binding-of-sp-1-to-myo-inositol-oxygenase-implication-in-the-pathobiology-of-diabetic-tubulopathy
#2
Isha Sharma, Rajesh K Dutta, Neel K Singh, Yashpal S Kanwar
The catabolic enzyme myo-inositol oxygenase (MIOX) is expressed in proximal tubules and up-regulated in the diabetic state. Previously, we reported its transcriptional and translation regulation by high glucose (HG), osmolytes, and fatty acids. However, its epigenetic regulation is unknown. Bisulfite sequencing revealed that both human and mouse MIOX promoters, enriched with CpG sites, are hypomethylated and unmethylated under HG ambience and hyperglycemic states associated with increased MIOX expression. Eletrophoretic mobility shift assays revealed increased binding of unmethylated oligos with nucleoproteins of cells maintained under HG...
February 13, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28204833/small-heterodimer-partner-attenuates-hydrogen-peroxide-induced-expression-of-cyclooxygenase-2-and-inducible-nitric-oxide-synthase-by-suppression-of-activator-protein-1-and-nuclear-factor-%C3%AE%C2%BAb-in-renal-proximal-tubule-epithelial-cells
#3
Jung Sun Park, Hoon In Choi, Eun Hui Bae, Seong Kwon Ma, Soo Wan Kim
The orphan nuclear receptor, small heterodimer partner (SHP), plays a negative regulatory role in innate immune responses and is involved in various inflammatory signaling pathways. In the present study, we aimed to ascertain whether SHP is effective in preventing hydrogen peroxide (H2O2)-induced kidney tubular inflammation and explored the molecular mechanisms underlying the protective effects of SHP. Renal ischemia/reperfusion (I/R) injury was induced in mice by clamping both renal pedicles for 30 min...
March 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28203358/the-renal-effects-of-sglt2-inhibitors-and-a-mini-review-of-the-literature
#4
REVIEW
Vasileios Andrianesis, Spyridoula Glykofridi, John Doupis
Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new and promising class of antidiabetic agents which target renal tubular glucose reabsorption. Their action is based on the blockage of SGLT2 sodium-glucose cotransporters that are located at the luminal membrane of tubular cells of the proximal convoluted tubule, inducing glucosuria. It has been proven that they significantly reduce glycated hemoglobin (HbA1c), along with fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus (T2DM)...
December 2016: Therapeutic Advances in Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28196131/altered-renal-sodium-handling-and-risk-of-incident-hypertension-results-of-the-olivetti-heart-study
#5
Lanfranco D'Elia, Francesco P Cappuccio, Roberto Iacone, Ornella Russo, Ferruccio Galletti, Pasquale Strazzullo
Renal tubular sodium (Na) handling plays a key role in blood pressure (BP) regulation. Several cross-sectional studies reported a positive association between higher proximal tubule fractional reabsorption of Na and BP, but no prospective investigation has been reported of this possible association. Hence, the purpose of this study was to estimate the predictive role of renal Na handling on the risk of incident hypertension and the changes in BP occurring in the 8-year follow-up observation of a sample of initially normotensive men (The Olivetti Heart Study)...
2017: PloS One
https://www.readbyqxmd.com/read/28196047/a-time-dependent-model-describes-methotrexate-elimination-and-supports-dynamic-modification-of-mrp2-abcc2-activity
#6
Jean-Baptiste Woillard, Jean Debord, Isabelle Benz-de-Bretagne, Franck Saint-Marcoux, Pascal Turlure, Stéphane Girault, Julie Abraham, Sylvain Choquet, Pierre Marquet, Chantal Barin-Le Guellec
BACKGROUND: MRP2/ABCC2, an efflux transporter expressed at the proximal renal tubule, is rate limiting for urine excretion of coproporphyrin (UCP) isomers I and III, translating in high UCP (I/(I+III)) ratio in MRP2-deficient patients presenting with the Dubin-Johnson Syndrome. MRP2 is also a major contributor to methotrexate (MTX) clearance. As MTX is both a substrate and an inhibitor of MRP2, time course of the concentrations of MTX in blood could induce functional modification of MRP2 over time, which in turn can modify its own elimination rate...
