Erythropoietin alters the pharmacokinetics of organic anions mainly eliminated by the kidney in rats

2021 ◽  
Vol 99 (4) ◽  
pp. 368-377
Author(s):  
María Julia Severin ◽  
María Herminia Hazelhoff ◽  
Romina Paula Bulacio ◽  
María Eugenia Mamprin ◽  
Anabel Brandoni ◽  
...  
Keyword(s):  
Organic Anion ◽  
Elimination Rate ◽  
Renal Tissue ◽  
Organic Anions ◽  
Saline Control ◽  
Control Group ◽  
Anion Transporters ◽  
Male Wistar Rats ◽  
Pah Clearance ◽  
Renal Expression

Erythropoietin (EPO) is a cytokine originally used for its effects on the hematopoietic system, and is widely prescribed around the world. In the present study, the effects of EPO administration on p-aminohippurate (PAH, a prototype organic anion) pharmacokinetics and on the renal expression of PAH transporters were evaluated. Male Wistar rats were treated with EPO or saline (control group). After 42 h, PAH was administered, and plasma samples were obtained at different time points to determine PAH levels. PAH levels in renal tissue and urine were also assessed. The renal expression of PAH transporters was evaluated by Western blotting. EPO-treated rats showed an increase in PAH systemic clearance, in its elimination rate constant, and in urinary PAH levels, while PAH in renal tissue was decreased. Moreover, EPO administration increased the expression of the transporters of the organic anions evaluated. The EPO-induced increase in PAH clearance is accounted for by the increase in its renal secretion mediated by the organic anion transporters. The goal of this study is to add important information to the wide knowledge gap that exists regarding drug–drug interactions. Owing to the global use of EPO, these results are useful in terms of translation into clinical practice.

Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats

2007 ◽  
Vol 292 (5) ◽  
pp. F1599-F1605 ◽  
Author(s):  
R. Schneider ◽  
C. Sauvant ◽  
B. Betz ◽  
M. Otremba ◽  
D. Fischer ◽  
...  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Organic Anion ◽  
Organic Anions ◽  
Organic Anion Transporters ◽  
Protein Levels ◽  
Anion Transporters ◽  
Pah Clearance ◽  
Ischemic Acute Renal Failure

Ischemic acute renal failure (iARF) was described to reduce renal extraction of the organic anion para-aminohippurate (PAH) in humans. The rate-limiting step of renal organic anion secretion is its basolateral uptake into proximal tubular cells. This process is mediated by the organic anion transporters OAT1 and OAT3, which both have a broad spectrum of substrates including a variety of pharmaceutics and toxins. Using a rat model of iARF, we investigated whether impairing the secretion of the organic anion PAH might be associated with downregulation of OAT1 or OAT3. Inulin and PAH clearance was determined starting from 6 up to 336 h after ischemia-reperfusion (I/R) injury. Net secretion of PAH was calculated and OAT1 as well as OAT3 expression was analyzed by RT-PCR and Western blotting. Inulin and PAH clearance along with PAH net secretion were initially diminished after I/R injury with a gradual recovery during follow-up. This initial impairment after iARF was accompanied by decreased mRNA and protein levels of OAT1 and OAT3 in clamped animals compared with sham-operated controls. In correlation to the improvement of kidney function, both mRNA and protein levels of OAT1 and OAT3 were upregulated during the follow-up. Thus decreased expression of OAT1 and OAT3 is sufficient to explain the decline of PAH secretion after iARF. As a result, this may have substantial impact on excretion kinetics and half-life of organic anions. As a consequence, the biological effects of a variety of organic anions may be affected after iARF.

Mechanism Involved in Fortification by Berberine in CDDP-Induced Nephrotoxicity

2020 ◽  
Vol 13 (4) ◽  
pp. 342-352 ◽  
Author(s):  
Vipin K. Verma ◽  
Salma Malik ◽  
Ekta Mutneja ◽  
Anil K. Sahu ◽  
Kumari Rupashi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Renal Tissue ◽  
Isoquinoline Alkaloid ◽  
Experimental Models ◽  
Beclin 1 ◽  
Control Treatment ◽  
Control Group ◽  
Treatment Groups ◽  
Single Intraperitoneal Injection ◽  
Male Wistar Rats

