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Dopamine D5 receptor-mediated decreases in mitochondrial reactive oxygen species production are cAMP and autophagy dependent

Abstract

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.

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Acknowledgements

This study was supported in part by grants from the National Institutes of Health (HL074940, HL023081, DK039308, HL092196, DK119652, and DK090918), the Children’s National Medical Center Intramural Avery Award, the National Natural Science Foundation of China (81670698, 91739119, 81670406, 30971186), the Second Hospital of Dalian Medical University Start-up Funds, and the Department of Education of Liaoning Province Grant (L2016020).

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HL and PAJ designed the experiments. HL, XJ, IP, PY, SR, JW, and YW performed the experiments. DRS supplied the mice. HL, PY, MH, RAF, BMP, IA, ZY, PQ, and PAJ interpreted the experimental results. HL and PAJ drafted the manuscript. All authors edited, revised, and approved the final manuscript.

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Correspondence to Pedro A. Jose.

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Lee, H., Jiang, X., Perwaiz, I. et al. Dopamine D5 receptor-mediated decreases in mitochondrial reactive oxygen species production are cAMP and autophagy dependent. Hypertens Res 44, 628–641 (2021). https://doi.org/10.1038/s41440-021-00646-w

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Keywords

  • Autophagy
  • Dopamine D5 receptor
  • Hypertension
  • Mitochondria
  • Reactive oxygen species

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