Rapamycin inhibition of mTORC1 reverses lithium-induced proliferation of renal collecting duct cells.

摘要: Nephrogenic diabetes insipidus (NDI) is the most common renal side effect in patients undergoing lithium therapy for bipolar affective disorders. Approximately 2 million US take of whom ∼50% will have altered function and develop NDI (2, 37). Lithium-induced a defect urinary concentrating mechanism. Lithium also leads to proliferation abundant cysts (microcysts), commonly collecting ducts cortico-medullary region. The mTOR pathway integrates nutrient mitogen signals control cell growth (size) via Complex 1 (mTORC1). To address our hypothesis that activation may be responsible lithium-induced ducts, we fed mice chronically assessed mTORC1 signaling medulla. We demonstrate activated lithium-treated mice; increased phosphorylation rS6 (Ser240/Ser244), p-TSC2 (Thr1462), p-mTOR (Ser2448). Consistent with hypothesis, treatment rapamycin, an allosteric inhibitor mTOR, reversed medullary duct cells reduced levels p-rS6 p-mTOR. Medullary p-GSK3β were medullas remained elevated following rapamycin treatment. However, inhibition did not improve restore expression proteins aquaporin-2 or UT-A1.