February 11, 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28190922/histopathological-background-data-of-the-systemic-organs-of-clawn-miniature-swine-with-coronary-artery-stent-implantation
#7
Atsushi Isobe, Masako Tasaki, Tomoki Inoue, Hisako Terao, Junko Souba, Kasuke Nagano, Hitomi Hagiwara
The aim of this study was to identify potential changes that could occur during histological evaluations of CLAWN miniature swine, with potential consequences for subsequent experiments. The systemic organs from male and female CLAWN miniature swine (16.3-42.3 months old) that had been used in long-term studies of coronary stent implantation were examined histologically. Commonly observed histopathological findings were testicular/epididymal atrophy, cyst-like follicles in the ovaries, hemosiderin deposition in the spleen, lipofuscin deposition in the proximal tubular epithelia and presence of eosinophilic globules in the Bowman's space and the lumen of the proximal tubules in the kidneys, and cellular infiltration in several organs, including the eyelids, respiratory organs, and digestive tract...
January 2017: Journal of Toxicologic Pathology
https://www.readbyqxmd.com/read/28190920/acute-alloxan-renal-toxicity-in-the-rat-initially-causes-degeneration-of-thick-ascending-limbs-of-henle
#8
Yui Terayama, Yasushi Kodama, Tetsuro Matsuura, Kiyokazu Ozaki
Alloxan (AL) is a material well-known to induce diabetes. Prior to inducing a prolonged diabetic state, AL causes acute tubulointerstitial nephritis. However, the precise primary target site and mechanism of its nephrotoxicity remain unclear. The objective of this study was to evaluate the morphological characteristics relevant to acute renal toxicity following AL administration. Rats were intravenously treated with AL. Eight hours after AL treatment, aquaporin 1-negative and Na/K pump-positive thick ascending limbs of Henle (TAL) were degenerated in the outer medulla...
January 2017: Journal of Toxicologic Pathology
https://www.readbyqxmd.com/read/28188231/diurnal-and-long-term-variation-in-plasma-concentrations-and-renal-clearances-of-circulating-markers-of-kidney-proximal-tubular-secretion
#9
Matthew B Rivara, Leila R Zelnick, Andrew N Hoofnagle, Rick Newitt, Russell P Tracy, Mario Kratz, David S Weigle, Bryan R Kestenbaum
BACKGROUND: The renal proximal tubule is essential for removing organic solutes and exogenous medications from the circulation. We evaluated diurnal, prandial, and long-term biological variation of 4 candidate endogenous markers of proximal tubular secretion. METHODS: We used LC-MS to measure plasma and urine concentrations of hippurate (HA), cinnamoylglycine (CMG), indoxyl sulfate (IS), and p-cresol sulfate (PCS) in 25 healthy adults. We measured plasma concentrations of secreted solutes at 13 time points over a 24-h period, and again after 2 weeks and 14 weeks of follow-up...
February 10, 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/28180992/comprehensive-functional-analysis-of-rab-gtpases-in-drosophila-nephrocytes
#10
Yulong Fu, Jun-Yi Zhu, Fujian Zhang, Adam Richman, Zhanzheng Zhao, Zhe Han
The Drosophila nephrocyte is a critical component of the fly renal system and bears structural and functional homology to podocytes and proximal tubule cells of the mammalian kidney. Investigations of nephrocyte cell biological processes are fundamental to understanding the insect renal system. Nephrocytes are highly active in endocytosis and vesicle trafficking. Rab GTPases regulate endocytosis and trafficking but specific functions of nephrocyte Rabs remain undefined. We analyzed Rab GTPase expression and function in Drosophila nephrocytes and found that 11 out of 27 Drosophila Rabs were required for normal activity...
February 8, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28179254/a-mathematical-model-of-the-rat-kidney-k-induced-natriuresis
#11
Alan M Weinstein
A model of the rat nephron (Am. J. Physiol. 308:F1098, 2015) has been extended with addition of medullary vasculature. Blood vessels contain solutes from the nephron model, plus additional species from the model of Atherton et al. (Am. J. Physiol. 247:F61, 1984), representing hemoglobin buffering. In contrast to prior models of the urine concentrating mechanism, reflection coefficients for DVR are near zero. Model unknowns are initial proximal tubule pressures and flows, connecting tubule pressure, and medullary interstitial pressures and concentrations...
