GENTAMICIN INHIBITS AGONIST STIMULATION OF THE PHOSPHATIDYLINOSITOL CASCADE IN PRIMARY CULTURES OF RABBIT PROXIMAL TUBULAR CELLS AND IN RAT RENAL CORTEX

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  • 1 December 1988
    • journal article
    • research article
    • Vol. 247  (3) , 989-996
Abstract
A growing body of evidence indicates that aminoglycoside antibiotics interact with phosphoinositides and this has led to the hypothesis that these drugs perturb the phosphatidylinositol (PI) cascade. To test this hypothesis we examined the effect of gentamicin on agonist stimulation of the PI cascade in primary culture of rabbit proximal tubular cells (RPTC) and in rat renal cortex. Parathyroid hormone (PTH) (10-6 M) stimulated a significant increase in total inositol phosphates, inositol monophosphate and inositol trisphosphate, but not inositol bisphosphate in RPTC with the peak effect at 2 min. This effect was completely inhibited in RPTC exposed to 10-3 M gentamicin for 48 and 24 hr. In other experiments were demonstrated that angiotensin II, phenylephrine, bradykinin and arginine vasopressin (all at 10-6 M) stimulated inositol trisphosphate generation in control PRTC but not in cells exposed to 10-3 M gentamicin for 24 h. In contrast gentamcin did not block PTH-stimulation of cyclic AMP generation, which indicates that gentamicin did not prevent PTH from interacting with its plasma membrane receptor. PTH also stimulated redistribution of protein kinase C from the cytosolic to the membrane fraction of RPTC. This effect was completely abolished in RPTC exposed to 10-3 M gentamicin for 2 days. PTH given i.p. to rats stimulated the redistribution of protein kinase C from the cytosolic to the membrane fraction of renal cortex. This effect was completely inhibited in rats injected with gentamicin, 100 mg/kg per day for 2 days. The results demonstrate that gentamicin disrupts agonist stimulation of the PI cascade in RPTC and in rat renal cortex and are consistent with the hypothesis that cationic gentamicin binds electrostatically with anionic phosphatidylinosital 4,5-bisphosphate and prevents phospholipase C hydrolysis of phosphatidylinositol 4,5-bisphosphate in response to agonist-receptor interaction. Disruption of the PI cascade may contribute to the pathogenesis of aminoglycoside toxicity.