Short-Term Exposure of Renal Proximal Tubules to Gentamicin Increases Long-Term Multidrug Resistance Protein 2 (Abcc2) Transport Function and Reduces Nephrotoxicant Sensitivity

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Abstract
We previously showed that the function of renal multidrug resistance protein (Mrp) 2 (Abcc2) is reduced by endothelin (ET)-1 signaling through an ETB receptor, nitric-oxide synthase (NOS), cGMP, and protein kinase C and that this pathway was activated by several nephrotoxicants (Masereeuw et al., 2000; Terlouw et al., 2001; Notenboom et al., 2002, 2004). Here, we determined the long-term effects on Mrp2-mediated transport (luminal fluorescein methotrexate accumulation) of short-term (30 min) exposure to ET-1 and the aminoglycoside antibiotic, gentamicin. Our data show that over the 3 h following exposure, proximal tubules recovered fully from the initial decrease in Mrp2-mediated transport and that transport activity was not changed 9 h later. However, 24 h after exposure, luminal accumulation of an Mrp2 substrate had increased by 50%. Increased transport at 24 h was accompanied by an increased transporter protein content of the luminal plasma membrane as measured by immunostaining. Blocking ET-1 signaling at the ETB receptor or downstream at NOS or guanylyl cyclase abolished both stimulation of transport and increased transporter expression. Thus, regardless of whether signaling was initiated by a short exposure to ET-1 or to a nephrotoxicant, the time course of Mrp2 response to ETB signaling was the same and was multiphasic. Finally, when tubules were exposed to gentamicin for 30 min and removed to gentamicin-free medium for 24 h, they were less sensitive to acute gentamicin toxicity than paired controls not initially exposed to the drug. Thus, short-term exposure to ET-1 or gentamicin resulted in long-term protection against a second insult.