Mechanisms of renal anionic drug transport

El-Sheikh, Azza A. K.; Masereeuw, Rosalinde; Rüssel, Frans G. M.

doi:10.1016/j.ejphar.2008.02.085

Cited by 110 publications

(72 citation statements)

References 173 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…3B). These predicted proteins are homologous to proteins present in the vertebrate kidney (Christensen and Birn, 2002;Delanote et al, 2005;Purkerson and Schwartz, 2007;El-Sheikh et al, 2008;Lisowska-Myjak, 2010). In conclusion, planarian protonephridia and the vertebrate kidney share similarities in addition to developmental roles for Six1/2 and POU2/3 genes: they both possess a cell type for fluid filtration (flame cells and podocytes), and the planarian tubule/tubule-associated cells and the vertebrate kidney tubule cells utilize a similar set of excretory fluid-processing proteins.…”

Section: Research Articlementioning

confidence: 99%

A regulatory program for excretory system regeneration in planarians

et al. 2011

View full text Add to dashboard Cite

SUMMARYPlanarians can regenerate any missing body part, requiring mechanisms for the production of organ systems in the adult, including their prominent tubule-based filtration excretory system called protonephridia. Here, we identify a set of genes, Six1/2-2, POU2/3, hunchback, Eya and Sall, that encode transcription regulatory proteins that are required for planarian protonephridia regeneration. During regeneration, planarian stem cells are induced to form a cell population in regeneration blastemas expressing Six1/2-2, POU2/3, Eya, Sall and Osr that is required for excretory system formation. POU2/3 and Six1/2-2 are essential for these precursor cells to form. Eya, Six1/2-2, Sall, Osr and POU2/3-related genes are required for vertebrate kidney development. We determined that planarian and vertebrate excretory cells express homologous proteins involved in reabsorption and waste modification. Furthermore, we identified novel nephridia genes. Our results identify a transcriptional program and cellular mechanisms for the regeneration of an excretory organ and suggest that metazoan excretory systems are regulated by genetic programs that share a common evolutionary origin.

show abstract

Section: Research Articlementioning

confidence: 99%

A regulatory program for excretory system regeneration in planarians

et al. 2011

View full text Add to dashboard Cite

show abstract

“…This system consists of organic anion exchangers located at the basolateral membrane representing the rate-determining step of elimination and the efflux step through the apical membrane (7,10). The classical basolateral organic anion exchanger is the terminal step in a tertiary active transport system, dependent on an inwarddirected Na ϩ gradient to drive the uptake of ␣-ketoglutarate, which is then exchanged for organic anions (13,41).…”

mentioning

confidence: 99%

Low-dose indomethacin after ischemic acute kidney injury prevents downregulation of Oat1/3 and improves renal outcome

Schneider

Meusel

Renker

et al. 2009

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

We have previously shown that expression of renal organic anion transporters Oat1 and Oat3 is diminished by prostaglandin E2 (PGE2) and that both transporters are downregulated after renal ischemia. Because PGE2 is increased after renal ischemia and is generated by cyclooxygenases (COX), we investigated the effect of the COX inhibitor indomethacin on expression of Oat1/3 after ischemic acute kidney injury (iAKI). iAKI was induced in rats by bilateral clamping of renal arteries for 45 min. Indomethacin (1 mg/kg) was given intraperitoneally as soon as reperfusion started. Sham-treated animals served as controls. Oat1/3 were determined by qPCR and Western blot. PGE2 in blood and urine was measured by enzyme-linked immunosorbent assay. Invasion of monocytes/macrophages was determined. Glomerular filtration rate and renal plasma flow were determined. All parameters were detected 24 h after ischemia. PAH net secretion, as well as clearance and secretion of PGE2 were calculated. In clamped animals, indomethacin restored expression of Oat1/3, as well as PAH net secretion, PGE2 clearance, or PGE2 secretion. Additionally, indomethacin substantially improved kidney function as measured by glomerular filtration and PAH clearance. Indomethacin did not affect ischemia-induced invasion of monocytes/macrophages. In conclusion, our study indicates that low-dose indomethacin applied after ischemia prevents ischemia-induced downregulation of Oat1/3 during reperfusion and has a substantial protective effect on kidney function after iAKI. The beneficial effect of low-dose indomethacin on renal outcome is likely due to an effect different from inhibition of inflammation. In accordance to the decreased PAH net secretion, renal excretion of an endogenous organic anion (PGE2) is also impaired after ischemia and reperfusion.

show abstract

“…Generating relevant activity data for this requires specific substrates that can be used both in vitro and in vivo. This is a problem for transporters, which can exhibit marked overlap in substrate specificity (101). Metabolomics approaches could be useful for identifying highly specific endogenous substrates of transporters that would be suitable for characterisation of activity in vivo (102).…”

Section: Discussionmentioning

confidence: 99%

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

View full text Add to dashboard Cite

Abstract.It is envisaged that application of mechanistic models will improve prediction of changes in renal disposition due to drug-drug interactions, genetic polymorphism in enzymes and transporters and/or renal impairment. However, developing and validating mechanistic kidney models is challenging due to the number of processes that may occur (filtration, secretion, reabsorption and metabolism) in this complex organ. Prediction of human renal drug disposition from preclinical species may be hampered by species differences in the expression and activity of drug metabolising enzymes and transporters. A proposed solution is bottom-up prediction of pharmacokinetic parameters based on in vitro-in vivo extrapolation (IVIVE), mediated by recent advances in in vitro experimental techniques and application of relevant scaling factors. This review is a follow-up to the Part I of the report from the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25th-29th October 2015) which focuses on IVIVE and mechanistic prediction of renal drug disposition. It describes the various mechanistic kidney models that may be used to investigate renal drug disposition. Particular attention is given to efforts that have attempted to incorporate elements of IVIVE. In addition, the use of mechanistic models in prediction of renal drugdrug interactions and potential for application in determining suitable adjustment of dose in kidney disease are discussed. The need for suitable clinical pharmacokinetics data for the purposes of delineating mechanistic aspects of kidney models in various scenarios is highlighted.KEY WORDS: active renal excretion; human kidney transporters; human renal drug clearance; kidney disease; non-hepatic drug metabolism.

show abstract

Mechanisms of renal anionic drug transport

Cited by 110 publications

References 173 publications

A regulatory program for excretory system regeneration in planarians

A regulatory program for excretory system regeneration in planarians

Low-dose indomethacin after ischemic acute kidney injury prevents downregulation of Oat1/3 and improves renal outcome

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

Contact Info

Product

Resources

About