engleski

Causes of Polyuria in Cis-diamminedichloroplatinum (cisPt) Nephrotoxicity in Rat

CisPt, a potent anticancer drug in humans and experimental animals, causes nephrotoxicity as its major side effect. Hypoosmotic polyuria is a marked symptom in cisPt nephrotoxicity. Polyuria develops in two stages: a vasopressin (V)-sensitive peak occurs 24 h following cisPt administration, and recedes the day after, whereas the late, V-insensitive stage starts at day 3, and steadily worsens thereafter. To study causes of polyuria and a role of water channels in these stages, we treated rats with a single dose of cisPt (5 mg/kg b.m., i.p.) and compared the distribution pattern of AQP1 and AQP2 by immunoblotting (WB) in total cell membranes (TCM) from various kidney regions and by immunocytochemistry in tissue cryosections at day 1 (D1) and day 5 (D5) following cisPt administration. In comparison with controls, at D1 the urine flow (UF) and osmolality (O) in cisPt-treated rats increased 3 fold and decreased 67%, respectively. However, similar density of protein bands in WB of TCM from the cortex (C), outer (OS) and inner stripe (IS), and papilla (PAP), and similar staining pattern in undamaged tubules indicated that the abundance and the intracellular distribution of AQP1 and AQP2 along the nephron were not affected at D1. At D5, however, the UF and O were 3.4-fold higher and 65% lower, respectively, than in control rats, and the animals exhibited glucosuria, proteinuria, and moderate phosphaturia. By WB, the abundance of AQP1 in TCM at D5 decreased between 10% (C) and 47% (OS), whereas the abundance of AQP2 decreased between 38% (PAP) and 74% (IS), the decrease in other regions being in between these extremes. By immunocytochemistry of D5 tissues we found: a) heavily denuded apical domain of the proximal tubule (PT) pars recta, b) decreased AQP1 and AQP2 staining in the respective nephron segments, and c) largely apical localization of the remaining AQP2 in the respective cells. We conclude that polyuria at D1 may result from the direct inhibition of water channels by cisPt, possibly via chelation of functionally important SH groups. At D5, polyuria is partially osmotic, and largely due to a loss of both reabsorptive surface along the PT and aquaporins in the respective nephron segments.

aquaporins; cisplatin; immunocytochemistry; kidney; nephron; water channels

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