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Nowadays metabolic syndrome (MS) cases are growing worldwide. Evidence shows that diet plays an important role in the MS development, being the western diet is the best example. This diet is characterized by a high consumption of Fructose, leading to hyperuricemia, cardiovascular damage, oxidative stress, inflammation, hypertension, inducing glomerular filtration rate decrease and renal disease. Fructose induces these metabolic effects primarily from the nucleotide degradation that results following metabolism of fructose by the C isoform of KHK, that lacks a negative feedback mechanism, thus depleting ATP levels by the fast fructose phosphorylation.
To avoid KHK over activation, natural compounds have been evaluated, such as Osthol (a coumarin isolated from the plant Angelica archangelica). Previous studies showed that Osthol inhibited KHK-C activity avoiding ATP depletion. However, its protective effects in ATP sources like mitochondrial in renal damage induced by metabolic syndrome has not been evaluated.
Experimental model consisted in 4 groups of male Wistar rats groups (260 - 300 g, n=6): (1) control (C), animals received a normal diet and tap water ad libitum; (2) Metabolic Syndrome (MS), animals received high fat high sugar (HF/HS) diet and a sweetened beverage 11% (3.8% glucose, 7.2% fructose); (3) Metabolic Syndrome plus Osthol (MS+OST), animals received HF/HS diet supplemented with 40 mg/kg Osthol and sweetened beverage 11%; and (4) Osthol group (OST), animals received a normal diet supplemented with Osthol, and tap water ad libitum.
The Osthol administration prevented the metabolic syndrome development induced by HF/HS, by as it showed by glucose, triglycerides, cholesterol levels and body weight reduction. This was elated to inflammatory cytokines and tubular damage markers renal increase (NGAL and KIM), suggested that renal hyperlipidemia and inflammation trigger the posterior kidney function lost. Osthol administration partially prevented both renal pathological processes. These was related to renal mitochondrial bioenergetics protection, by mitochondrial respiratory state 3 (S3) and 4 (S4o), restoration, with together with the lack of mitochondrial decoupling, suggested a HF/HS induced reduction in mitochondrial biogenesis prevented by Osthol. However, deeper studies are still necessary.
Osthol prevented lipotoxicity and inflammation in renal tissues in metabolic syndrome induced by HF/HS diet. These protective effects would be related not only to KHK inhibition, as previously reported, but also to renal bioenergetics mitochondria preservation by the restauration of the respiratory states and membrane potential.