Organic anion transporter 5 (Oat5) renal expression and urinary excretion in rats treated with cisplatin: a potential biomarker of cisplatin-induced nephrotoxicity

It has been described renal damage in rats with vascular calcification. The organic anion transporter 5 (Oat5) is only expressed in kidney, and its urinary excretion was proposed as potential early biomarker of renal injury. The aim of this study was to evaluate the Oat5 renal expression and its urinary excretion in an experimental model of vascular calcification in comparison with traditional markers of renal injury. Vascular calcification was obtained by the administration of an overdose of vitamin D3(300,000 IU/kg, b.w., i.m.) to male Wistar rats. Oat5 urinary abundance was evaluated by Western blotting. Traditional markers of renal injury, such as creatinine and urea plasma levels, urinary protein levels, and urinary alkaline phosphatase (AP) activity, were determined using commercial kits. Histology was assessed by hematoxylin/eosin staining. Oat5 renal expression was evaluated by Western blotting and by immunohistochemistry. An increased expression of Oat5 in renal homogenates, in apical membranes, and in its urinary excretion was observed in rats with vascular calcification. The traditional parameters used to evaluate renal function were not modified, with the exception of histology. It is possible to postulate the urinary excretion of Oat5 as a potential noninvasive biomarker of renal injury associated with vascular calcification.

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Organic Anion Transporter 5 (Oat5) Urinary Excretion Is a Specific Biomarker of Kidney Injury: Evaluation of Urinary Excretion of Exosomal Oat5 afterN-Acetylcysteine Prevention of Cisplatin Induced Nephrotoxicity

Chemical Research in Toxicology ◽

10.1021/acs.chemrestox.5b00176 ◽

2015 ◽

Vol 28 (8) ◽

pp. 1595-1602 ◽

Cited By ~ 16

Author(s):

Romina Paula Bulacio ◽

Naohiko Anzai ◽

Motoshi Ouchi ◽

Adriana Mónica Torres

Keyword(s):

Urinary Excretion ◽

Organic Anion ◽

Kidney Injury ◽

Organic Anion Transporter ◽

Anion Transporter

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

Human & Experimental Toxicology ◽

10.1177/0960327120958109 ◽

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.

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Cisplatin induces renal expression of P-glycoprotein and canalicular multispecific organic anion transporter

AJP Renal Physiology ◽

10.1152/ajprenal.1999.277.6.f832 ◽

1999 ◽

Vol 277 (6) ◽

pp. F832-F840 ◽

Cited By ~ 11

Author(s):

Michel Demeule ◽

Mathieu Brossard ◽

Richard Béliveau

Keyword(s):

Chemotherapeutic Agent ◽

Organic Anion ◽

Organic Anion Transporter ◽

Rat Tissues ◽

Glycoprotein P ◽

P Glycoprotein ◽

Anion Transporter ◽

Renal Brush Border Membranes ◽

Renal Expression ◽

Renal Brush Border

The expression of two members of the ATP-binding cassette family of transport proteins, P-glycoprotein (P-gp) and the canalicular multispecific organic anion transporter (cMOAT or Mrp2), was evaluated in renal brush-border membranes (BBM) and various rat tissues after cisplatin treatment. One administration of cisplatin (5 mg/kg) increased P-gp expression by >200–300% in renal BBM and in crude membranes from liver and intestine. The increase in P-gp expression in the kidney was also detected in photolabeling experiments, suggesting the induction of functional P-gp. cMOAT expression was increased by >10-fold in renal BBM after cisplatin administration, although it had no effect on liver cMOAT expression. The increase in the levels of both proteins was maximal at 2 days after cisplatin treatment and lasted for at least 8 days. These results indicate that a single administration of cisplatin induces overexpression of P-gp and cMOAT in specific tissues. This may be of significant relevance to the design of clinical trials using cisplatin as a single chemotherapeutic agent or in combination with other drugs.

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

Nephrology ◽

10.1111/nep.12838 ◽

2017 ◽

Vol 22 (8) ◽

pp. 642-648 ◽

Cited By ~ 5

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

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Generation of Knockout and Transgenic Zebrafish to Characterize Abcc4 Functions in Detoxification and Efflux of Lead

International Journal of Molecular Sciences ◽

10.3390/ijms22042054 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2054

Author(s):

Xing Lu ◽

Yong Long ◽

Xixi Li ◽

Lang Zhang ◽

Qing Li ◽

...

Keyword(s):

Organic Anion ◽

Water Environment ◽

Environmental Pollutants ◽

Lead Contamination ◽

Organic Anion Transporter ◽

Transgenic Zebrafish ◽

Proximal Tubule Cell ◽

Anion Transporter ◽

Potential Biomarker ◽

Wide Range

Lead (Pb) is one of the major heavy metals that are toxic to vertebrates and usually considered as environmental pollutants. ABCC4/MRP4 is an organic anion transporter that mediates cellular efflux of a wide range of exogenous and endogenous compounds such as cyclic nucleotides and anti-cancer drugs; however, it remains unclear whether ABCC4 and its orthologs function in the detoxification and excretion of toxic lead. In this study, we found that the transcriptional and translational expression of zebrafish abcc4 was significantly induced under lead exposure in developing zebrafish embryos and adult tissues. Overexpression of zebrafish Abcc4 markedly decreased the cytotoxicity and accumulation of lead in pig renal proximal tubule cell line (LLC-PK1 cells). To further understand the functions of zebrafish Abcc4 in lead detoxification, the clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 system was used to create an abcc4−/− mutant zebrafish line. In comparison with the wild-type (WT) zebrafish, the abcc4−/− mutants showed a higher death rate and lead accumulation upon exposure to lead. Furthermore, a stable abcc4-transgenic zebrafish line was successfully generated, which exerted stronger ability to detoxify and excrete lead than WT zebrafish. These findings indicate that zebrafish Abcc4 plays a crucial role in lead detoxification and cellular efflux and could be used as a potential biomarker to monitor lead contamination in a water environment.

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