scholarly journals Diurnal and Long-term Variation in Plasma Concentrations and Renal Clearances of Circulating Markers of Kidney Proximal Tubular Secretion

2017 ◽  
Vol 63 (4) ◽  
pp. 915-923 ◽  
Author(s):  
Matthew B Rivara ◽  
Leila R Zelnick ◽  
Andrew N Hoofnagle ◽  
Rick Newitt ◽  
Russell P Tracy ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Plasma Concentrations ◽  
Baseline Period ◽  
Tubular Secretion ◽  
Biological Variation ◽  
Renal Proximal Tubule ◽  
Intraindividual Variation ◽  
Proximal Tubular ◽  
Renal Clearances

Abstract 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. We further measured 24-h renal clearances of secreted solutes at baseline, 2 weeks, and 14 weeks. RESULTS Plasma concentrations of secreted solutes varied over the 24-h baseline period. Diurnal variation was greatest for HA, followed by CMG, IS, and PCS. Plasma concentrations of HA (P = 0.002) and IS (P = 0.02), but not CMG and PCS, increased significantly following meals. Long-term intraindividual biological variation (CVI) in plasma concentrations of secreted solutes over 14 weeks varied from 21.8% for IS to 67.3% for PCS, and exceeded that for plasma creatinine (CVI, 7.1%). Variation in 24-h renal clearances was similar among the secreted solutes [intraindividual variation (CVA+I), 33.6%–47.3%] and was lower using pooled plasma samples from each study visit. CONCLUSIONS Plasma concentrations of HA, CMG, IS, and PCS fluctuate within individuals throughout the day and over weeks. Renal clearances of these secreted solutes, which serve as estimates of renal proximal tubule secretion, are also subject to intraindividual biological variation that can be improved by additional plasma measurements.

scholarly journals Generation and characterization of iPSC-derived renal proximal tubule-like cells with extended stability

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Vidya Chandrasekaran ◽  
Giada Carta ◽  
Daniel da Costa Pereira ◽  
Rajinder Gupta ◽  
Cormac Murphy ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Retinoic Acid Receptor ◽  
Renal Proximal Tubule ◽  
Whole Body ◽  
Proper Function ◽  
Genome Wide ◽  
Glomerular Filtrate ◽  
Proximal Tubular ◽  
Induced Pluripotent

AbstractThe renal proximal tubule is responsible for re-absorption of the majority of the glomerular filtrate and its proper function is necessary for whole-body homeostasis. Aging, certain diseases and chemical-induced toxicity are factors that contribute to proximal tubule injury and chronic kidney disease progression. To better understand these processes, it would be advantageous to generate renal tissues from human induced pluripotent stem cells (iPSC). Here, we report the differentiation and characterization of iPSC lines into proximal tubular-like cells (PTL). The protocol is a step wise exposure of small molecules and growth factors, including the GSK3 inhibitor (CHIR99021), the retinoic acid receptor activator (TTNPB), FGF9 and EGF, to drive iPSC to PTL via cell stages representing characteristics of early stages of renal development. Genome-wide RNA sequencing showed that PTL clustered within a kidney phenotype. PTL expressed proximal tubular-specific markers, including megalin (LRP2), showed a polarized phenotype, and were responsive to parathyroid hormone. PTL could take up albumin and exhibited ABCB1 transport activity. The phenotype was stable for up to 7 days and was maintained after passaging. This protocol will form the basis of an optimized strategy for molecular investigations using iPSC derived PTL.

scholarly journals Evaluation of Novel Biomarkers of Nephrotoxicity in Two Strains of Rat Treated with Cisplatin

2010 ◽  
Vol 38 (6) ◽  
pp. 943-956 ◽  
Author(s):  
Jean-Charles Gautier ◽  
Björn Riefke ◽  
Jakob Walter ◽  
Petra Kurth ◽  
Lou Mylecraine ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Collecting Duct ◽  
Kidney Injury ◽  
Renal Proximal Tubule ◽  
Tubular Injury ◽  
Sprague Dawley ◽  
Glutathione S Transferase ◽  
Proximal Tubular ◽  
Novel Biomarkers ◽  
Noninvasive Biomarkers

