Complement 5a-Receptor 2 Attenuates Diabetic Kidney Disease by Promoting Mitochondria-Associated Endoplasmic Reticulum Membrane Formation Mediated by PSS-MFN2 Interaction

Background: Complement-mediated metabolic dysregulation, especially via the C3a/C5a axis, plays a key role in diabetic kidney disease (DKD). Preclinical studies show that deleting or inhibiting C5a receptor 1 (C5aR1) reduces proteinuria and tubulointerstitial injury in DKD models. However, the role of the second C5a receptor, C5aR2, remains unclear due to conflicting early findings and limited understanding. Methods: We assessed C5aR2 expression in kidney biopsies from DKD patients. Diabetic C5ar2-knockout (KO) mice were used for in vivo studies. Lipidomic and transcriptomic profiling revealed metabolic changes. The therapeutic potential of a C5aR2-specific agonist (P59) was tested in diabetic mice. Results: We found that C5aR2 expression was upregulated in the tubulointerstitium of DKD patients, and correlated with disease severity and renal outcomes. C5aR2 deficiency in diabetic mice aggravated DKD phenotype, including pronounced lipid deposition, mitochondrial and endoplasmic reticulum (ER) dysfunction, and reduced phosphatidylserine (PS) levels in kidneys. Mechanistically, C5aR2 activated c-FOS nuclear translocation, upregulating phosphatidylserine synthase (PSS) expression and promoting the interaction between PSS and mitochondrial fusion protein 2 (MFN2), which facilitated mitochondria-associated ER membrane (MAM) formation and PS biosynthesis, improving mitochondrial and ER function. Treatment with the P59 significantly improved PS homeostasis and MAM formation, offering protective effects in DKD. Conclusion: Collectively, this study uncovers a previously unrecognized metabolic role of C5aR2 and suggests that future therapies targeting the C5a axis in DKD may require activation of C5aR2 to achieve optimal therapeutic outcomes.