Background: The activation of Nrf2/HO-1 pathway has been shown to protect against cisplatin- induced nephrotoxicity by reducing oxidative stress. Berberine (Ber), an isoquinoline alkaloid, has demonstrated antioxidant, anti-inflammatory and anti-apoptotic activities in various experimental models. Aim: To check the effect of Ber on cisplatin-induced nephrotoxicity and to explore the involved mechanism. Methods: Adult male Wistar rats were divided into 6 groups: Normal, cisplatin-control, treatment groups and per se group. Normal saline and Ber (20, 40 and 80 mg/kg; p.o.) was administered to rats for 10 days. A single intraperitoneal injection of cisplatin (8 mg/kg) was injected on 7th day to induced nephrotoxicity. On 10th day, rats were sacrificed, the kidney was removed and stored for the estimation of various parameters. Results: As compared to cisplatin-control group, Ber pretreatment improved renal function system and preserved renal architecture. It also diminished oxidative stress by upregulating the expression of Nrf2/HO-1 proteins. In addition, Ber attenuated the cisplatin mediated inflammation and apoptosis. Furthermore, it also reduced the phosphorylation of p38/JNK and PARP/Beclin-1 expression in the kidney. Conclusion: Ber attenuated renal injury by activating Nrf2/HO-1 and inhibiting JNK/p38MAPKs/ PARP/Beclin-1 expression which prevented oxidative stress, inflammation, apoptosis and autophagy in renal tissue.

scholarly journals Effects of Pistacia atlantica Subsp. Kurdica on Cadmium-Induced Oxidative Damage in Rat Kidney

2020 ◽  
Vol 1 (1) ◽  
pp. 10-14
Author(s):  
Seyed Salam Kohnepoushi ◽  
Dara Dastan ◽  
Amir Nili-Ahmadabadi
Keyword(s):  
Oxidative Damage ◽  
Rat Kidney ◽  
Radical Scavenging ◽  
Renal Tissue ◽  
Positive Control ◽  
Saline Control ◽  
Control Group ◽  
Pistacia Atlantica ◽  
Serum Blood Urea Nitrogen ◽  
Group 2

Background: Pistacia atlantica kurdica has recently been shown to possess free radical scavenging ability. The current study aims to investigate the protective effect of this plant against cadmium-induced nephrotoxicity. Methods: Thirty-six rats were divided into 6 groups (6 in each), and treated as follows: group 1 received normal saline (control group), group 2 (positive control) received cadmium by drinking water (100 mg/ L/d), group 3 received 200 mg/kg of P. atlantica extract, and groups 4-6 received cadmium as well as 50, 100 and 200 mg/kg/d of P. atlantica extract (orally), respectively. After 2 weeks, oxidative damage and renal function markers were assayed by standard methods. Results: In cadmium group, a significant increase was observed in serum blood urea nitrogen (BUN) (P<0.01) and lipid peroxidation (LPO) level of renal tissue (P<0.001) and a remarkable decrease was found in total thiol molecules (TTM) of the kidney (P<0.001). Despite the decreased renal antioxidant capacity, these changes were not significant. P. atlantica extract improved the LPO, TTM, and histopathological changes in renal tissue. Conclusion: In this study, although the P. atlantica extract did not have a significant effect on cadmiuminduced renal dysfunction, it did improve the oxidative/antioxidant balance in renal tissue.

Novel aspects of the transport of organic anions by the malpighian tubules of Drosophila melanogaster

2000 ◽  
Vol 203 (23) ◽  
pp. 3575-3584 ◽  
Author(s):  
S.M. Linton ◽  
M.J. O'Donnell
Keyword(s):  
Drosophila Melanogaster ◽  
Organic Acid ◽  
Organic Anion ◽  
Indigo Carmine ◽  
Organic Anions ◽  
Malpighian Tubules ◽  
Principal Cells ◽  
Anion Transporters ◽  
Mode Of Transport

