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.
Abstract
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.