Cisplatin is an anticancer agent that induces renal proximal tubule lesions in many species. Studies were conducted in Sprague-Dawley and Han-Wistar rats to evaluate the utility of novel preclinical biomarkers of nephrotoxicity for renal lesions caused by this compound. Groups of 10 males of each strain were given a single intraperitoneal injection of 0.3, 1, or 3 mg/kg cisplatin and were sacrificed on days 2, 3, and 5. The novel biomarkers α-glutathione-S-transferase (α-GST) (for proximal tubular injury), μ-glutathione-S-transferase (μ-GST) (for distal tubular injury), clusterin (for general kidney injury), and renal papillary antigen-1 (RPA-1) (for collecting duct injury) were measured in urine by enzyme immunoassay. Histologically, degeneration and necrosis of the S3 segment of the renal proximal tubule were observed on day 2 (Han-Wistar) and days 3 and 5 (both strains) at 1 and 3 mg/kg. Results showed that in both strains of rats, urinary α-GST and clusterin can be detected in urine soon after injury, are more sensitive than BUN and serum creatinine, and therefore are usable as noninvasive biomarkers of proximal tubule injury. Changes in both μ-GST or RPA-1 were considered to represent secondary minor effects of proximal tubular injury on distal segments of the nephron.

Short- and Long-Term Influences of Heavy Metals on Anionic Drug Efflux from Renal Proximal Tubule

2002 ◽  
Vol 301 (2) ◽  
pp. 578-585 ◽  
Author(s):  
Sylvie A. Terlouw ◽  
Claudia Graeff ◽  
Pascal H. E. Smeets ◽  
Gert Fricker ◽  
Frans G. M. Russel ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Proximal Tubule ◽  
Renal Proximal Tubule ◽  
Drug Efflux ◽  
Short And Long Term

Evidence for PAH extraction from superficial cortical efferent vessel plasma

1983 ◽  
Vol 245 (5) ◽  
pp. F577-F583
Author(s):  
S. W. Weinstein ◽  
R. Klose ◽  
A. M. Kumar
Keyword(s):  
Proximal Tubule ◽  
Tubular Secretion ◽  
Proximal Convoluted Tubule ◽  
Peritubular Capillary ◽  
Blood Samples ◽  
Rapid Extraction ◽  
Peritubular Capillaries ◽  
Pars Recta ◽  
Proximal Tubular

Consistent with its anatomical association with the proximal tubule we have previously shown that superficial cortical efferent vessel blood contains an admixture of early and late proximal tubular reabsorbate. Since tubular secretion of p-aminohippurate (PAH) occurs predominantly in the late proximal tubule, extraction of this compound should occur preferentially from efferent vessel blood. As a result, the midportion of the proximal convoluted tubule supplied by the more downstream peritubular capillaries would receive blood containing a disproportionately reduced concentration of PAH. To study this, proximal and distal tubular fluid and efferent vessel blood samples were collected from rats. The data confirm that preferential secretion of PAH occurs in the pars recta and demonstrate that PAH is extracted from efferent vessel plasma by the pars recta. This in turn preferentially reduces PAH concentration in early postglomerular blood before it reaches the peritubular capillary network. We speculate that PAH and similar substances secreted by the pars recta are short-circuited by rapid extraction from early postglomerular blood, reducing their delivery to the mid-proximal convoluted tubule. Such circumstances must be considered in any analysis of organic compound secretion by the in vivo proximal tubule.

