Proteomic profile of urinary extracellular vesicles from rats with lithium-induced nephrogenic diabetes insipidus

Lithium (Li) salts have been widely used to treat bipolar disorder and unipolar depression for more than 50 yr. However, up to 40% of people taking Li develop nephrogenic diabetes insipidus (NDI). NDI is associated with cellular remodeling in the rodent kidney collecting duct (CD) and reduced aquaporin-2. Patients taking Li for more than 10-20 yr are at risk of chronic kidney disease, which ultimately can lead to end-stage renal disease, hemodialysis, transplantation, or death. The purpose of this study was to investigate whether the rat urinary proteome can be used as an indicator of Li-induced changes in the kidney. Extracellular vesicles were isolated from the urine of rats treated with Li for 2 or 4 wk, followed by LC-MS/MS analysis. The results showed a limited correlation between protein changes in the urine and the kidney. However, the urine contained markers of mitochondrial dysfunction. The cytoskeletal protein, keratin 8, showed a tendency to be higher in the urine and was greatly increased in collecting duct principal cells in response to Li, suggesting a potential role in cellular remodeling. Canonical histone H4 was increased in the urine and was observed in the nuclei of collecting duct principal and intercalated cells following Li. Moreover, histone H4-positive cells colocalized with the proliferation marker, proliferating cell nuclear antigen (PCNA). This correlates with the known increased proliferation in the collecting duct in response to Li. Thus, replication-dependent histone H4 is a possible urinary marker for the Li-induced cellular remodeling of the collecting duct.NEW & NOTEWORTHY Lithium (Li) increases replication-dependent histone H4 in urine and in principal and intercalated cells, so histone H4 is a possible urinary marker for Li-induced cellular remodeling.