Complement C5a Induces Renal Injury in Diabetic Kidney Disease by Disrupting Mitochondrial Metabolic Agility

Area of Science:

• Immunology
• Nephrology
• Metabolic disease

Background:

• Diabetic kidney disease (DKD) involves glucose-mediated renal injury, inflammation, and fibrosis.
• Mitochondrial dysfunction is implicated in DKD pathogenesis.
• The role of the innate immune system, specifically complement component C5a, in DKD is not fully understood.

Purpose of the Study:

• To investigate the role of the C5a/C5aR1 axis in the pathogenesis of DKD.
• To explore the impact of C5a on renal mitochondrial function in diabetes.
• To evaluate the therapeutic potential of C5aR1 inhibition in DKD.

Main Methods:

• Assessed C5a activity in patients with diabetes.
• Utilized rodent models of diabetes to study C5a and C5aR1 expression.
• Employed genetic deletion of C5aR1 and pharmacological inhibition (PMX53) in vivo.
• Performed transcriptomic and lipidomic profiling of kidney tissues.
• Conducted in vitro studies using human renal proximal tubular epithelial cells.

Main Results:

• Elevated C5a activity was observed in diabetic patients, unaffected by conventional therapies.
• C5a and C5aR1 were upregulated early in experimental diabetes, preceding kidney injury.
• Genetic or pharmacological inhibition of C5aR1 protected against renal injury and normalized mitochondrial function.
• Diabetes induced downregulation of mitochondrial fatty acid metabolism and abnormal cardiolipin remodeling in kidneys.
• C5a exposure in vitro impaired mitochondrial respiration and increased reactive oxygen species.

Conclusions:

• The C5a/C5aR1 axis plays a critical role in DKD pathogenesis by promoting inflammation and disrupting renal mitochondrial metabolism.
• Targeting the C5a/C5aR1 pathway represents a novel immunometabolic therapeutic strategy for DKD.
• This study establishes a new link between innate immunity and metabolic dysfunction in diabetic kidney injury.