Mechanistic Insight into the Role of Maresin-1 in Attenuating Lithium-Induced Nephrogenic Diabetes Insipidus in Rats via Regulation of cAMP/AQP2 Signaling and SERCA2b Dependant Endoplasmic Reticulum Stress.

BACKGROUND: Nephrogenic diabetes insipidus (NDI), one of the common complications of chronic administration of lithium, is characterized by severe urine concentrating defects. It is associated with aberrant regulation of aquaporin-2 (AQP2) proteins as well as endoplasmic reticulum (ER) stress. Therefore, we evaluated renoprotective effects of Maresin-1 (MaR-1) and its associated molecular mechanisms in Li-induced NDI. METHODS: forty-eight adult male Wistar albino rats were randomly distributed into four equal groups: control, MaR-1 control (40 ug/kg/day intraperitoneally), NDI (LiCl; 40 mmol/kg dry food), and NDI + MaR-1 groups for 14 days. Renal function status was assayed in blood and urine. The gene expression of AQP2 and SERCA2b in renal tissue homogenates was assessed by qRT- PCR. Biochemical analyses of autophagy and ER stress markers as well as cAMP levels were detected. Also, histopathological analysis was determined. RESULTS: Administration of MaR-1 significantly improved polyuria and urine osmolality which are attributed to marked elevation of cAMP level and upregulated AQP2 expression. Furthermore, MaR-1 significantly increased SERCA2b expression leading to attenuated ER stress (GRP78 and CHOP) and decreased autophagy markers (beclin-1 and LC3BII). CONCLUSION: MaR-1 exhibits a novel therapeutic approach for attenuation of Li-induced NDI via regulation of cAMP/AQP2 signaling and modulation of SERCA2b dependent ER stress.