REGULATION OF RENAL XENOBIOTIC EXCRETION

Environmental Health Sciences

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Abstract

The vertebrate renal proximal tubule is responsible for the excretory transport of a large number of potentially toxic chemicals, including, waste products of normal metabolism, drugs, environmental pollutants and drug and pollutant metabolites. These chemicals are handled by multiple specific, transport proteins that remove them from the blood and concentrate them in urine. Our research focus is understanding the control of these transporters. We use comparative models (intact proximal tubules from teleost fish and mammalian renal slices and cells in culture) in combination with confocal microscopy to identify the physiologically relevant extracellular signals (hormones, metabolites, xenobiotics), and the intracellular signalling pathways involved in the control of xenobiotic excretion in proximal tubule. Our recent experiments show separate mechanisms for short-term and long-term regulation of transport. In the short-term, all xenobiotic transport systems in proximal tubule are under control of hormones acting through protein kinase C (PKC). For example, endothelin (ET), acting through a basolateral, B-type ET receptor, a G-protein and PKC, rapidly (minutes) reduces transport mediated by the luminal transporters, p-glycoprotein and Mrp2, and parathyroid hormone (PTH) acting through a basolateral receptor and PKC rapidly reduces organic anion transport mediated by the basolateral transporter OAT. P-glycoprotein and Mrp2 are relatively insensitive to regulation by PTH, whereas OAT is relatively insensitive to regulation by ET, suggesting hormonal signaling through different phospholipases or PKC isoforms. Recent experiments indicate that two structurally unrelated classes of nephrotoxin (radiocontrast agents and aminoglycoside antibiotics) fire the endothelin B-receptor/PKC signalling pathway and thus reduce transport on Mrp2 and p-glycoprotein, suggesting an early, common event in nephrotoxin action. Finally, over the longer-term, (hours to days) micromolar concentrations of heavy metals, such as, Zn and Cd, upregulate transport mediated by Mrp2.