RECOVERY OF THE WT1 RENAL PHENOTYPE AND ATHEROGENESIS REDUCTION: A NOVEL PROTECTIVE MECHANISM BY ORGANOSULFUR COMPOUNDS TREATMENT DURING CARDIOVASCULAR DISEASE

TORRES-PALAZZOLO C.; DE PAOLA M.; ARLANDI M.; MAZZEI L.; FORNÉS M. W.; CUELLO CARRIÓN, F. D.; CAMARGO A.; CASTRO C. M.; MANUCHA W.

San Luis

Congreso; XXXVII Reunión Científica Anual de la Sociedad de Biología de Cuyo; 2019

Atherosclerosis is one of the leading causes of death from cardiovascular disease (CVD). Of interest, alterations in the transcription factor WT1 precede the development of CVD. The organogenic process -regulated by WT1- is modulated by oxidative/inflammatory (OI) mediators, and in this sense, it has been suggested to implement functional foods carrying organosulfur compounds (AF-OSCs) as a preventive anti-oxidative/anti-inflammatory strategy in CVD. So we decided to evaluate in a model of atherosclerosis, the possible renal changes of WT1, its correlation with OI markers, the impact on the development of atherosclerotic plaques, as well as the protection by the use of certain AF-OSCs. We used female mice deficient in apolipoprotein E (ApoE-KO) (N=8 per group) who received: a-standard feed (A); b-standard food + sunflower oil (B); or c-standard food + oil mashed with crushed garlic (380 ppm 2-vinyldithiine, 30 ppm garlic and 40 ppm diallyl sulfide) (C). After 2 months of the food protocol, blood was taken to evaluate biochemical parameters, renal tissue for microscopy, ultrastructure, IHQ, PCR, OI markers and thoracic aortas to quantify atheroma plaques by staining with Oil-red O. Group A evidenced a lipid, histological and functional profile consistent with the atherogenic process of the ApoE-KO hypercholesterolemic model. However, mice in group C showed a decrease in triglyceridemia after 2 months of treatment compared to group B (36.9 mg% ± 6.3 vs. 60.8 mg% ± 5.9; p<0.05). No changes were observed in blood glucose and cholesterolemia. In group B, the expression of OI markers (IL-6, TNF-α, NADPH activity, and decreased nitric oxide availability) was exacerbated. Significant changes in renal WT1 expression/localization and consequent apoptosis were also evidenced. On the other hand, group C showed a reduction of OI markers with the recovery of the adult renal WT1 phenotype and lower apoptosis. The atherogenesis in the aortic arch was quantified, and it was found that garlic macerated oil reduces the formation of atherosclerotic lesions by 40%, compared to group B. We demonstrated unpublished phenotypic changes of WT1 at the renal level consistent with OI markers and cardiovascular correlate (development of atheroma plaques). The incorporation of AF-OSCs in the diet managed to reverse this phenotype, reduce OI markers, and reduce plaque size. These findings suggest WT1 as an unprecedented factor whose alteration could be critical in the natural history of atherosclerotic CVD. The confirmation of the implication of WT1 in the atherogenic process and its modulation by AF-OSCs would allow us to propose new therapeutic interventions.