Early targets of lithium in rat kidney inner medullary collecting duct include p38 and ERK1/2

Abstract

Almost half of patients receiving lithium salts have nephrogenic diabetes insipidus. Chronic lithium exposure induces AQP2 downregulation and changes in the cellular composition of the collecting duct. In order to understand these pathophysiological events, we determined the earliest lithium targets in rat inner medullary collecting duct (IMCD) by examining changes in the IMCD phosphoproteome after acute lithium administration. IMCDs were isolated 9 h after lithium exposure, a time when urinary concentrating impairment was evident. We found 1093 unique phosphopeptides corresponding to 492 phosphoproteins identified and quantified by mass spectrometry. Label-free quantification identified 152 upregulated and 56 downregulated phosphopeptides in response to lithium. Bioinformatic analysis highlighted several signaling proteins including MAP kinases and cell-junction proteins. The majority of the upregulated phosphopeptides contained a proline-directed motif, a known target of MAPK. Four hours after lithium exposure, phosphorylation sites in the activation loops of ERK1/2 and p38 were upregulated. Increased expression of phospho-Ser261-AQP2 (proline-directed motif) was concomitant with the increase in urine output. Pretreatment with MAPK inhibitors reversed the increased Ser261-AQP2 phosphorylation. Thus, in IMCD, ERK1/2 and p38 are early targets of lithium and may play a role in the onset of lithium-induced polyuria.

Unraveling the Mechanistic Complexity of the Glomerulocystic Phenotype in Dicer Conditional KO Mice by 2D Gel Electrophoresis Coupled Mass Spectrometry

“…Proteomic analysis was based on tissue homogenate of the whole cortex; therefore, we could not rule out that ERK activation is linked to the development of interstitial fibrosis leading to chronic renal failure in Dicer cKO mice. Since the phenotype of Dicer cKO mice included a progressively severe polyuria, ERK activation could be one of the mechanisms sustaining the polyuria in agreement with previous reports demonstrating that alteration in ERK pathway is one of the underlying mechanisms promoting Li‐induced polyuria in mice …”

Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus

“…However, despite major progress, no clear consensus regarding the "trigger" for the onset of the condition exists. For example, data from large-scale proteomic (7) and metabonomic approaches (8), coupled with targeted studies in animal models and gene-modified mice, have illustrated changes in renal prostaglandins (9); purinergic signaling (10); and the activity of glycogen synthase kinase 3 (GSK3) (11), PKC (12), MAPKs, ERKs ERK1/2 and P38α (13), and the phosphatidylinositol signalPsychiatric patients treated with lithium (Li + ) may develop nephrogenic diabetes insipidus (NDI). Although the etiology of Li + -induced NDI (Li-NDI) is poorly understood, it occurs partially due to reduced aquaporin-2 (AQP2) expression in the kidney collecting ducts.…”

CaSR signaling down‐regulates AQP2 expressionviaa novel microRNA pathway in pendrin and NaCl cotransporter knockout mice

“…A role for AQP2 phosphorylation at Ser261 via p38‐MAPK and polyubiquitination in the control of AQP2 protein degradation has been suggested (42, 43).…”

“…Several authors have suggested a critical role for AQP2 phosphorylation at Ser261 and polyubiquitination in the control of AQP2 levels (42, 43). Specifically, a role for p38‐MAPK in the promotion of AQP2 phosphorylation at Ser261 has been reported (42, 43).…”