Nephrotoxicity of uranyl acetate: effect on rat kidney brush border membrane vesicles.
Since the Gulf war exposure to depleted uranium, a known nephrotoxic agent, there is a renewed interest in the toxic effects of uranium in general and its mechanism of nephrotoxicity which is still largely unknown in particular. In order to investigate the mechanism responsible for uranium nephrotoxicity and the therapeutic effect of urine alkalization, we utilized rat renal brush border membrane vesicles (BBMV). Uranyl acetate (UA) caused a decrease in glucose transport in BBMV. The apparent K (i) of uranyl was 139+/-30 microg uranyl/mg protein of BBMV. Uranyl at 140 microg/mg protein of BBMV reduced the maximal capacity of the system to transport glucose [V (max) 2.2+/-0.2 and 0.96+/-0.16 nmol/mg protein for control and uranyl treated BBMV (P<0.001), respectively] with no effect on the apparent K (m) (1.54+/-0.33 and 1.54+/-0.51 mM for control, and uranyl treated BBMV, respectively). This reduction in V(max) is at least partially due to a decrease in the number of sodium-coupled glucose transporters as apparent from the reduction in phlorizin binding to the uranyl treated membranes, V (max) was reduced from 247+/-13 pmol/mg protein in control BBMV to 119+/-3 pmol/mg protein in treated vesicles (P<0.001). The pH of the medium has a profound effect on the toxicity of UA on sodium-coupled glucose transport in BBMV: higher toxicity at neutral pH (around pH 7.0), and practically no toxicity at alkaline pH (7.6). This is the first report showing a direct inhibitory dose and pH dependent effect of uranyl on the glucose transport system in isolated apical membrane from kidney cortex.
Department of Pediatrics, Assaf Harofeh Medical Center, 70300, Zerifin, Israel. mgoldman@walla.co.il
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M
Goldman
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Yaari
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Doshnitzki
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Cohen-Luria
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Moran
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008871:Microvilli / Q000187:drug effects* / Q000378:metabolism; D009942:Organometallic Compounds / Q000633:toxicity*; D010695:Phlorhizin / Q000378:metabolism; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism; D014501:Uranium / Q000633:toxicity*
D009942:Organometallic Compounds; C005460:uranyl acetate; D014501:Uranium; D010695:Phlorhizin; D000469:Alkaline Phosphatase; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose