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

Figure 2

Interaction between renin angiotensin system and oxidative stress. (1) ROS can activate the mitochondrial uncoupling protein 2 (UCP-2), leading to inefficient renal O₂ usage and contributing to renal hypoxia. (2) Hypoxia induces the transcription factor hypoxia-inducible factor-1α (HIF-1α) which coordinates the expression of diverse adaptive genes against the hypoxic injury. (3) HIF-1α transcriptionally upregulates the expression of soluble growth factors (TGF-β and VEGF). (4) Increased sodium tubular transport, luminal flow, or cytokines release upregulates NADPH oxidase, which produces ROS. (5) Superoxide anion increases Na-K-2Cl cotransport activity in the thick ascending limb, enhancing further oxidative stress. (6) Hypoxia regulates ANP. (7) ANP in addition to its natriuretic actions exerts protective effects on several cell types in response to the oxidative stress and fibrosis and on the adaptation to hypoxia. (8) TGF-β1 upregulates the transcription of serum and glucocorticoid-dependent kinase hSGK1, involved in the regulation of two important factors for cell volume regulation, as the renal epithelial Na⁺ channel ENaC and the thick ascending limb Na⁺, K⁺, 2Cl⁻ cotransporter NKCC. (9) ROS, especially superoxide, degrade HIF-1α by activating ubiquitin-proteasome and thereby decrease the activation of many oxygen-sensitive genes. (10) Angiotensin-converting enzyme 2 regulates renal ANP through angiotensin-(1–7). (11) The signal transduction of Ang II through AT1R enhances ROS production. (12) NADPH oxidase contributes to renal damage through NF-κB.