Para-aminohippuric acid (PAH) is a negatively charged organic ion that can pass across the epithelium of Malpighian tubules. Its mode of transport was studied in Malpighian tubules of Drosophila melanogaster. PAH transport was an active process, with a K(m) of 2. 74 mmol l(−)(1) and a V(max) of 88.8 pmol min(−)(1). Tubules had a low passive permeability to PAH, but PAH transport rates (832 nmol min(−)(1)mm(2)) and concentrative ability ([PAH](secreted fluid):[PAH](bath)=81.2) were the highest measured to date for insects. Competition experiments indicated that there were two organic anion transporters, one that transports carboxylate compounds, such as PAH and fluorescein, and another that transports sulphonates, such as amaranth and Indigo Carmine. PAH transport appears to be maximal in vivo because the rate of transport by isolated tubules is not increased when these are challenged with cyclic AMP, cyclic GMP, leucokinin I or staurosporine. Basolateral PAH transport was inhibited by ouabain and dependent on the Na(+) gradient. The Malpighian tubules appeared not to possess an organic acid/ α -keto acid exchanger because PAH accumulation was not affected by low concentrations (100 μmol l(−)(1)) of α -keto acids (α -ketoglutarate, glutarate, citrate and succinate) or the activity of phosphokinase C. PAH transport may be directly coupled to the Na(+) gradient, perhaps via Na(+)/organic acid cotransport. Fluorescence microscopy showed that transport of the carboxylate fluorescein was confined to the principal cells of the main (secretory) segment and all the cells of the lower (reabsorptive) segment. Organic anions were transported across the cytoplasm of the principal cells both by diffusion and in vesicles. The accumulation of punctate fluorescence in the lumen is consistent with exocytosis of the cytoplasmic vesicles. Apical PAH transport was independent of the apical membrane potential and may not occur by an electrodiffusive mechanism.

Effect of erythropoietin on mercury-induced nephrotoxicity: Role of membrane transporters

2020 ◽  
pp. 096032712095810
Author(s):  
MH Hazelhoff ◽  
AM Torres
Keyword(s):  
Renal Function ◽  
Organic Anion ◽  
Absorption Spectrometry ◽  
Renal Tissue ◽  
Mercury Content ◽  
Organic Anion Transporter ◽  
Tubular Injury ◽  
Human Erythropoietin ◽  
Anion Transporter ◽  
Renal Expression

Mercury is a widespread pollutant. Mercuric ions uptake into tubular cells is supported by the Organic anion transporter 1 (Oat1) and 3 (Oat3) and its elimination into urine is through the Multidrug resistance-associated protein 2 (Mrp2). We investigated the effect of recombinant human erythropoietin (Epo) on renal function and on renal expression of Oat1, Oat3, and Mrp2 in a model of mercuric chloride (HgCl2)-induced renal damage. Four experimental groups of adult male Wistar rats were used: Control, Epo, HgCl2, and Epo + HgCl2. Epo (3000 IU/kg, b.w., i.p.) was administered 24 h before HgCl2 (4 mg/kg, b.w., i.p.). Experiments were performed 18 h after the HgCl2 dose. Parameters of renal function and structure were evaluated. The protein expression of Oat1, Oat3 and Mrp2 in renal tissue was assessed by immunoblotting techniques. Mercury levels were determined by cold vapor atomic absorption spectrometry. Pretreatment with Epo ameliorated the HgCl2-induced tubular injury as assessed by histopathology and urinary biomarkers. Immunoblotting showed that pretreatment with Epo regulated the renal expression of mercury transporters in a way to decrease mercury content in the kidney. Epo pretreatment ameliorates HgCl2-induced renal tubular injury by modulation of mercury transporters expression in the kidneys.

scholarly journals Renoprotective Effect of Fucoidan from Seaweed Sargassum angustifolium C. Agardh 1820 on Gentamicin-Induced Nephrotoxicity: From Marine Resources to Therapeutic Uses

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Khalil Pourkhalili ◽  
Zeinab Karimi ◽  
Mohammad Reza Farzaneh ◽  
Elham Ehsandoost ◽  
Mehdi Mohammadi ◽  
...  
Keyword(s):  
Urine Volume ◽  
Renal Tissue ◽  
Sulfated Polysaccharides ◽  
Control Group ◽  
Sod Activity ◽  
Tissue Samples ◽  
Therapeutic Uses ◽  
Male Wistar Rats ◽  
Sargassum Angustifolium ◽  
First Time

