Redox Signalling and Role of Antioxidant in Heart and Kidney Disease

Abstract

Redox signalling refers to oxidation–reduction reactions involved in cellular signalling pathways. Reactive oxygen species (ROS) regulates various physiological, pathological and stress response pathways through redox signalling. Low level of ROS is responsible for cellular processes such as immune response, metabolism, transcriptional signalling, cell cycle, apoptosis and cell differentiation. Elevated levels of ROS lead to oxidative stress and imbalance in redox equilibrium. Disruption of redox homeostasis triggers the onset of metabolic disorders especially diabetes, cardiovascular and chronic kidney diseases causing organ damage. Endogenous antioxidants molecules such as superoxide dismutase (SOD), catalase, glutathione reductase (GRD) and glutathione peroxidase (GPx) play significant role under pathophysiological conditions in maintaining redox balance. In this article, the importance of redox‐activated NF‐E2‐related factor 2 (Nrf2) is discussed as an example for transcriptional antioxidant response. Thus understanding the mechanism behind the modulation of transcription factors and receptors may provide therapeutic interventions in redox‐related diseases.

Key Concepts

  • Cellular ROS sensing and metabolism are tightly regulated by a variety of signalling molecules involved in the redox (reduction/oxidation) mechanism.
  • Oxidative stress refers to the imbalance due to excess ROS and the incapability of the cell to respond to an effective antioxidant.
  • Redox signalling through H2O2 activates prosurvival transcriptional pathways including Nrf2.
  • Both NADPH oxidase and mitochondrial electron gradient play roles in hyperglycaemia‐induced ROS generation.
  • Normal redox signalling is disrupted in diabetes leading to several pathological mechanisms that cause tissue damage and further leading to organ dysfunction.
  • Enzymatic and nonenzymatic antioxidants defence system satiates ROS in heart.
  • Nrf2/ARE (antioxidant response element) regulates expression of many detoxifying genes and confers protection against cardiac and vascular disorders.
  • Imbalance between ROS and antioxidant enzymes results in pathology of chronic kidney disease.
  • Hyperoxaluria plays an important role in excessive ROS generation leading to kidney damage.
  • Modulation of cannabinoid receptors ameliorates chronic kidney disease.

Keywords: oxidative stress; redox signalling; hyperglycaemia; advanced glycosylation end products; nuclear factor erythroid 2‐related factor; antioxidant response element; cardiovascular disease; chronic kidney disease; cannabinoid receptors; hyperoxaluria

Figure 1. Hyperglycaemia‐induced methylglyoxals (MGO's), advanced glycation end products (AGE's) and reactive oxygen species (ROS) leading to diabetes‐associated complications. MGO's are produced in the triose pathway of glycolysis, leads to increased AGE by reacting with NH2 group of protein. Excess glucose activates NADPH oxidase (NOX), causes mitochondrial dysfunction, increases superoxide free radical production (O2·−). Elevated ROS causes oxidative stress and diabetic complications such as heart and kidney damage.
Figure 2. ROS generation and Nrf2/ARE signalling mediated cardio/athero‐protection through the transcriptional activation of Nrf2‐targeted antioxidant enzymes.
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Sasikumar, Sundaresan, Vasudevan, Varadaraj, Abhishek, Albert, Divya, Ganesan, Selvam, Govindan S, and Saso, Luciano(Dec 2018) Redox Signalling and Role of Antioxidant in Heart and Kidney Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027100]