Pathophysiological regulation of renal SLC22A organic ion transporters in acute kidney injury: Pharmacological and toxicological implications
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The kidneys play a primary role in maintaining homeostasis and detoxification of diverse hydrophilic xenobiotics as well as endogenous by-products. Solute carrier (SLC)22A organic ion transporter family members mediate renal excretion of both endogenous and exogenous substances. Thus, the functional and molecular variations of renal SLC22A transporters under acute kidney injury (AKI) have an impact on systemic clearance of their substrate drugs, resulting in altered pharmacokinetics or unexpected adverse events caused by the accumulation of drugs. Recently, there have been significant advances in our understanding of the regulatory mechanisms for transcription, membrane trafficking and/or kidney-specific expression of SLC22A6/OAT1, SLC22A8/OAT3 and SLC22A2/OCT2. Hepatocyte nuclear factor (HNF)-1α/β and HNF-4 appear to play key roles in the transcriptional regulation of OAT1 and OAT3. Furthermore, OAT1 activity/function is modulated via phosphorylation mediated by protein kinase C (PKC) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. AKI affects renal disposition of organic ions in association with the deteriorated glomerular filtration and tubular transport functions. Thus, dysfunctional regulation of SLC22A transporters during AKI induced by ischemia or toxicants, such as cisplatin, inorganic mercury or uranyl nitrate, cause uremic syndromes or adverse drug reactions. Indoxyl sulfate, a uremic toxin and substrate of OAT1 and OAT3, appears to mediate the progression of AKI evoked by renal ischemia and cisplatin treatment. Precise mechanisms for regulation of the SLC22A transporters in AKI require studies based on the transcription, trafficking, phosphorylation and endogenous factor-dependent modulation. Such analysis will provide a better understanding of the pathophysiological implications of SLC22A transporters.
- Pharmacology & Therapeutics
Pharmacology & Therapeutics, 2009