Oxidative Stress and Inflammation in Renal and Cardiovascular Complications of Diabetes

Abstract

Oxidative stress and inflammation are considered major drivers in the pathogenesis of diabetic complications, including renal and cardiovascular disease. A symbiotic relationship also appears to exist between oxidative stress and inflammation. Several emerging therapies target these crucial pathways, to alleviate the burden of the aforementioned diseases. Oxidative stress refers to an imbalance between reactive oxygen species (ROS) and antioxidant defenses, a pathological state which not only leads to direct cellular damage but also an inflammatory cascade that further perpetuates tissue injury. Emerging therapeutic strategies tackle these pathways in a variety of ways, from increasing antioxidant defenses (antioxidants and Nrf2 activators) to reducing ROS production (NADPH oxidase inhibitors and XO inhibitors) or inhibiting the associated inflammatory pathways (NLRP3 inflammasome inhibitors, lipoxins, GLP-1 receptor agonists, and AT-1 receptor antagonists). This review summarizes the mechanisms by which oxidative stress and inflammation contribute to and perpetuate diabetes associated renal and cardiovascular disease along with the therapeutic strategies which target these pathways to provide reno and cardiovascular protection in the setting of diabetes.

Keywords: cardiovascular disease; diabetes mellitus; diabetic complications; diabetic kidney disease; inflammation; reactive oxygen species.

Figure 1

Pathophysiology and therapeutic strategies of diabetic kidney disease. ACEi, angiotensin-converting-enzyme inhibitors; ARBs, angiotensin receptor blockers; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; H₂O₂, hydrogen peroxide; IL, interleukin; MCP-1, monocyte chemotactic protein-1; NF-κB, nuclear factor-κB; NLRP3, NLR family pyrin domain containing 3; Nox, NADPH oxidase; Nrf2, nuclear factor erythroid 2–related factor 2; O^-₂, superoxide; PDGF, platelet-derived growth factor; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; SGLT2, sodium–glucose co-transporter 2; TNF-α, tumor necrosis factor alpha; XO, xanthine oxidase.

Figure 2

Pathophysiology and therapeutic strategies of diabetes associated cardiovascular disease. AT-1, angiotensin II type 1; GLP-1, glucagon-like peptide 1; IL, interleukin; MCP-1, monocyte chemotactic protein-1; Nox, NADPH oxidase; Nrf2, nuclear factor erythroid 2–related factor 2; ROS, reactive oxygen species; TNF-α, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion protein 1; XO, xanthine oxidase.