A1 adenosine receptor knockout mice are protected against acute radiocontrast nephropathy in vivo

2006 ◽  
Vol 290 (6) ◽  
pp. F1367-F1375 ◽  
Author(s):  
H. Thomas Lee ◽  
Michael Jan ◽  
Soo Chan Bae ◽  
Jin Deok Joo ◽  
Farida R. Goubaeva ◽  
...  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Proximal Tubule ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cell ◽  
Proximal Tubule Cells ◽  
Proximal Tubular ◽  
Tubule Cells

The role of renal A1 adenosine receptors (A1AR) in the pathogenesis of radiocontrast nephropathy is controversial. We aimed to further elucidate the role of A1AR in the pathogenesis of radiocontrast nephropathy and determine whether renal proximal tubule A1AR contribute to the radiocontrast nephropathy. To induce radiocontrast nephropathy, A1AR wild-type (WT) or knockout (KO) mice were injected with a nonionic radiocontrast (iohexol, 1.5–3 g iodine/kg). Some A1WT mice were pretreated with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; a selective A1AR antagonist) before iohexol injection. A1AR contribute to the pathogenesis of radiocontrast nephropathy in vivo as the A1WT mice developed significantly worse acute renal failure, more renal cortex vacuolization, and had lower survival 24 h after iohexol treatment compared with the A1KO mice. DPCPX pretreatment also protected the A1WT mice against radiocontrast-induced acute renal failure. No differences in renal cortical apoptosis or inflammation were observed between A1WT and A1KO mice. To determine whether the proximal tubular A1AR mediate the direct renal cytotoxicity of radiocontrast, we treated proximal tubules in culture with iohexol with or without 2-chloro- N6-cyclopentyladenosine (a selective A1AR agonist) or DPCPX pretreatment. We also subjected cultured proximal tubule cells overexpressing A1AR or lacking A1AR to radiocontrast injury. Iohexol caused a direct dose-dependent reduction in proximal tubule cell viability as well as proliferation. Neither the A1AR agonist nor the antagonist treatment affected proximal tubule viability or proliferation. Moreover, overexpression or lack of A1AR failed to impact the iohexol toxicity on proximal tubule cells. Therefore, we conclude that radiocontrast causes acute renal failure via mechanisms dependent on A1AR; however, renal proximal tubule A1AR do not contribute to the direct tubular toxicity of radiocontrast.

Early postglomerular plasma concentrations of chloride, sodium, and inulin in the rat kidney

1976 ◽  
Vol 231 (3) ◽  
pp. 822-831 ◽  
Author(s):  
SW Weinstein ◽  
J Szyjewicz
Keyword(s):  
Sodium Chloride ◽  
Proximal Tubule ◽  
Blood Supply ◽  
Functional Relationship ◽  
Rat Kidney ◽  
Plasma Concentrations ◽  
Chloride Concentration ◽  
Sodium Concentration ◽  
Peripheral Plasma ◽  
Proximal Tubular

Sodium, chloride, and inulin concentrations were measured in plasma collected from the terminal portions of long efferent vessels at the subcapsular surface of the rat kidney. Sodium concentration equaled and the concentrations of chloride and inulin were less than those in peripheral plasma. During benzolamide infusion, chloride concentration equaled while inulin concentration remained less than in peripheral plasma. In free-flow micropuncture samples collected randomly during control conditions, chloride concentration rose rapidly in the early proximal tubule and then remained elevated and constant throughout the remainder of the proximal tubule accessible to micropuncture. These experiments indicate that normally tubular reabsorbate low in chloride and inulin is added to the blood traversing the early postglomerular vessels before reaching the kidney surface. Bases on the analyses of proximal tubular fluid, this type of reabsorbate appears available only from the early proximal tubular segment. We conclude that a close functional relationship exists between the first segment of the proximal tubule and the early postglomerular blood supply characteristic of the superficial cortical nephron.

