scholarly journals Molecular and Cellular Physiology of Renal Organic Cation and Anion Transport

2004 ◽  
Vol 84 (3) ◽  
pp. 987-1049 ◽  
Author(s):  
Stephen H. Wright ◽  
William H. Dantzler
Keyword(s):  
Critical Role ◽  
Plasma Concentrations ◽  
Transport Processes ◽  
The Body ◽  
Transepithelial Transport ◽  
Renal Secretion ◽  
Proximal Tubule Cells ◽  
Renal Tubular Cells ◽  
Heterologous Expression Systems ◽  
Renal Tubular

Organic cations and anions (OCs and OAs, respectively) constitute an extraordinarily diverse array of compounds of physiological, pharmacological, and toxicological importance. Renal secretion of these compounds, which occurs principally along the proximal portion of the nephron, plays a critical role in regulating their plasma concentrations and in clearing the body of potentially toxic xenobiotics agents. The transepithelial transport involves separate entry and exit steps at the basolateral and luminal aspects of renal tubular cells. It is increasingly apparent that basolateral and luminal OC and OA transport reflects the concerted activity of a suite of separate transport processes arranged in parallel in each pole of proximal tubule cells. The cloning of multiple members of several distinct transport families, the subsequent characterization of their activity, and their subcellular localization within distinct regions of the kidney now allows the development of models describing the molecular basis of the renal secretion of OCs and OAs. This review examines recent work on this issue, with particular emphasis on attempts to integrate information concerning the activity of cloned transporters in heterologous expression systems to that observed in studies of physiologically intact renal systems.

scholarly journals Competitive Inhibition of Renal Tubular Secretion of Gemifloxacin by Probenecid

2009 ◽  
Vol 53 (9) ◽  
pp. 3902-3907 ◽  
Author(s):  
Cornelia B. Landersdorfer ◽  
Carl M. J. Kirkpatrick ◽  
Martina Kinzig ◽  
Jürgen B. Bulitta ◽  
Ulrike Holzgrabe ◽  
...  
Keyword(s):  
Competitive Inhibition ◽  
Concomitant Administration ◽  
Tubular Secretion ◽  
Transport Processes ◽  
The Body ◽  
Renal Elimination ◽  
Oral Tablet ◽  
Renal Tubular Secretion ◽  
Drug Concentrations ◽  
Renal Tubular

ABSTRACT Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones, renal clearance is reduced by concomitant administration of probenecid. The interaction between gemifloxacin and probenecid has not yet been studied. We studied the extent, time course, site(s), and mechanism of this interaction. Seventeen healthy volunteers participated in a randomized, two-way crossover study. Subjects received 320 mg gemifloxacin as an oral tablet without and with 4.5 g probenecid divided in eight oral doses. Drug concentrations in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry. WinNonlin was used for noncompartmental analysis, compartmental modeling, and statistics, and NONMEM was used for visual predictive checks. Concomitant administration of probenecid increased plasma gemifloxacin concentrations and amounts excreted in urine compared to baseline amounts. Data are average estimates (percent coefficients of variation). Modeling showed a competitive inhibition of the renal tubular secretion of gemifloxacin by probenecid as the most likely mechanism of the interaction. The estimated Km and V max for the saturable part of renal elimination were 9.16 mg/liter (20%) and 113 mg/h (21%), respectively. Based on the molar ratio, the affinity for the renal transporter was 10-fold higher for gemifloxacin than for probenecid. Since probenecid reached an ∼200-times-higher area under the molar concentration-time curve from 0 to 24 h than gemifloxacin, probenecid inhibited the active tubular secretion of gemifloxacin. Probenecid also reduced the nonrenal clearance of gemifloxacin from 25.2 (26%) to 21.0 (23%) liters/h. Probenecid inhibited the renal tubular secretion of gemifloxacin, most likely by a competitive mechanism, and slightly decreased nonrenal clearance of gemifloxacin.

