Comella, Federica (2023) Possible synergic interaction between endogenous lipids and natural products in the management of cardiovascular alterations, secondary to metabolic impairment. [Tesi di dottorato]

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Abstract

The interaction between the kidneys and the heart has been recognized as a clinical entity called cardiorenal syndrome (CRS). CRS represents concomitant cardio-vascular and renal disorders that result from systemic diseases with common pathophysiological pathways. Whether in the heart or the kidney, fibrosis is the expected consequence of inflammation and oxidative stress-related endothelial dysfunction in hypertension, diabetes mellitus, and obesity, ultimately leading to cardiovascular disease (CVD), heart failure, and chronic kidney disease (CKD). Peroxisome proliferator-activated receptor (PPAR)- is a member of the nuclear hormone receptor family of ligand-activated transcription factors and is mainly involved in regulating inflammation, fibrogenesis, and lipid oxidation [Lin et al., 2022]. Oleoylethanolamide (OEA), belonging to the family of N-acylethanolamines, is an endogenous lipid mediator derived from the monounsaturated fatty acid oleic acid. OEA, a PPAR-α high-affinity agonist, controls feeding behaviour, body weight, and lipid metabolism [Bowen et al., 2017]. This study aimed to investigate OEA potential in counteracting cardio-renal alterations in a mouse model of obesity induced by a high-fat diet (HFD) and to evaluate the possible OEA synergic effect with Gingko Biloba leaf extract (EGb). In our experimental conditions, after 12 weeks of HFD feeding, EGb alone or combined with OEA did not show any significant effect after 6-week treatment. No difference was shown among HFD-fed mice and EGb- or EGb and OEA-treated mice in metabolic, cardiovascular, and renal function parameters. Similarly, the evaluation of molecular markers related to macrophage recruitment or fibrosis in the kidney did not show any potential of EGb or EGb/OEA combination in damping renal damage. However, long-term administration of OEA (2.5mg/kg/day) in obese mice limited metabolic alterations and heart and kidney damage. In particular, OEA normalizes cardiac metabolic factors, modulates tissue lipid profile, and reduces inflammatory and fibrotic markers. OEA also improved functional renal readouts, accompanied by a reduction of kidney inflammatory factors. Furthermore, to assess the direct effect of this acylethanolamide on kidney function and damage, regardless of its metabolic activity, its antifibrotic and anti-inflammatory effects were investigated in a mouse model of CKD induced by a high dose of folic acid (FA). In FA-induced CKD, short-term administration of OEA (2.5mg/kg/day) for eleven days prevents inflammation, fibrosis, and oxidative stress. All those OEA effects were blunted in FA-challenged PPAR-α KO mice, indicating a pivotal involvement of PPAR-α in the OEA renoprotective effect. In vitro experiments on human proximal tubular cells HK-2 exposed to transforming growth factor (TGF)-β1 confirmed the direct and specific impact of OEA, which reduced the inflammatory and fibrotic processes. The in vitro activity of OEA on HK-2 was contingent on PPAR- activation since the preincubation with a PPAR- specific antagonist blunted OEA effects. These results indicate that OEA may be a promising molecule for treating cardiometabolic alterations and kidney dysfunction, limiting the molecular mechanisms associated with the transition toward chronic diseases.

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