Proximal tubular secretion of angiotensin II in rats

1993 ◽  
Vol 264 (5) ◽  
pp. F891-F898 ◽  
Author(s):  
B. Braam ◽  
K. D. Mitchell ◽  
J. Fox ◽  
L. G. Navar
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Enzyme Inhibitor ◽  
Isotonic Saline ◽  
Tubular Secretion ◽  
Ang Ii ◽  
Local Formation ◽  
Enhanced Sensitivity ◽  
Proximal Tubular ◽  
Nanomolar Range

It is now established that all of the components necessary for the local formation of angiotensin II (ANG II) coexist in the kidney and can alter local ANG II production rate. However, data on ANG II concentrations in different compartments within the kidney are limited. Recently, proximal tubule fluid ANG II concentrations in the nanomolar range were reported. Using an ANG II radioimmunoassay procedure with enhanced sensitivity, we performed experiments to explore proximal tubular fluid ANG II levels further and to determine the source of the ANG II. Total free-flow proximal tubular fluid samples (n = 11) had an average ANG II concentration of 13 +/- 2 nM. These concentrations were similar (10 +/- 2 nM) in samples collected into pipettes containing the inhibitors enalaprilat and EDTA (n = 17). Fluid collected from blocked proximal tubules that were perfused with artificial tubular fluid showed similar ANG II concentrations both in the presence (22 +/- 3 nM) and absence (22 +/- 4 nM) of the angiotensin-converting-enzyme inhibitor, enalaprilat, in the perfusate. Plasma ANG II concentrations were much lower and averaged 155 +/- 26 pM. Isotonic saline expansion lowered plasma ANG II levels to 30 +/- 5 pM (P < 0.01) but did not significantly decrease intraluminal ANG II (8 +/- 1 nM). These data provide further evidence that intratubular ANG II concentrations are in the nanomolar range and are regulated independently of the plasma ANG II levels. The data obtained from perfused tubules indicate that the proximal tubule adds substantial amounts of ANG II or a precursor into the tubular lumen.

Growth hormone directly stimulates gluconeogenesis in canine renal proximal tubule

1989 ◽  
Vol 257 (5) ◽  
pp. E751-E756
Author(s):  
S. A. Rogers ◽  
I. E. Karl ◽  
M. R. Hammerman
Keyword(s):  
Growth Hormone ◽  
Proximal Tubule ◽  
Glucose Production ◽  
Renal Proximal Tubule ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Igf I ◽  
Proximal Tubular

To characterize the action of growth hormone (GH) on gluconeogenesis in renal proximal tubule, glucose production was measured in suspensions of canine renal proximal tubular segments incubated with 1 mM L-alanine, 10 mM lactate, 1 mM succinate, and various concentrations (10(-11) to 10(-6) M) of recombinant bovine GH (bGH). Production of glucose increased as a function of time for 120 min. Bovine growth hormone (10(-6) M) increased glucose production at 120 min by 55 +/- 16%. Significant enhancement of glucose production occurred in suspensions of segments incubated with as little as 10(-10) M bGH. Half-maximal stimulation occurred at between 10(-9) and 10(-8) M. To ascertain whether these actions of bGH are mediated directly, we determined the effects of insulin-like growth factors (IGFs) I and II on glucose production. Addition of IGF-I to segments enhanced glucose production in a concentration-dependent manner. However, incubation with bGH did not induce measurable IGF-I production in the segments. In contrast to the action of IGF-I, IGF-II did not affect glucose production. We conclude that bGH acts directly on cells within proximal tubular segments to enhance gluconeogenesis. Stimulation of gluconeogenesis in vitro could reflect a counterregulatory action of GH exerted on renal proximal tubule in vivo.

Pathways involved in PTH-induced rise in cytosolic Ca2+ concentration of rat renal proximal tubule

1995 ◽  
Vol 268 (2) ◽  
pp. F330-F337 ◽  
Author(s):  
H. Tanaka ◽  
M. Smogorzewski ◽  
M. Koss ◽  
S. G. Massry
Keyword(s):  
Proximal Tubule ◽  
G Protein ◽  
Positive Control ◽  
Renal Proximal Tubule ◽  
Channel Blockers ◽  
Proximal Tubular ◽  
The Media ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubule Cells ◽  
Renal Proximal Tubular

