Complement 5a receptor 2 attenuates diabetic kidney disease by promoting mitochondria-associated endoplasmic reticulum membrane formation mediated by PSS-MFN2 interaction

Complement-mediated metabolic disorders are considered important contributors to the pathogenesis of diabetic kidney disease (DKD). This study investigated the non-canonical roles of complement 5a receptor 2 (C5aR2) in metabolism and its underlying molecular mechanisms in DKD. In patients with DKD, we found that C5aR2 expression was upregulated in the tubulointerstitium and correlated with both disease severity and adverse renal outcomes. C5aR2 deficiency in diabetic mice exacerbated the DKD phenotype, including pronounced lipid accumulation, mitochondrial and endoplasmic reticulum (ER) dysfunction, and reduced phosphatidylserine (PS) levels in the kidney. Mechanistically, C5aR2 activated cellular Fos proto-oncogene (c-FOS) nuclear translocation, upregulated phosphatidylserine synthase (PSS) expression, and promoted 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 C5aR2-specific agonist P59 ameliorated the DKD phenotype, improved PS homeostasis and MAM formation, and thereby reversed lipid accumulation, ER stress, and mitochondrial dysfunction in db/db mice. Single-cell RNA sequencing (scRNA-seq) analysis revealed that P59 restored Pss expression in injured proximal tubular cells. These results highlight C5aR2 activation as a promising strategy for DKD treatment.