Peroxiredoxin-4 and Dopamine D5 Receptor Interact to Reduce Oxidative Stress and Inflammation in the Kidney

Reactive oxygen species are highly reactive molecules generated in different subcellular compartments. Both the dopamine D5 receptor (D₅R) and endoplasmic reticulum (ER)-resident peroxiredoxin-4 (PRDX4) play protective roles against oxidative stress. This study is aimed at investigating the interaction between PRDX4 and D₅R in regulating oxidative stress in the kidney. Fenoldopam (FEN), a D₁R and D₅R agonist, increased PRDX4 protein expression, mainly in non-lipid rafts, in D₅R-HEK 293 cells. FEN increased the co-immunoprecipitation of D₅R and PRDX4 and their colocalization, particularly in the ER. The efficiency of Förster resonance energy transfer was increased with FEN treatment measured with fluorescence lifetime imaging microscopy. Silencing of PRDX4 increased hydrogen peroxide production, impaired the inhibitory effect of FEN on hydrogen peroxide production, and increased the production of interleukin-1β, tumor necrosis factor (TNF), and caspase-12 in renal cells. Furthermore, in Drd5^-/- mice, which are in a state of oxidative stress, renal cortical PRDX4 was decreased whereas interleukin-1β, TNF, and caspase-12 were increased, relative to their normotensive wild-type Drd5^+/+ littermates. Our findings demonstrate a novel relationship between D₅R and PRDX4 and the consequent effects of this relationship in attenuating hydrogen peroxide production in the ER and the production of proinflammatory cytokines. This study provides the potential for the development of biomarkers and new therapeutics for renal inflammatory disorders, including hypertension. PRDX4 interacts with D₅R to decrease oxidative stress and inflammation in renal cells that may have the potential for translational significance. Antioxid. Redox Signal. 38, 1150-1166.