Abstract
Lithium is widely used in the treatment of bipolar disorders and may lead to nephrogenic diabetes insipidus (NDI), following long-term treatment. Metformin is considered the preferred initial therapy for patients with type 2 diabetes mellitus (T2D). To investigate the protective effect of metformin on the kidney damage caused by lithium administration. Using an animal model of chronic lithium-induced NDI, rats were divided into 4 groups: sham, metformin, lithium, and lithium + metformin. The effects of these treatments were examined using serum electrolytes, blood and tissue total antioxidant status, total oxidant status, the oxidative stress index, urine and blood osmolality, and tissue aquaporin-2 (AQP2) levels. Additionally, histopathological changes, including congestion, hydropic swelling, tubular necrosis, tubular atrophy, and Bowman's capsule dilatation, were evaluated. The total histopathological score was obtained by summing the scores for each pathological finding. In the lithium group, biochemical variables indicating NDI, including sodium, chloride and blood osmolality, increased, and urine osmolality decreased, compared to the sham group. With metformin treatment, the blood osmolality decreased from 328.17 mOsm/kg to 306.33 mOsm/kg, and urine osmolality increased from 349.67 mOsm/kg to 754.50 mOsm/kg (p = 0.004 and p = 0.001, respectively). Tissue AQP2 levels decreased with lithium administration but stabilized with metformin treatment. Additionally, in comparison to the lithium group, the total histopathological score in the metformin group declined from 8.0 to 2.0 (p = 0.002). Metformin may help protect the kidneys from lithium-induced NDI through the AQP2 regulating effect and a reduction in oxidative stress.
Highlights
Lithium is widely used in the treatment of bipolar disorders and may lead to nephrogenic diabetes insipidus (NDI), following long-term treatment
The blood osmolality decreased from 328.17 mOsm/kg to 306.33 mOsm/kg, and urine osmolality increased from 349.67 mOsm/kg to 754.50 mOsm/kg (p = 0.004 and p = 0.001, respectively)
Metformin may help protect the kidneys from lithium-induced NDI through the AQP2 regulating effect and a reduction in oxidative stress
Summary
Lithium is widely used in the treatment of bipolar disorders and may lead to nephrogenic diabetes insipidus (NDI), following long-term treatment. Previous studies have shown that the urinary concentration defect, associated with lithium toxicity, is mainly connected to a decrease in the amount of aquaporin-2 (AQP2) protein in the collecting duct principal cells.[4] Another mechanism responsible for lithium-induced nephrotoxicity is a change in the epithelial sodium channels (ENaCs), collecting channels, which are essential sites for sodium reabsorption.[1] It has been shown that when inhibition of the functioning of ENaCs in the collecting ducts is prevented, the expected polyuria due to lithium is inhibited, and introduction of lithium into the cell through ENaCs is a central step in the development of NDI.[5] oxidative stress has been proposed as an alternative mechanism for lithium toxicity in renal tissue through impairment of the mitochondrial respiratory system, that leads to an increased generation of free radicals through lipid peroxidation of the cell membrane.[2]
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