C5aR2 attenuates diabetic kidney disease by promoting mitochondria-associated endoplasmic reticulum membrane formation

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C5aR2 attenuates diabetic kidney disease by promoting mitochondria-associated endoplasmic reticulum membrane formation

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Co-author 1

Yiyang Zhao ashelyzhaoyiyang@163.com Peking University First Hospital, Institute of Nephrology Department of Medicine Peking China *

Co-author 2

Dong-yuan Chang cdy@outlook.com Peking University First Hospital, Institute of Nephrology Department of Medicine Beijing China -

Co-author 3

Ming-Hui Zhao mhzhao@bjmu.edu.cn Peking University First Hospital, Institute of Nephrology Department of Medicine Beijing China -

Co-author 4

Sydney Tang scwtang@hku.hk School of Clinical Medicine, The University of Hong Kong Division of Nephrology, Department of Medicine Hong Kong China -

Co-author 5

Min Chen chenmin74@sina.com Peking University First Hospital, Institute of Nephrology Department of Medicine Beijing China -

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Introduction

Cumulative evidences demonstrated that complement system-mediated metabolic dysregulation, particularly through the complement 3a (C3a) and complement 5a (C5a) axis, plays a critical role in the pathogenesis of diabetic kidney disease (DKD). Preclinical studies have shown that deletion of C5a receptor 1 (C5aR1) or pharmacological inhibition of C5aR1 with PMX53 can mitigate proteinuria and tubulointerstitial injury in mouse models of DKD. However, as the second receptor of C5a, C5aR2 has been referred to as an "enigmatic receptor" due to conflicting findings in early studies and limited understanding of its functions.

Methods

We assessed C5aR2 expression in kidney biopsies from DKD patients and analyzed its correlation with clinical outcomes. Diabetic C5ar2-knockout (KO) mice were used for in vivo studies. Lipidomic and transcriptomic profiling revealed metabolic changes. Mechanistic studies employed dual-luciferase reporter assays, co-immunoprecipitation (Co-IP), and proximity ligation assays (PLA) assays. 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 C5aR2-specific agonist 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.

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