engleski

Water channel AQP2 in cisplatin (cisPt) nephrotoxicity

An anticancer drug cisPt (cis-diamminedichloroplatinum) causes nephrotoxicity as a side effect. Hypoosmotic polyuria, a marked symptom in cisPt nephrotoxicity, develops in two stages: a vasopressin (V)-sensitive peak occurs one day, whereas the V-insensitive peak occurs 3-7 days following cisPt administration. The role of AQP2, the V-regulated mediator of water transport in the mammalian collecting duct (CD), in cisPt-induced polyuria is poorly known. To study it, rats were injected a single dose of cisPt (5 mg/kg b.m., i.p.), and one (D1) and 5 days (D5) later the abundance of AQP2 in total cell membranes from various kidney zones by immunoblotting, and the pattern of AQP2 distribution in tissue cryosections by immunostaining, were compared. These data were correlated with the abundance of a-tubulin in tissue homogenates and immunostaining of microtubules (MT) in various zones. In comparison with control rats, at D1 and D5 the urine flow and osmolality increased 3-4 fold and decreased 65-67%, respectively. At D1, similar density of the AQP2 (29 kDa) band in total cell membranes and the a-tubulin (55 kDa) band in tissue homogenates indicated an unchanged abundance of these proteins along the nephron. In the papillary CD, AQP2 was strongly intracellular and MT were intensely stained. At D5, the proximal tubule S3 segment was heavily damaged. The AQP2 band density in tissue homogenates decreased between 38% (papilla) and 74% (inner stripe). The AQP2 immunostaining was decreased in the CD from all zones, and it showed basolateral localization in most ducts. The abundance of a-tubulin clearly increased only in the outer stripe homogenate, whereas MT were intensely stained in tubules of all zones. Conclusion: At D1, water reabsorption may be diminished due to: a) direct inhibition of AQP2 by cisPt, possibly via chelation of functionally important SH-groups, and b) loss of the apical AQP2 in the papillary CD, possibly via impaired intracellular trafficking caused by an increased stabilization of MT. At D5, in addition to the causes listed at D1, water reabsorption may be impaired by the loss of functional surface in the heavily damaged S3 segments.

aquaporins; immunocytochemistry; kidney; nephron; polyuria

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