Restoration of CREB function ameliorates cisplatin cytotoxicity in renal tubular cells

2008 ◽  
Vol 294 (3) ◽  
pp. F577-F581 ◽  
Author(s):  
Istvan Arany ◽  
Johann Herbert ◽  
Zsolt Herbert ◽  
Robert L. Safirstein
Keyword(s):  
Cell Death ◽  
Oxidant Stress ◽  
Erk Signaling ◽  
Proximal Tubule Cells ◽  
Renal Tubular Cells ◽  
Cancer Cell Death ◽  
Element Binding Protein ◽  
Renal Tubular ◽  
Responsive Element ◽  
Phosphorylated Creb

We have shown that mouse proximal tubule cells (TKPTS) survive H2O2 stress by activating the cAMP-responsive element binding protein (CREB)-mediated transcription via the canonical EGFR-Ras/ERK pathway. By contrast, cisplatin activates EGFR/Ras/ERK signaling in TKPTS cells yet promotes cell death rather than survival. We now demonstrate that the cisplatin-induced activated EGFR/Ras/ERK signaling cascade fails to activate CREB-mediated transcription even in the presence of phosphorylated CREB. CREB-mediated transcription as well as survival was restored by the histone deacetylase (HDAC) inhibitor trichostatine A (TSA), an effective chemotherapeutic agent. Similar to severe oxidant stress, TSA-mediated survival could be abrogated by inhibition of CREB-mediated transcription. These studies confirm the importance of CREB-mediated transcription in the survival of renal cells subjected to either oxidant- or cisplatin-induced stress. The use of cisplatin and TSA in combined chemotherapy protocols may be an effective strategy to enhance cancer cell death and limit nephrotoxicity.

Epigenetic mechanisms of nephroprotection in diabetic nephropathy: focus is on sirtuin-1

2021 ◽  
Vol 25 (6) ◽  
pp. 9-15
Author(s):  
K. A. Aitbaev ◽  
I. T. Murkamilov ◽  
V. V. Fomin ◽  
Zh. A. Murkamilova ◽  
F. A. Yusupov
Keyword(s):  
Diabetic Nephropathy ◽  
Kidney Diseases ◽  
Critical Role ◽  
Protective Role ◽  
Kidney Damage ◽  
Sirtuin 1 ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Nephroprotective Effect

Numerous studies have shown the critical role of sirtuin-1 deacetylase (SIRT1) in the protection of renal cells from endogenous and exogenous stresses. A protective role for SIRT1 has been established in both podocytes and renal tubular cells in many kidney diseases, including diabetic nephropathy (DN). SIRT1 has also been shown to have nephroprotective effects in DN, in part through the deacetylation of transcription factors involved in disease pathogenesis, such as p53, FOXO, RelA / p65NF-KB, STAT3, and PGC1a / PPARy. Recently, it was found that podocyte-specific overexpression of SIRT1 attenuates proteinuria and kidney damage in an experimental model of DN, suggesting the possibility of using SIRT1 as a potential target for the treatment of kidney disease. In addition, SIRT1 agonists such as resveratrol and BF175 have been shown to reduce diabetic kidney damage in several experimental animal models. It has also been shown that puerarin, a Chinese herbal medicine, activates SIRT1, providing nephroprotection in a mouse model of DN. In addition to SIRT1 agonists, inhibitors of bromodomain, in particular, MS417, also have a nephroprotective effect. These results suggest that SIRT1 agonists and bromodomain inhibitors may be new potential therapeutic agents that slow the progression of DN.

scholarly journals Methionine Ameliorates Polymyxin-Induced Nephrotoxicity by Attenuating Cellular Oxidative Stress

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Mohammad A. K. Azad ◽  
Sivashangarie Sivanesan ◽  
Jiping Wang ◽  
Ke Chen ◽  
Roger L. Nation ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Plasma Concentrations ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Superoxide Production ◽  
Dependent Manner ◽  
Renal Tubular Cells ◽  
Mitochondrial Superoxide ◽  
Total Body ◽  
Renal Tubular