February 8, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28177761/temporo-spacial-micoranatomical-distribution-of-the-murine-sodium-dependent-ascorbic-acid-transporters-slc23a1-and-slc23a2-in-the-kidney-throughout-development
#12
Peter Karl Eck, Christopher Corpe, Mark Alan Levine
The two membrane transporters Slc23a1 and Slc23a2 mediate ascorbic acid uptake into cells. We recently determined the key role of Slc23a1 in renal re-absorption of ascorbic acid in a knockout mouse model. However, the renal spatial and temporal expression patterns of murine Slc23a1 and Slc23a2 are not defined. This study utilizes database evidence combined with experimental confirmation via in situ hybridization to define spatial and temporal expression of Slc23a1 in the murine kidney. Slc23a1 is expressed in the early proximal tubule, but not in its precursors during embryonic development, and exclusive proximal tubular expression persists throughout the animal's lifetime...
December 20, 2016: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/28176881/functional-coupling-of-human-microphysiology-systems-intestine-liver-kidney-proximal-tubule-blood-brain-barrier-and-skeletal-muscle
#13
Lawrence Vernetti, Albert Gough, Nicholas Baetz, Sarah Blutt, James R Broughman, Jacquelyn A Brown, Jennifer Foulke-Abel, Nesrin Hasan, Julie In, Edward Kelly, Olga Kovbasnjuk, Jonathan Repper, Nina Senutovitch, Janet Stabb, Catherine Yeung, Nick C Zachos, Mark Donowitz, Mary Estes, Jonathan Himmelfarb, George Truskey, John P Wikswo, D Lansing Taylor
Organ interactions resulting from drug, metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media...
February 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28168227/urine-metabolomic-analysis-to-detect-metabolites-associated-with-the-development-of-contrast-induced-nephropathy
#14
Deborah B Diercks, Kelly P Owen, Jeffrey A Kline, Mark E Sutter
OBJECTIVE: Contrast induced nephropathy (CIN) is a result of injury to the proximal tubules. The incidence of CIN is around 11% for imaging done in the acute care setting. We aim to analyze the metabolic patterns in the urine, before and after dosing with intravenous contrast for computed tomography (CT) imaging of the chest, to determine if metabolomic changes exist in patients who develop CIN. METHODS: A convenience sample of high risk patients undergoing a chest CT with intravenous contrast were eligible for enrollment...
December 2016: Clinical and Experimental Emergency Medicine
https://www.readbyqxmd.com/read/28165842/stagnation-of-autophagy-a-novel-mechanism-of-renal-lipotoxicity
#15
Yoshitsugu Takabatake, Takeshi Yamamoto, Yoshitaka Isaka
Excessive fat intake can lead to cellular injury and inflammation (termed lipotoxicity), but studies on lipid metabolism in the kidney have been scarce. We recently identified a novel mechanism of lipotoxicity in the kidney proximal tubules especially focusing on the effect of lipid overload on lysosomal function and autophagic activity. Lipid overload basically stimulates macroautophagy/autophagy for renovation of the plasma and organelle membranes, which plays an essential role in maintaining the integrity of proximal tubules...
February 6, 2017: Autophagy
https://www.readbyqxmd.com/read/28161386/podocyturia-parallels-proximal-tubule-dysfunction-in-type-2-diabetes-mellitus-patients-independently-of-albuminuria-and-renal-function-decline-a-cross-sectional-study
#16
Ligia Petrica, Mihaela Vlad, Adrian Vlad, Gheorghe Gluhovschi, Florica Gadalean, Victor Dumitrascu, Roxana Popescu, Cristina Gluhovschi, Petru Matusz, Silvia Velciov, Flaviu Bob, Sorin Ursoniu, Daliborca Vlad
AIMS: Detection of podocytes in the urine of patients with type 2 diabetes may indicate severe injury to the podocytes. In the course of type 2 diabetes the proximal tubule is involved in urinary albumin processing. We studied the significance of podocyturia in relation with proximal tubule dysfunction in type 2 diabetes. METHODS: A total of 86 patients with type 2 diabetes (34-normoalbuminuria; 30-microalbuminuria; 22-macroalbuminuria) and 28 healthy subjects were enrolled in the study and assessed concerning urinary podocytes, podocyte-associated molecules, and biomarkers of proximal tubule dysfunction...
