Received for publication May 4, 2005.
Revised August 4, 2005.
Accepted for publication August 4, 2005.

Short-term exposure of renal proximal tubules to gentamicin increases long-term Mrp2 (Abcc2) transport function and reduces nephrotoxicant sensitivity

Abstract

We previously showed that the function of renal Multidrug resistance protein 2 (Mrp2; Abcc2) is reduced by endothelin-1 (ET-1) signaling through an ET_B receptor, NOS, cGMP and protein kinase C and that this pathway was activated by several nephrotoxicants (Masereeuw et al., 2000; Notenboom et al., 2002; Notenboom et al., 2004; Terlouw et al., 2001). 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 3h following exposure proximal tubules recovered fully from the initial decrease in Mrp2-mediated transport and that transport activity was not changed 9h later. However, 24h after exposure, luminal accumulation of an Mrp2 substrate had increased by 50%. Increased transport at 24h was accompanied by an increased transporter protein content of the luminal plasma membrane as measured by immunostaining. Blocking ET-1 signaling at the ET_B 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 ET_B signaling was the same and was multiphasic. Finally, when tubules were exposed to gentamicin for 30 min and removed to gentamicin-free medium for 24h 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.

Key words: endothelin signaling, gentamicin, multidrug resistance protein 2, nephrotoxicity, renal drug transport, transport protein expression

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