Lithium Potentiates Epithelial–Mesenchymal Transition in the Kidney through Induction of Matrix Metallopeptidase‐9

Abstract

Lithium is a common therapeutic agent that is used to effectively treat patients with various mood disorders. Unfortunately there are many renal side effects of lithium therapy, including tubular atrophy and chronic interstitial fibrosis, which are not fully understood. To identify the intracellular signaling cascades that cause the proliferative action of lithium in the inner medullary collecting duct (IMCD), mIMCD3 cells were incubated with increasing concentrations of lithium chloride for 48 h. We found that lithium inhibited glycogen synthase kinase 3β (GSK‐3β) activity through serine‐9 phosphorylation in a dose responsive manner. Lithium inhibition of GSK‐3β induced ERK phosphorylation a concentration‐dependent manner. Both GSK‐3β and ERK are known to be involved in a variety of biological processes and are suggested to be key in the proliferative and antiapoptotic actions of lithium in the renal collecting duct. A reported downstream target of these kinases is matrix metallopeptidase 9 (MMP‐9), an enzyme that induces tubular cell epithelial‐mesenchymal transition (EMT) and therefore a major contributor to renal fibrosis. We found that protein abundance of MMP9 was elevated with increasing lithium concentrations in mIMCD3 cells. These results suggest that lithium inactivation of GSK‐3β potentiates EMT through ERK induction of MMP‐9 in the collecting duct.