Nrf2 activation protects against lithium-induced nephrogenic diabetes insipidus
Soma Jobbagy, Dario A. Vitturi, Sonia R. Salvatore, Maria F. Pires, Pascal Rowart, David R. Emlet, Mark Ross, Scott Hahn, Claudette St. Croix, Stacy G. Wendell, Arohan R. Subramanya, Adam C. Straub, Roderick J. Tan, Francisco J. Schopfer
Soma Jobbagy, Dario A. Vitturi, Sonia R. Salvatore, Maria F. Pires, Pascal Rowart, David R. Emlet, Mark Ross, Scott Hahn, Claudette St. Croix, Stacy G. Wendell, Arohan R. Subramanya, Adam C. Straub, Roderick J. Tan, Francisco J. Schopfer
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Research Article Nephrology Therapeutics

Nrf2 activation protects against lithium-induced nephrogenic diabetes insipidus

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.

Authors

Soma Jobbagy, Dario A. Vitturi, Sonia R. Salvatore, Maria F. Pires, Pascal Rowart, David R. Emlet, Mark Ross, Scott Hahn, Claudette St. Croix, Stacy G. Wendell, Arohan R. Subramanya, Adam C. Straub, Roderick J. Tan, Francisco J. Schopfer

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Figure 1

Lithium administration rapidly induces NDI but does not activate renal Nrf2 signaling.

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Lithium administration rapidly induces NDI but does not activate renal N...
(A) Schematic of experimental Li-NDI model. Mice received normal chow (control) or 0.17% dietary LiCl (LiCl) for 0–7 days. (B) Water intake was significantly increased after Li administration. Results plotted as mean ± SD of 4 (control) or 6 (LiCl) animals per group and statistical significance assessed by 2-way ANOVA with Dunnett correction for multiple comparisons. (C) Immunoblotting and densitometry for glycosylated (red arrowhead, 30–42 kDa) and nonglycosylated (black arrowhead, 24 kDa) AQP2 expression in kidney homogenates. Full blot is shown in Supplemental Figure 1C. (D) Spot urine osmolality from day 7. (E) Immunoblotting and densitometry for NQO1 protein expression in kidneys from Nrf2–/–, Keap1hm, control, and LiCl-fed mice. (F) Immunofluorescence microscopy evaluating NQO1 (green) and Muc1 (red) protein abundance, with F-actin (phalloidin, white) and DAPI (blue) costains in WT mouse kidney. Expanded images shown in Supplemental Figure 3. Images captured as 3 × 3 image stitch; original magnification, 20×. (G) Representative immunoblotting for NQO1 in primary human renal cortical cells immunoaffinity enriched for Muc1 or CD13 and cultured in presence of 10 or 50 mM LiCl for 6 hours. Densitometry shows average results of 3 experiments on primary human renal cortical cell lines from 3 independent donors and normalized to internal vehicle control; NS, not statistically significant by 1-way ANOVA with Tukey correction for multiple comparisons comparing to vehicle control.