Significance: The metabolic disorder,
diabetes mellitus, results in microvascular complications, including
diabetic kidney disease (DKD), which is partly believe to involve disrupted energy generation in the kidney, leading to injury that is characterized by
inflammation and
fibrosis. An increasing body of evidence indicates that the innate immune
complement system is involved in the pathogenesis of DKD; however, the precise mechanisms remain unclear. Recent Advances:
Complement, traditionally thought of as the prime line of defense against microbial intrusion, has recently been recognized to regulate immunometabolism. Studies have shown that the complement activation products,
Complement C5a and C3a, which are potent pro-inflammatory mediators, can mediate an array of metabolic responses in the kidney in the diabetic setting, including altered fuel utilization, disrupted mitochondrial respiratory function, and
reactive oxygen species generation. In diabetes, the
lectin pathway is activated via autoreactivity toward altered self-surfaces known as danger-associated molecular patterns, or via sensing altered
carbohydrate and acetylation signatures. In addition, endogenous
complement inhibitors can be glycated, whereas diet-derived
glycated proteins can themselves promote complement activation, worsening DKD, and lending support for environmental influences as an additional avenue for propagating
complement-induced
inflammation and kidney injury. Critical Issues: Recent evidence indicates that conventional renoprotective agents used in DKD do not target the
complement, leaving this web of inflammatory stimuli intact. Future Directions: Future studies should focus on the development of novel pharmacological agents that target the
complement pathway to alleviate
inflammation, oxidative stress, and kidney
fibrosis, thereby reducing the burden of microvascular diseases in diabetes. Antioxid. Redox Signal. 37, 781-801.