Explore the vast range of titles available.

Overproduction of reactive oxygen species (ROS) plays an important role in the pathogenesis of hypertension. The dopamine D5 receptor (D5R) is known to decrease ROS production, but the mechanism is not completely understood. In HEK293 cells overexpressing D5R, fenoldopam, an agonist of the two D1-like receptors, D1R and D5R, decreased the production of mitochondria-derived ROS (mito-ROS). The fenoldopam-mediated decrease in mito-ROS production was mimicked by Sp-cAMPS but blocked by Rp-cAMPS. In human renal proximal tubule cells with DRD1 gene silencing to eliminate the confounding effect of D1R, fenoldopam still decreased mito-ROS production. By contrast, Sch23390, a D1R and D5R antagonist, increased mito-ROS production in the absence of D1R, D5R is constitutively active. The fenoldopam-mediated inhibition of mito-ROS production may have been related to autophagy because fenoldopam increased the expression of the autophagy hallmark proteins, autophagy protein 5 (ATG5), and the microtubule-associated protein 1 light chain (LC)3-II. In the presence of chloroquine or spautin-1, inhibitors of autophagy, fenoldopam further increased ATG5 and LC3-II expression, indicating an important role of D5R in the positive regulation of autophagy. However, when autophagy was inhibited, fenoldopam was unable to inhibit ROS production. Indeed, the levels of these autophagy hallmark proteins were decreased in the kidney cortices of Drd5−/− mice. Moreover, ROS production was increased in mitochondria isolated from the kidney cortices of Drd5−/− mice, relative to Drd5+/+ littermates. In conclusion, D5R-mediated activation of autophagy plays a role in the D5R-mediated inhibition of mito-ROS production in the kidneys.

Background Salt-sensitive hypertension (SSH) is the most severe form of hypertension, and the presence of NLRP3 inflammasome plays a crucial role in its pathogenesis. Although MCC950 has shown therapeutic potential for hypertension and kidney injury, its mechanism of action remains unclear. Methods Dahl salt-sensitive (SS) rats and their salt-tolerant aptamer control SS-13 BN (BN) rats were randomly assigned to four groups: SS rats intraperitoneally administered physiological saline (SS + vehicle) or MCC950 (SS + MCC950), and BN rats intraperitoneally administered physiological saline (BN + vehicle) or MCC950 (BN + MCC950). All rats were given 2% saline for drinking and received intraperitoneal injections of physiological saline or MCC950 (5 mg/kg) every other day. Biomarkers such as serum creatinine, urinary protein, sodium retention, NLRP3 inflammasome, inflammation, apoptosis, fibrosis, sodium channels and histopathological changes in kidney injury were evaluated in blood, urine, and kidney tissues. Results Compared with the SS + vehicle group, the SS + MCC950 group showed significantly lower blood pressure levels. Additionally, inhibition of NLRP3 inflammasome activation was observed along with reduced inflammation, apoptosis, fibrosis, and sodium retention in the kidneys. Conclusions The findings suggest that pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure in SS rats and alleviates related kidney injury by suppressing inflammation, apoptosis, fibrosis, and sodium retention.

Overproduction of reactive oxygen species (ROS) plays an important role in the pathogenesis of hypertension. The dopamine D receptor (D R) is known to decrease ROS production, but the mechanism is not completely understood. In HEK293 cells overexpressing D R, fenoldopam, an agonist of the two D -like receptors, D R and D R, decreased the production of mitochondria-derived ROS (mito-ROS). The fenoldopam-mediated decrease in mito-ROS production was mimicked by Sp-cAMPS but blocked by Rp-cAMPS. In human renal proximal tubule cells with DRD1 gene silencing to eliminate the confounding effect of D R, fenoldopam still decreased mito-ROS production. By contrast, Sch23390, a D R and D R antagonist, increased mito-ROS production in the absence of D R, D R is constitutively active. The fenoldopam-mediated inhibition of mito-ROS production may have been related to autophagy because fenoldopam increased the expression of the autophagy hallmark proteins, autophagy protein 5 (ATG5), and the microtubule-associated protein 1 light chain (LC)3-II. In the presence of chloroquine or spautin-1, inhibitors of autophagy, fenoldopam further increased ATG5 and LC3-II expression, indicating an important role of D R in the positive regulation of autophagy. However, when autophagy was inhibited, fenoldopam was unable to inhibit ROS production. Indeed, the levels of these autophagy hallmark proteins were decreased in the kidney cortices of Drd5 mice. Moreover, ROS production was increased in mitochondria isolated from the kidney cortices of Drd5 mice, relative to Drd5 littermates. In conclusion, D R-mediated activation of autophagy plays a role in the D R-mediated inhibition of mito-ROS production in the kidneys.