Parathyroid hormone (PTH) raises cytosolic Ca2+ concentration ([Ca2+]i) in isolated or cultured renal proximal tubule cells. The pathways through which this action is mediated are not fully delineated. This study explored these pathways utilizing fura 2. [Ca2+]i of freshly prepared renal proximal tubular cells increased from 150 +/- 3.6 to 281 +/- 9.0 nM after the exposure to 10(-7) M angiotensin II, which served as a positive control. Both PTH-(1-84) and PTH-(1-34) produced a dose-dependent rise in [Ca2+]i. The effects of both moieties were similar up to 10(-7) M, but with higher doses the rise in [Ca2+]i with PTH-(1-84) was greater (P < 0.01) than with PTH-(1-34). This effect of the hormone occurred in the presence or absence of calcium in the media, but the rise in [Ca2+]i was significantly greater in the presence of calcium. The PTH-induced rise in [Ca2+]i was markedly inhibited by PTH antagonist [Nle8,18,Tyr34]bPTH-(7-34)-NH2 (bPTH is bovine PTH), verapamil, or nifedipine. 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, increased [Ca2+]i of cells, but its effect was less than PTH. Staurosporine abolished the TPA effect and partially inhibited that of PTH. A G protein activator raised [Ca2+]i, whereas a G protein inhibitor and pertussis toxin partially blocked the effect of PTH. Sodium or chloride channel blockers or sodium-free media did not modify the effect of PTH.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Transcription Factor ChREBP Mediates High Glucose-Evoked Increase in HIF-1α Content in Epithelial Cells of Renal Proximal Tubules

2021 ◽  
Vol 22 (24) ◽  
pp. 13299
Author(s):  
Aleksandra Owczarek ◽  
Katarzyna B. Gieczewska ◽  
Robert Jarzyna ◽  
Zuzanna Frydzinska ◽  
Katarzyna Winiarska
Keyword(s):  
Transcription Factor ◽  
Epithelial Cells ◽  
Proximal Tubule ◽  
High Glucose ◽  
Target Genes ◽  
Renal Proximal Tubule ◽  
Diabetes Type Ii ◽  
Nadh Ratio ◽  
Proximal Tubular ◽  
Hif1a Gene

Hyperglycemia/diabetes appears to be accompanied by the state of hypoxia, which especially affects kidneys. The aim of the study was to elucidate the mechanism of high glucose action on HIF-1α expression in renal proximal tubule epithelial cells. The research hypotheses included: (1) the participation of transcription factor ChREBP; and (2) the involvement of the effects resulting from pseudohypoxia, i.e., lowered intracellular NAD+/NADH ratio. The experiments were performed on HK-2 cells and primary cells: D-RPTEC (Diseased Human Renal Proximal Tubule Epithelial Cells—Diabetes Type II) and RPTEC (Renal Proximal Tubule Epithelial Cells). Protein and mRNA contents were determined by Western blot and RT-qPCR, respectively. ChREBP binding to DNA was detected applying chromatin immunoprecipitation, followed by RT-qPCR. Gene knockdown was performed using siRNA. Sirtuin activity and NAD+/NADH ratio were measured with commercially available kits. It was found that high glucose in HK-2 cells incubated under normoxic conditions: (1) activated transcription of HIF-1 target genes, elevated HIF-1α and ChREBP content, and increased the efficacy of ChREBP binding to promoter region of HIF1A gene; and (2), although it lowered NAD+/NADH ratio, it affected neither sirtuin activity nor HIF-1α acetylation level. The stimulatory effect of high glucose on HIF-1α expression was not observed upon the knockdown of ChREBP encoding gene. Experiments on RPTEC and D-RPTEC cells demonstrated that HIF-1α content in diabetic proximal tubular cells was lower than that in normal ones but remained high glucose-sensitive, and the latter phenomenon was mediated by ChREBP. Thus, it is concluded that the mechanism of high glucose-evoked increase in HIF-1α content in renal proximal tubule endothelial cells involves activation of ChREBP, indirectly capable of HIF1A gene up-regulation.

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