January 20, 2017: Journal of Diabetes and its Complications
https://www.readbyqxmd.com/read/28155123/p66shc-mediated-toxicity-of-high-dose-%C3%AE-tocopherol-in-renal-proximal-tubule-cells
#17
Dustin K Reed, Anthony Carter, Mehul Dixit, Istvan Arany
α-Tocopherol (TOC) is a widely used supplement known for its role as an antioxidant. Previously, we have shown that TOC elicits adaptive responses by upregulating the ERK/CREB/HO-1 pathway, which depends on its concentration in cultured renal proximal tubule cells (RPTCs). This suggests that high-dose TOC (hTOC) may elicit adverse effects via inflicting oxidative stress. Since the pro-oxidant p66shc is a major mediator of oxidant injury in various models of renal toxicants, we tested the hypothesis that hTOC elicits renal toxicity through activation of p66shc and consequent oxidative stress...
February 2, 2017: Journal of Physiology and Biochemistry
https://www.readbyqxmd.com/read/28151777/longitudinal-assessment-of-proximal-tubular-dysfunction-in-hiv-seropositive-and-seronegative-persons-correlates-and-implications
#18
Kerry M Schnell, Mohamed G Atta, Derek M Fine, Katie Zook, Allison M Mcfall, Michelle M Estrella, George J Schwartz, Gregory M Lucas
BACKGROUND: Proximal tubule dysfunction (PTD) is common in HIV-positive persons and has been associated with tenofovir disoproxil fumarate (TDF). However, few studies have assessed the natural history PTD in HIV-positive and -negative individuals, or the association of PTD with the subsequent trajectory of directly measured glomerular filtration rate (mGFR). METHODS: We followed 192 HIV-positive and 100 HIV-negative, non-diabetic participants for three years. We measured 3 PTD markers (normoglycemic glycosuria, fractional excretion of phosphorus, and tubular proteinuria) and mGFR (by iohexol disappearance from serum) annually...
February 1, 2017: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/28149983/role-of-the-kidney-in-type-2-diabetes-and-mechanism-of-action-of-sodium-glucose-cotransporter-2-inhibitors
#19
Matthew L Mintz
The aim of this supplement is to discuss the important role of the kidney in glucose homeostasis. It produces glucose via gluconeogenesis, it filters glucose from the blood, and reabsorbs the filtered glucose in the proximal tubule, mainly via the sodium-glucose cotransporter-2 (SGLT-2). SGLT-2 is paradoxically upregulated in individuals with type 2 diabetes (T2D), which results in increased glucose reabsorption and hyperglycemia. This core defect in the pathophysiology of T2D provides the rationale for the use of SGLT-2 inhibitors to increase urinary glucose excretion and reduce hyperglycemia in an insulin-independent manner...
December 2016: Journal of Family Practice
https://www.readbyqxmd.com/read/28149671/macrophage-tgf-%C3%AE-1-and-the-proapoptotic-extracellular-matrix-protein-bigh3-induce-renal-cell-apoptosis-in-prediabetic-and-diabetic-conditions
#20
Robert J Moritz, Richard G LeBaron, Clyde F Phelix, Rajesha Rupaimoole, Hong Seok Kim, Andrew Tsin, Reto Asmis
Metabolically stressed kidney is in part characterized by infiltrating macrophages and macrophage-derived TGF-β1 that promote the synthesis of various ECM molecules. TGF-β1 strongly enhances the expression of the gene TGFBI that encodes a cell-adhesion class, proapoptotic ECM protein called BIGH3. We hypothesized that in a diabetic environment a relationship between infiltrating macrophages, macrophage-derived TGF-β1, and BIGH3 protein promotes renal cell death. To investigate this hypothesis, we used our mouse model of diabetic complications...
July 2016: International Journal of Clinical Medicine
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