title: Rapamycin inhibition of mTORC1 reverses lithium-induced proliferation of renal collecting duct cells.
abstract: Nephrogenic diabetes insipidus (NDI) is the most common renal side effect in patients undergoing lithium therapy for bipolar affective disorders. Approximately 2 million US patients take lithium of whom ∼50% will have altered renal function and develop NDI (2, 37). Lithium-induced NDI is a defect in the urinary concentrating mechanism. Lithium therapy also leads to proliferation and abundant renal cysts (microcysts), commonly in the collecting ducts of the cortico-medullary region. The mTOR pathway integrates nutrient and mitogen signals to control cell proliferation and cell growth (size) via the mTOR Complex 1 (mTORC1). To address our hypothesis that mTOR activation may be responsible for lithium-induced proliferation of collecting ducts, we fed mice lithium chronically and assessed mTORC1 signaling in the renal medulla. We demonstrate that mTOR signaling is activated in the renal collecting ducts of lithium-treated mice; lithium increased the phosphorylation of rS6 (Ser240/Ser244), p-TSC2 (Thr1462), and p-mTOR (Ser2448). Consistent with our hypothesis, treatment with rapamycin, an allosteric inhibitor of mTOR, reversed lithium-induced proliferation of medullary collecting duct cells and reduced levels of p-rS6 and p-mTOR. Medullary levels of p-GSK3β were increased in the renal medullas of lithium-treated mice and remained elevated following rapamycin treatment. However, mTOR inhibition did not improve lithium-induced NDI and did not restore the expression of collecting duct proteins aquaporin-2 or UT-A1.
authors.affiliation: Dept. of Physiology, College of Medicine, Univ. of Arizona, MRB, 1656 E Mabel St., Tucson, AZ 85724-5218. brooksh@email.arizona.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Romero-Aleshire
authors.forename: Qi
authors.initials: Q
authors.lastname: Cai
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
authors.forename: Heddwen L
authors.initials: HL
authors.lastname: Brooks
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D018500:Diabetes Insipidus, Nephrogenic / Q000139:chemically induced / Q000517:prevention & control; D004353:Drug Evaluation, Preclinical; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism*; D008094:Lithium / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008813:Mice, Inbred ICR; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D014150:Antipsychotic Agents; D046912:Multiprotein Complexes; D008094:Lithium; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: GSK3β; aquaporin-2; collecting ducts; urea transporter