Abstract
Lithium (Li) is the mainstay pharmacotherapeutic mood stabilizer in bipolar disorder. Its efficacious use is complicated by acute and chronic renal side effects, including nephrogenic diabetes insipidus (NDI) and progression to chronic kidney disease (CKD). The nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway senses and coordinates cellular responses to oxidative and electrophilic stress. Here, we identify that graded genetic activation of Nrf2 protects against Li-induced NDI (Li-NDI) and volume wasting via an aquaporin 2-independent mechanism. Renal Nrf2 activity is differentially expressed on functional segments of the nephron, and its activation along the distal tubule and collecting duct directly modulates ion transporter expression, mimicking paradoxical effects of diuretics in mitigating Li-NDI. In addition, Nrf2 reduces cyclooxygenase expression and vasoactive prostaglandin biosynthesis. Pharmacologic activation of Nrf2 confers protective effects, confirming this pathway as a potentially novel druggable target for the prevention of acute and chronic renal sequelae of Li therapy.
Highlights
For over 60 years, lithium (Li) has been the gold-standard agent for prophylaxis and treatment of bipolar disorder
Our results demonstrate that activation of the Keap1/Nrf2 signaling pathway completely protects mice from polydipsia/polyuria in Li-nephrogenic diabetes insipidus (NDI)
The reduction in polydipsia occurs without altering aquaporin 2 (AQP2) expression or increasing urine osmolality
Summary
For over 60 years, lithium (Li) has been the gold-standard agent for prophylaxis and treatment of bipolar disorder. Its efficacy in acute treatment and chronic prevention of both manic and depressive episodes make it the first-line drug administered for long-term mood stabilization, and it remains the only therapeutic that is documented to reduce the incidence of suicide-related events [1]. In addition to reducing quality of life, Li-induced NDI (Li-NDI) in the long term poses a more severe iatrogenic risk, as it correlates with increased progression to chronic kidney disease (CKD) and, renal failure [5,6,7,8,9,10,11]. Li has been demonstrated to target the epithelium lining the distal tubule (DT) and collecting duct (CD) of the nephron, where its uptake is mediated by the epithelial sodium channel (ENaC) [12,13,14] and where it induces loss of function through uncoupling the effects of arginine vasopressin and downregulating aquaporin 2 (AQP2) to yield pronounced polyuria with compensatory polydipsia [15,16,17]
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