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Gentamicin causes endocytosis of Na/Pi cotransporter protein (NaPi-2).

Authors: Sorribas, V  Halaihel, N  Puttaparthi, K  Rogers, T  Cronin, RE  Alcalde, AI  Aramayona, J  Sarasa, M  Wang, H  Wilson, P  Zajicek, H  Levi, M 
Citation: Sorribas V, etal., Kidney Int. 2001 Mar;59(3):1024-36.
Pubmed: (View Article at PubMed) PMID:11231357
DOI: Full-text: DOI:10.1046/j.1523-1755.2001.0590031024.x

BACKGROUND: Renal toxicity is a major side-effect of aminoglycoside antibiotics and is characterized by an early impairment in proximal tubular function. In a previous study, we have shown that gentamicin administration to the rat causes an early impairment in sodium gradient-dependent phosphate (Na/Pi) cotransport activity. The purpose of our current study was to determine the molecular mechanisms of the impairment in Na/Pi cotransport activity, specifically the role of the proximal tubular type II Na/Pi cotransporter. METHODS: Rats were treated for one, two, and three days with two daily injections of 30 mg/kg body weight gentamicin or the vehicle. RESULTS: Gentamicin caused a progressive decrease in superficial cortical apical brush-border membrane (SC-BBM) Na/Pi cotransporter activity (856 +/- 93 in control vs. 545 +/- 87 pmol/mg BBM protein in 3-day gentamicin, P < 0.01). Western blot analysis showed a parallel and progressive decrease in SC-BBM Na/Pi cotransporter protein abundance, a 50% decrease after one day of treatment, a 63% decrease after two days of treatment, and an 83% decrease after three days treatment with gentamicin. In contrast, gentamicin treatment had no effect on Na/Pi cotransport activity or Na/Pi cotransporter protein abundance in BBM isolated from the juxtamedullary cortex (JMC-BBM). Immunofluorescence microscopy showed a major decrease in the expression of Na/Pi cotransporter protein in the apical membrane of the proximal convoluted tubule, with progressive intracellular accumulation of Na/Pi protein. Colocalization studies showed that in gentamicin-treated rats, Na/Pi protein was colocalized in the early endosomes and especially in the lysosomes. Northern blot analysis of cortical RNA interestingly showed no reduction in Na/Pi cotransporter mRNA abundance even after three days of gentamicin treatment. CONCLUSION: We conclude that gentamicin inhibits Na/Pi cotransport activity by causing a decrease in the expression of the type II Na/Pi cotransport protein at the level of the proximal tubular apical BBM and that inhibition of Na/Pi cotransport activity is most likely mediated by post-transcriptional mechanisms.

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CRRD Object Information
CRRD ID: 7243145
Created: 2013-05-08
Species: All species
Last Modified: 2013-05-08
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.