Background: Nephrotoxicity is a major side effect of aminoglycoside antibiotics, caused by oxidative damage and inflammation. Fucoidan, a group of sulfated polysaccharides derived from different species of brown algae, are well recognized for their antioxidant and anti-inflammatory activities. Objectives: In the present study, we aimed to investigate, for the first time, the efficacy of fucoidan extracted from Sargassum angustifolium C. Agardh 1820 against gentamicin-induced nephrotoxicity in rats. Methods: Twenty-eight male Wistar rats were divided into 4 groups of control, gentamicin (100 mg/kg), and gentamicin plus 50- and 100-mg/kg/day fucoidan pretreatment. In the end, all rats were killed, and then urine, blood, and tissue samples were prepared. Kidney weight (KW), body weight (BW), and 24-hour urine volume, as well as serum creatinine (Cr), blood urea nitrogen (BUN), Cr clearance, and malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity, were measured. Kidney samples were also evaluated for histopathological changes. Results: Gentamicin significantly increased KW, KW/BW ratio, 24-hour urine volume, serum Cr, MDA, and BUN levels; however, fucoidan pretreatment, especially at a dose of 50 mg/kg, significantly returned these variables near to the control group values. Gentamicin also decreased BW gain, Cr clearance, SOD activity, and the degree of renal tissue damage compared to the control group, while treatment with fucoidan significantly reversed these alterations. Conclusions: The results show that fucoidan from S. angustifolium C. Agardh 1820 ameliorates gentamicin-induced nephrotoxicity by alleviating oxidative stress and augmenting antioxidant enzymes activity in renal tissue, suggesting the potential use of this fucoidan in a clinical setting.

scholarly journals Ameliorative Effects of Gallic Acid on Cisplatin-Induced Nephrotoxicity in Rat Variations of Biochemistry, Histopathology, and Gene Expression

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Zahra Eslamifar ◽  
Abbas Moridnia ◽  
Susan Sabbagh ◽  
Reza Ghaffaripour ◽  
Leila Jafaripour ◽  
...  
Keyword(s):  
Gene Expression ◽  
Uric Acid ◽  
Single Dose ◽  
Gallic Acid ◽  
Biochemical Parameters ◽  
Standard Condition ◽  
Renal Tissue ◽  
Control Group ◽  
Male Wistar Rats ◽  
Histopathological Studies

Background. Cisplatin is a powerful chemotherapeutic drug mainly used in the treatment of solid tumors. Aggregation of the drug in renal proximal tubule cells causes nephrotoxicity and renal failure. Investigations showed nephrotoxicity as Cisplatin’s dose-limiting side effect. One of the Cisplatin toxicity mechanisms is generation of reactive oxygen species, which leads to oxidative stress and renal damage. The purpose of this study was evaluation of the modulating effects of Gallic acid on Cisplatin-induced variations including Caspase-3 and Clusterin expression and histopathological and biochemical parameters in adult male Wistar rats. Method. Rats were kept under standard condition of temperature, light, and humidity. The animals were divided into 4 groups: GpI: control group (received distilled water for 10 days); GpII: Gallic acid (alone) (50 mg/kg bw, once a day for 10 days); GpIII: Cisplatin (alone), single dose (6 mg/kg bw, I.P. on 5th day of study); GpIV: Gallic acid (50 mg/kg bw, once a day for 10 days) and also injected with single dose of Cisplatin (6 mg/kg bw, I.P., on 5th day of study). After 10 days, all rats were anaesthetized and plasma collected to estimate urea, creatinine, and uric acid. The right kidneys were removed for the study of gene expression and biochemical parameters. The left kidneys were used for histopathological studies. Results. The Cisplatin-induced nephrotoxicity was evident from the elevated levels of creatinine, urea, uric acid, and renal tissue MDA and also decreased levels of SOD, CAT, GPX, and GSH in renal tissue. Administration of Gallic acid significantly modulated nephrotoxicity markers, gene expression variations, and histopathological damage. Conclusion. Outcomes of the present investigation suggest that Gallic acid provides protection against CP-induced nephrotoxicity, but for application in people, further studies are needed.