ABSTRACT Polymyxins are a last line of defense against multidrug-resistant Gram-negative pathogens. Recent pharmacological data show that intravenous polymyxins can cause nephrotoxicity in up to 60% of patients, and the plasma concentrations of polymyxins achieved with the currently recommended dosage regimens are suboptimal in a large proportion of patients. Simply increasing the daily dose of polymyxins is not possible due to nephrotoxicity. This study aimed to examine the protective effect of methionine against polymyxin-induced nephrotoxicity. Methionine (400 mg/kg of body weight), polymyxin B (35 mg/kg), a combination of methionine (100 or 400 mg/kg) and polymyxin B, and saline were administered to mice twice daily over 3.5 days. Kidneys were collected immediately at the end of the experiment for histological examination. The effect of methionine on the pharmacokinetics of polymyxin B was investigated in rats. The attenuation of polymyxin B (0.75 mM)-induced mitochondrial superoxide production by methionine (10.0 mM) was examined in rat kidney (NRK-52E) cells. Histological results revealed that the polymyxin-induced nephrotoxicity in mice was ameliorated by methionine in a dose-dependent manner. The methionine doses were well tolerated in the mice and rats, and the pharmacokinetics of polymyxin B in rats were not affected by methionine. In the group receiving polymyxin B-methionine, the total body clearance of polymyxin B was very similar to that in the group receiving polymyxin B alone (3.71 ± 0.57 versus 3.12 ± 1.66 ml/min/kg, P > 0.05). A substantial attenuation of polymyxin-induced mitochondrial superoxide production in NRK-52E cells was observed following pretreatment with methionine. Our results demonstrate that coadministration of methionine significantly ameliorated polymyxin-induced nephrotoxicity and decreased mitochondrial superoxide production in renal tubular cells.

RENAL LYMPHANGIECTASIA IN A PATIENT AFFECTED BY COVID-19

2021 ◽  
pp. 191-193
Author(s):  
Stephany Soledad Martínez Hidalgo ◽  
Patricia Elena Pazmiño Pazmiño ◽  
Daily Malinivska Romero Hachig ◽  
Paola Fernanda Sánchez Pucha
Keyword(s):  
Low Frequency ◽  
Pulmonary Involvement ◽  
The Body ◽  
Liquid Content ◽  
Short Term ◽  
Renal Sinus ◽  
Sinus Disease ◽  
Renal Tubular Cells ◽  
Global Pandemic ◽  
Renal Tubular

SUMMARY: In December 2019, a new subspecies of coronavirus was identied in China, which they called SARS-CoV-2, responsible for the subsequent disease that the WHO called COVID-19. The disease has spread rapidly causing a global pandemic. Much is still unknown about SARS-CoV-2, but early research supports the hypothesis that the severity of Covid-19 is conditioned by the hyperinammatory response that occurs in our body when in contact with SARS-CoV-2. The severity of the condition is related to the respiratory failure it causes, however, there are studies that do not limit pulmonary involvement. Research indicates that the access mechanism of SARS-CoV-2 to the body is closely related to the ACE2 enzyme. An enzyme that, among other tissues, can be found in the epithelium of renal tubular cells. This is the reason why there are data from patients with Covid-19 that have a great effect on kidney function. It is for this reason that this clinical case of renal lymphagectasia is presented. Renal lymphagectasia is a rare entity of renal lymphatics that occurs in both children and adults, it can be unilateral or bilateral and has no sex predilection. It is characterized because there is dilation of the lymphatic ducts, generating cavities occupied by a liquid content corresponding to lymph. Its most frequent locations are the neck (70%) and the armpit (20%). Renal lymphangiectasia (RFL) is of very low frequency and can be confused with other cystic pathologies of the kidney. RFL has been described by various names such as: renal lymphangioma, peri-pelvic lymphangiectasia, polycystic renal sinus disease, renal hygroma, and multicystic perippelvic renal lymphangiectasia. It is believed to occur due to an alteration in the communication between the renal lymphatic ducts and the retroperitoneal lymphatics. We report the case of an elderly patient with Covid-19 infection, and LFR, in which this alteration was discovered incidentally in the study of abdominal pain associated with microscopic hematuria. OBJECTIVE: Describe bilateral renal lymphangiectasia associated with covid-19 infection. DESIGN: Prospective, observational in a single center. METHODOLOGY: This is a systematic review of bilateral renal lymphangiectasia in a patient affected by the new coronavirus (Covid-19); emphasizing its clinical characteristics and its short-term complications. The information and images obtained belong to the medical staff in charge of the case, whose reinforcements are provided by the Excel, Word and JPG statistical package.

scholarly journals Functional map of TEA transport activity in isolated rabbit renal proximal tubules

2004 ◽  
Vol 287 (3) ◽  
pp. F442-F451 ◽  
Author(s):  
Stephen H. Wright ◽  
Kristen K. Evans ◽  
Xiaohong Zhang ◽  
Nathan J. Cherrington ◽  
Daniel S. Sitar ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Organic Cation ◽  
Transport Processes ◽  
Transport Activity ◽  
Renal Secretion ◽  
Proximal Tubule Cells ◽  
Concerted Activity ◽  
S3 Segment ◽  
Functional Map ◽  
Similar Affinity

