Signaling Pathways Involved in Renal Oxidative Injury: Role of the Vasoactive Peptides and the Renal Dopaminergic System

Figure 4

Renal dopamine receptors and its antioxidants properties. Dopamine (DA) binds to D1 receptor (D1R) coupled to stimulatory G proteins (Gs and Gα) (1a) and to active adenylyl cyclase (AC) (1b) which in turn increases second messenger levels of cAMP (1c) and activates the protein kinase A (PKA) (1d). PKA inhibits directly the Na/K exchanger (1e) in the apical membrane and also stimulates phospholipase A₂ (PLA₂) (1f). A metabolite of arachidonic acid (AA) (1g), 20-hydroxyeicosatetraenoic acid (20-HETE) (not shown) activates PKC (1h). In addition, D1R via G protein (Gq) activates PLC (2a) with generation of inositol 1,3,4-trisphosphate (IP₃) and diacylglycerol (DAG) (2b). IP₃ induces calcium (Ca⁺⁺) release (2c) and DAG stimulates PKC (2d). Both PKA (1i) and PKC (2e) can inhibit Na⁺, K⁺-ATPase activity (1i) and promote tubular sodium excretion. A crosstalk between PKA (1j) and PKC (2f) results in a negative regulation of NADPH oxidase (Nox) activity. D2 receptors (D2R) are coupled to inhibitory G-protein (Gi/o) (3a) which inhibits AC activity. The D2-R stimulates the expression of antioxidant complex (3b) such as Parkinson protein 7 (PARK-7), paraoxonase 2 (PON2), heme oxygenase 2 (HO-2), catalase, superoxide dismutase (SOD), and glutathione peroxidase (3c). By displaying this antioxidant role, the physiological effect of D2R is to reduce Nox (3d) activity. The activation of Nox (4a) leads to an imbalance in the redox state by generation of reactive oxygen species (ROS) (4b). This conduces to an activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the cytoplasm and its translocation to the nucleus (4c). NF-κB promotes the transcription of several genes, including PKC (4d) and AT-1 receptor (4g). Activation of PKC stimulates the translocation of G protein-coupled receptor kinase 2 (GRK-2) to the membrane (4e). The GRK-2 causes D1R serine hyperphosphorylation and uncoupling of G-protein to D1 receptor (4f). TEMPOL (5), an antioxidant permeable compound, reduces ROS production and prevents cell damage by oxidative stress. Thin red arrows indicate inhibition. Thick green arrows indicate activation.