Maresin 1 Alleviates Diabetic Kidney Disease via LGR6-Mediated cAMP-SOD2-ROS Pathway

Abstract

Background. Chronic hyperglycemia-induced inflammation is recognized as the most important pathophysiological process in diabetic kidney disease (DKD). As maresin 1 (MaR1) is an extensive anti-inflammatory lipid mediator, the present study investigated the protective role of MaR1 in the pathogenesis of DKD and its clinical relevance. Methods. Serum MaR1 concentrations were analyzed in 104 subjects with normal glucose tolerant, type 2 diabetes (T2DM), or DKD. Streptozotocin (STZ) together with high fat diet was used to induce male C57BL/6 J mice into diabetic mice which were treated with MaR1. Human renal tubule epithelial cells (HK-2 cells) were treated by high glucose for glucotoxicity cell model and transfected with LGR6 siRNA for knockdown with MaR1 added，and detected oxidative stress and inflammatory related factors. Results. Serum MaR1 concentrations were significant decreased in T2DM with or without kidney disease compared with normal participant and were lowest in patients with DKD. Serum MaR1 concentrations were negatively correlated with hemoglobin A1c (HbA1c), duration of diabetes, urinary albumin to creatinine ratio (UACR), neutrophil, and neutrophil-lymphocyte ratio and were positively correlated with high-density lipoprotein-cholesterol (HDL-C) and estimated glomerular filtration rate (eGFR). In mouse model, MaR1 injection alleviated hyperglycemia, UACR and the pathological progression of DKD. Interestingly, the renal expression of LGR6 was down-regulated in DKD and high glucose treated HK-2 cells but up-regulated by MaR1 treatment. Mechanistically, MaR1 alleviated inflammation via LGR6-mediated cAMP-SOD2 antioxidant pathway in DKD mice and high glucose treated HK-2 cells. Conclusions. Our study demonstrates that decreased serum MaR1 levels were correlated with the development of DKD. MaR1 could alleviate DKD and glucotoxicity-induced inflammation via LGR6-mediated cAMP-SOD2 antioxidant pathway. Thus, our present findings identify MaR1 as a predictor and a potential therapeutic target for DKD.

Methyltransferase METTL3‐mediated maturation of miR‐4654 facilitates high glucose‐induced apoptosis and oxidative stress in lens epithelial cells via decreasing SOD2

“…SOD2 is a member of the SOD family that encodes the manganese SOD (Mn‐SOD) to dismutate superoxide radicals (O2−) to H 2 O 2 and molecular oxygen, thereby involving in regulating oxidative stress in cells (Alateyah et al., 2022; Becuwe et al., 2014; Zelko et al., 2002). Moreover, the deregulation of SOD2 has been identified to be related to various diseases, such as mitochondrial dysfunction, neurodegeneration, and diabetes (Flynn & Melov, 2013; Li et al., 2022). In the present work, a decreased SOD2 content in DC patients and HG‐induced LECs was found.…”

Maresin‐1 ameliorates hypertensive vascular remodeling through its receptor LGR6

“…Additionally, the decreased serum MaR1 level was associated with postmenopausal osteoporosis 27 . The serum level of MaR1 was significantly reduced in type 2 diabetic patients compared with normal participants, particularly in patients with diabetic foot ulcer or diabetic kidney disease 28 . The decreased serum MaR1 concentration tightly associated with obesity, impaired glucose and lipid metabolism, reduced first‐phase of glucose‐stimulated insulin secretion, and enhanced insulin resistance 29 .…”

Possibility of averting cytokine storm in SARS-COV 2 patients using specialized pro-resolving lipid mediators

“…MaR1 stimulate tissue regeneration and reduce pain They inhibit capsaicin-induced (TRPV1) transient receptor potential vanilloid 1 fluxes in neurons. Mar 1 subdues diabetic kidney disease via modulation of LGR6-Mediated cAMP-SOD2-ROS Pathway [222] . MaR1 acts via ROR α this ligand binding is essential to activate switch from M1to M2 polarity in kuffer cells, prevents progression of high-fat diet-induced nonalcoholic steatohepatitis (NASH) [217] .…”