Effect of Regular Exercise and Resveratrol on Hypertension-Induced Cellular Stress Response and Senescence in Renal and Vascular Tissues of Rats

Abstract: Hypertension remains the leading cause of morbidity and mortality worldwide and requires more understanding of its molecular basis. This study investigated cellular stress responses and senescence signaling in vascular and renal tissues of deoxycorticosterone-acetate-salt hypertensive rats and the effect of resveratrol and exercise on these processes. Biochemical measurements in plasma and molecular (using Western Blot and Quantitative Real-Time-polymerase chain reaction methods) and histopathologic (Hematoxylin-Eosin and Masson's Trichrome staining) examinations in the kidney and aorta were performed. The increase in kidney weight, kidney/body weight ratio, plasma blood urea nitrogen, and creatinine levels of hypertensive animals was improved by exercise and resveratrol. Both interventions reduced GRP78/p-PERK–mediated endoplasmic reticulum stress and restored mitophagy via PINK1-SIRT3 in hypertensive renal and vascular tissues. Decreased vascular enos mRNA expression in hypertensive rats was enhanced by resveratrol treatment. The expression of NLRP3 inflammasome-related molecules and nf-ĸb in both tissues was increased in hypertensive animals. The positive effect of both treatments on inflammatory parameters was more pronounced in the kidney than in the aorta. The increased cellular senescence-related molecules p53 and il-6 were reversed by exercise and resveratrol in both tissues of hypertensive rats. Hypertension caused more obvious structural and inflammatory histopathologic changes in renal tissue than in vascular tissue. Regular exercise ameliorated these hypertension-induced renal alterations more than resveratrol. This study revealed that hypertension induces cellular stress responses including endoplasmic reticulum stress, impaired mitophagy, inflammation, and consequently senescence, leading to structural alterations in a tissue-dependent manner. Regular exercise and resveratrol have different positive regulatory effects on these renal and vascular impairments caused by hypertension.