Title

Genetic background determines renal response to chronic lithium treatment in female mice.

Document Type

Article

Publication Date

9-2021

Publication Title

Physiological genomics

Keywords

JMG

JAX Source

Physiol Genomics 2021 Sep; 53(9):406-415

Volume

53

Issue

9

First Page

406

Last Page

415

ISSN

1531-2267

PMID

34378418

DOI

https://doi.org/10.1152/physiolgenomics.00149.2020

Grant

Niels Stensen Fellowship and Marie Curie Fellowship

Abstract

Chronic lithium treatment for bipolar disease causes mainly side effects in the kidney. A subset of lithium users develops nephrogenic diabetes insipidus (NDI), a urinary concentrating disorder, and chronic kidney disease (CKD). Age, lithium dose, and duration of treatment are important risk factors, whereas genetic background might also play an important role. To investigate the role of genetics, female mice of 29 different inbred strains were treated for 1 year with control or lithium chow and urine, blood, and kidneys were analyzed. Chronic lithium treatment increased urine production and/or reduced urine osmolality in 21 strains. Renal histology showed that lithium increased interstitial fibrosis and/or tubular atrophy in eight strains, whereas in none of the strains glomerular injury was induced. Interestingly, lithium did not elevate urinary albumin-creatinine ratio (ACR) in any strain, whereas eight strains even demonstrated a lowered ACR. The protective effect on ACR coincided with a similar decrease in urinary IgG levels, a marker of glomerular function, whereas the adverse effect of lithium on interstitial fibrosis/tubular atrophy coincided with a severe increase in urinary β2-microglobulin (β2M) levels, an indicator of proximal tubule damage. Genetic background plays an important role in the development of lithium-induced NDI and chronic renal pathology in female mice. The strong correlation of renal pathology with urinary β2M levels indicates that β2M is a promising biomarker for chronic renal damage induced by lithium.

Comments

We thank Holly Savage, Thomas O'Rourke, and Rita O'Rourke (from The Jackson Laboratory) for expert help.

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