The organic cation (OC) transporters OCT1 and OCT2 are suspected of mediating substrate entry from the blood into proximal tubule cells as the first step in renal secretion of OCs. We examined the contribution of each process in different rabbit renal proximal tubule (RPT) segments, taking advantage of the fact that rabbit orthologs of OCT1 and OCT2 can be distinguished by the high affinity of the former for tyramine (TYR) and of the latter for cimetidine (CIM). We verified that TEA uptake, for which both transporters share a similar affinity, is relatively constant in all three segments (apparent inhibitory constant of 33, 74, and 30 μM and maximal rate of mediated TEA uptake of 0.8, 1.0, and 1.2 pmol·mm−1·min−1 in S1, S2, and S3, respectively). In the S1 segment, TYR was a more effective inhibitor of TEA uptake than CIM (IC50 values of 39 and 328 μM, respectively), implicating OCT1 as the predominant pathway for TEA transport. The opposite profiles were noted in the S2 segment (IC50 values of 302 and 20 μM for TYR and CIM, respectively) and S3 segment (IC50 values of 2,900 and 54 μM for TYR and CIM, respectively), suggesting that OCT2 is the predominant TEA transporter in the later portion of RPT. TEA sufficient to saturate OCT1 and OCT2 blocked only 37% of mediated amantadine transport in the S2 segment, confirming the functional presence of at least one additional OC transporter (perhaps OCT3). These data indicate that renal OC transport involves the concerted activity of a suite of transport processes.

Modulation of jejunal ion and water absorption by endogenous angiotensin after dehydration

1984 ◽  
Vol 246 (6) ◽  
pp. G700-G709 ◽  
Author(s):  
N. R. Levens
Keyword(s):  
Water Absorption ◽  
Enzyme Inhibitor ◽  
Plasma Concentrations ◽  
Extracellular Volume ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Transport Processes ◽  
Transepithelial Transport ◽  
Volume Depletion ◽  
Jejunal Absorption

In the pentobarbital sodium-anesthetized rat, dehydration for 24 h increased ion and water absorption from the jejunum. Dehydration also elevated plasma concentrations of angiotensin peptides and plasma renin activity but did not significantly alter plasma aldosterone concentrations. Infusion of tyramine, norepinephrine, and angiotensin II (AII) also stimulated jejunal absorption in a manner similar to dehydration. The elevation of jejunal absorption in response to dehydration is totally inhibited by the converting enzyme inhibitor captopril and the angiotensin receptor antagonist [lle7]AIII. Thus, increased jejunal absorption following dehydration is mediated by the renin-angiotensin system and is not secondary to either aldosterone or to antidiuretic hormone release. Further experiments demonstrated that the increase in jejunal absorption in response to dehydration was unaffected by propranolol but was totally abolished by phentolamine, prazosin, and peripheral sympathectomy. It is proposed that AII stimulates jejunal absorption by enhancing transepithelial transport processes and/or by altering the balance of Starling forces governing fluid absorption across enteric capillaries. Angiotensin thus appears to be a physiologically important mediator of jejunal absorption in states characterized by extracellular volume depletion.

Updating long-held assumptions about fat stigma: For women, body shape plays a critical role

2020 ◽  
Author(s):  
Jaimie Krems ◽  
Steven L. Neuberg
Keyword(s):  
Body Shape ◽  
Critical Role ◽  
The Body ◽  
Theoretical Assumption ◽  
Obesity Stigma ◽  
Obese Female ◽  
Three Samples ◽  
Female Bodies ◽  
Different Parts ◽  
Fat Stigma

Heavier bodies—particularly female bodies—are stigmatized. Such fat stigma is pervasive, painful to experience, and may even facilitate weight gain, thereby perpetuating the obesity-stigma cycle. Leveraging research on functionally distinct forms of fat (deposited on different parts of the body), we propose that body shape plays an important but largely underappreciated role in fat stigma, above and beyond fat amount. Across three samples varying in participant ethnicity (White and Black Americans) and nation (U.S., India), patterns of fat stigma reveal that, as hypothesized, participants differently stigmatized equally-overweight or -obese female targets as a function of target shape, sometimes even more strongly stigmatizing targets with less rather than more body mass. Such findings suggest value in updating our understanding of fat stigma to include body shape and in querying a predominating, but often implicit, theoretical assumption that people simply view all fat as bad (and more fat as worse).

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