Impact of the induced organic anion transporter 1 (Oat1) renal expression by furosemide on the pharmacokinetics of organic anions

Nephrology ◽  
2017 ◽  
Vol 22 (8) ◽  
pp. 642-648 ◽  
Author(s):  
María Julia Severin ◽  
María Herminia Hazelhoff ◽  
Romina Paula Bulacio ◽  
María Eugenia Mamprin ◽  
Anabel Brandoni ◽  
...  
Keyword(s):  
Organic Anion ◽  
Organic Anions ◽  
Organic Anion Transporter ◽  
Anion Transporter ◽  
Renal Expression

scholarly journals Nano Ellagic Acid Counteracts Cisplatin-Induced Upregulation in OAT1 and OAT3: A Possible Nephroprotection Mechanism

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3031
Author(s):  
Thikryat Neamatallah ◽  
Nagla El-Shitany ◽  
Aymn Abbas ◽  
Basma G. Eid ◽  
Steve Harakeh ◽  
...  
Keyword(s):  
Ellagic Acid ◽  
Organic Anion ◽  
Elevated Serum ◽  
Protective Role ◽  
Oxidative Stress Marker ◽  
Protein Levels ◽  
Renal Tubular Cells ◽  
Anion Transporters ◽  
Male Wistar Rats

Cisplatin is an anticancer drug commonly used for solid tumors. However, it causes nephrotoxicity. OAT1 and OAT3 are organic anion transporters known to contribute to the uptake of cisplatin into renal tubular cells. The present study was designed to examine the protective role of ellagic acid nanoformulation (ellagic acid nano) on cisplatin-induced nephrotoxicity in rats, and the role of OAT1/OAT3 in this effect. Four groups of male Wistar rats were used (n = 6): (1) control, (2) cisplatin (7.5 mg/kg single dose, intraperitoneal), (3) cisplatin + ellagic acid nano (1 mg/kg), and (4) cisplatin + ellagic acid nano (2 mg/kg). Nephrotoxic rats treated with ellagic acid nano exhibited a significant reduction in elevated serum creatinine, urea, and oxidative stress marker, malondialdehyde (MDA). Additionally, ellagic acid nano restored renal glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Ellagic acid nano improved the histopathological changes induced by cisplatin, such as tubular dilatation, necrosis, and degeneration. Interestingly, OAT1 and OAT3 showed significantly lower expression at both mRNA and protein levels following ellagic acid nano treatment relative to the cisplatin-exposed group. These findings reveal a potential inhibitory role of ellagic acid antioxidant on OAT1 and OAT3 expression and thus explains its nephroprotective effect against cisplatin nephrotoxicity.

Attenuation of Tissue Thrombosis and Hemorrhage by ala-TFPI Does not Account for Its Protection against E. coli

1998 ◽  
Vol 79 (05) ◽  
pp. 1048-1053 ◽  
Author(s):  
M. M. Randolph ◽  
G. L. White ◽  
S. D. Kosanke ◽  
G. Bild ◽  
C. Carr ◽  
...  
Keyword(s):  
Renal Tissue ◽  
Saline Control ◽  
Control Group ◽  
Target Tissue ◽  
E Coli ◽  
Mild Degree ◽  
Target Organs ◽  
Tissue Factor Pathway ◽  
Failure To Protect ◽  
Experimental Group

SummaryThis study was designed to determine the effect of a delayed infusion (T+120 min) of alanyl tissue factor pathway inhibitor (ala-TFPI) on the response to LD100 E. coli. We hypothesized that baboons treated with a low dose of TFPI (5 mg/kg) which did not survive would exhibit thrombosis, infarction and hemorrhage of target tissues such as that seen in untreated animals infused with LD100 E. coli. Eight baboons were infused with 5 mg/kg of ala-TFPI over a 10 h period beginning immediately after a 2 h infusion of LD100 E. coli (experimental group). Four baboons were infused with E. coli followed by a 10 h infusion of saline (control group). Of the 12 baboons, the 11 non-survivors (TFPI = 7 out of 8; controls = 4 out of 4) were evaluated for the extent of thrombosis, necrosis, hemorrhage, and congestion of target tissues and for changes in clinical chemical parameters. We expected that failure to protect would correlate with failure to inhibit thrombosis of target tissue (8). Surprisingly ala-TFPI significantly inhibited thrombosis, hemorrhage and necrosis of adrenal and renal tissues and attenuated the rise in creatinine in the 7 treated non-survivors. The lungs of these non-survivors, however, exhibited intra-alveolar fibrin and a mild degree of hemorrhage and edema. We concluded that low doses of ala-TFPI begun as late as T+120 in minutes failed to protect against the lethal effects of LD100 E. coli in spite of completely preventing thrombosis and hemorrhage in target organs, and that thrombosis, infarction and hemorrhage of adrenal and renal tissue are not part of the lethal chain of events in this IV model of E. coli sepsis.

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