Rapamycin, an inhibitor of mTOR signaling pathway, reverses lithium‐induced cell proliferation in renal collecting ducts

Abstract

The most common side effect in patients undergoing lithium therapy is nephrogenic diabetes insipidus (NDI), in addition, lithium treatment can cause collecting duct cells to proliferate. The mammalian target of rapamycin (mTOR) signaling pathway is a key regulator of cell proliferation. We hypothesized that the mTOR signaling pathway may be playing a role in lithium‐induced cell proliferation of renal collecting duct. We fed mice lithium for 14d; AQP2 protein expression was significantly decreased (16 ± 4.0% vs control 100 ± 8.8%) and proliferating cell nuclear antigen (PCNA) protein expression was significantly increased (172 ± 8.6% vs control 100 ± 1.4%) in renal inner medulla (IM). We demonstrate that p‐mTOR (Ser 2448) was increased (154 ± 26.5%), as was phosphorylation of ribosomal S6 protein (p‐rS6), a downstream component of mTOR pathway (404 ± 151.4%) in renal IM of lithium‐treated mice. To test whether the inhibition of mTOR signaling pathway could reverse lithium‐induced cell proliferation, we treated mice with Rapamycin (Rapa), an inhibitor of mTOR. Rapa reversed lithium‐induced proliferation of IM collecting duct cells and decreased lithium‐induced p‐mTOR and p‐rS6 levels. Rapa had no effect on the upstream components of mTOR; p‐Akt and p‐TSC2 remained elevated by lithium. In conclusion, the mTOR signaling pathway is involved in lithium‐induced collecting duct cell proliferation.