Podocyte-specific expression of organic cation transporter PMAT: implication in puromycin aminonucleoside nephrotoxicity

Li, Xia; Zhou, Mingyan; Kalhorn, Thomas F.; Ho, Horace T. B.; Wang, Joanne

doi:10.1152/ajprenal.00046.2009

Cited by 29 publications

(34 citation statements)

References 31 publications

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“…In addition, although low pH in the extracellular medium has been found to stimulate the uptake of PMAT substrates, we found it significantly inhibited CQ uptake. Last, PMAT and OCTs are not extensively expressed in normal, distal tubular cells (Karbach et al, 2000;Xia et al, 2009). Therefore, all available evidence indicates that CQ crosses biological membranes of MDCK cells by passive diffusion (Fig.…”

Section: Discussionmentioning

confidence: 97%

Effect of Phospholipidosis on the Cellular Pharmacokinetics of Chloroquine

Zheng

Zhang

Rosania³

2010

J Pharmacol Exp Ther

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In vivo, the weakly basic, lipophilic drug chloroquine (CQ) accumulates in the kidney to concentrations more than a thousand-fold greater than those in plasma. To study the cellular pharmacokinetics of chloroquine in cells derived from the distal tubule, Madin-Darby canine kidney cells were incubated with CQ under various conditions. CQ progressively accumulated without exhibiting steady-state behavior. Experiments failed to yield evidence that known active transport mechanisms mediated CQ uptake at the plasma membrane. CQ induced a phospholipidosis-like phenotype, characterized by the appearance of numerous multivesicular and multilamellar bodies (MLBs/ MVBs) within the lumen of expanded cytoplasmic vesicles. Other induced phenotypic changes including changes in the volume and pH of acidic organelles were measured, and the integrated effects of all these changes were computationally modeled to establish their impact on intracellular CQ mass accumulation. Based on the passive transport behavior of CQ, the measured phenotypic changes fully accounted for the continuous, nonsteady-state CQ accumulation kinetics. Consistent with the simulation results, Raman confocal microscopy of live cells confirmed that CQ became highly concentrated within induced, expanded cytoplasmic vesicles that contained multiple MLBs/MVBs. Progressive CQ accumulation was increased by sucrose, a compound that stimulated the phospholipidosislike phenotype, and was decreased by bafilomycin A1, a compound that inhibited this phenotype. Thus, phospholipidosisassociated changes in organelle structure and intracellular membrane content can exert a major influence on the local bioaccumulation and biodistribution of drugs.

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Section: Discussionmentioning

confidence: 97%

Effect of Phospholipidosis on the Cellular Pharmacokinetics of Chloroquine

Zheng

Zhang

Rosania³

2010

J Pharmacol Exp Ther

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“…Recovery occurs within several weeks of PAN administration [34,35,36]. To date, the mechanism(s) underlying the reversibility of podocyte impairment in this PAN model has/have not yet been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Nestin Protects Podocytes from Apoptosis Induced by Puromycin Aminonucleoside

Wen

Li²,

Zhang³

et al. 2011

Am J Nephrol

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Background: Nestin is an intermediate filament protein widely used as a marker of stem cells or progenitor cells. Nestin is also highly expressed in the glomerular podocyte, a type of terminally differentiated epithelial cell. Little is known about the significance of nestin in podocytes. Methods: Puromycin aminonucleoside (PAN) was injected into the rats to produce a PAN nephrosis model. Transmission electronic microscopy and terminal dUTP nick end-labeling assay were used to examine the podocyte foot process (FP) effacement and apoptosis, respectively. A mouse podocyte cell line was cultured and incubated with PAN. Immunoblot was used to examine the level of nestin expression both in vivo and in vitro. Enhanced green fluorescence protein-tagged plasmids containing nestin shRNA were transfected into the cultured podocytes to silence nestin expression. F-actin arrangement within cultured podocytes was investigated by immunofluorescence, while the apoptosis rate was examined by both Hoechst stain and flow cytometry. Results: In the PAN-induced rat nephrosis model, podocyte nestin expression was increased in the absence of apparent podocyte apoptosis, even though the FP was significantly effaced. In the cultured mouse podocytes, PAN upregulated nestin expression in a time-dependent manner within 24 h of treatment. Notably, no significant apoptosis occurred, however knocking down nestin expression resulted in a remarkable derangement of actin cytoskeleton and an increase in apoptosis in the cultured podocytes 24 h after being incubated with PAN. Conclusions: Upregulation of nestin expression during PAN nephrosis could protect podocytes from apoptosis and that this process is mediated by maintaining the regular arrangement of actin cytoskeleton.

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“…We then analyzed PMAT protein expression in human CP using a PMAT-specific polyclonal antibody, P469, which was previously developed and validated in our laboratory (24,29). Western blot analysis of human CP homogenate detected a strong band with expected molecular mass of human PMAT (58 kDa) (Fig.…”

Section: Pmat Is the Predominant Organic Cation/monoamine Transportermentioning

confidence: 99%

Impaired Monoamine and Organic Cation Uptake in Choroid Plexus in Mice with Targeted Disruption of the Plasma Membrane Monoamine Transporter (Slc29a4) Gene

Duan

Wang

2013

Journal of Biological Chemistry

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Background: Some CNS active compounds are transported into or out of the brain by transporters in the choroid plexus (CP). Results: PMAT is a major CP transporter for bioactive amines and xenobiotic cations. Conclusion: PMAT transports organic cations from the cerebrospinal fluid into the CP. Significance: PMAT may be an important determinant of brain exposure to cationic neurotoxins and bioactive amines.

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Podocyte-specific expression of organic cation transporter PMAT: implication in puromycin aminonucleoside nephrotoxicity

Abstract: . Podocyte-specific expression of organic cation transporter PMAT: implication in puromycin aminonucleoside nephrotoxicity. Am J Physiol Renal Physiol 296: F1307

Cited by 29 publications

References 31 publications

Effect of Phospholipidosis on the Cellular Pharmacokinetics of Chloroquine

Effect of Phospholipidosis on the Cellular Pharmacokinetics of Chloroquine

Upregulation of Nestin Protects Podocytes from Apoptosis Induced by Puromycin Aminonucleoside

Impaired Monoamine and Organic Cation Uptake in Choroid Plexus in Mice with Targeted Disruption of the Plasma Membrane Monoamine Transporter (Slc29a4) Gene

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