Complement C5aR Signaling Dysregulates Lipid Metabolism in High-Fat Diet-Induced Kidney Disease

Background: Dysregulation of lipid metabolism is a hallmark of diabetic kidney disease (DKD), however the underlying pathogenic mechanisms leading to DKD progression is not fully understood. Lipid accumulation in the kidney triggers kidney cell damage by promoting inflammation and mitochondrial dysfunction leading to fibrosis and DKD progression. We previously showed that pharmacological inhibition of the complement 5a receptor (C5aR) modulates lipid metabolism and ameliorates kidney injury in diabetic mice, and the precise mechanism linking C5aR blockade and improved lipid homeostasis warrants further investigation. Methods: The experimental model of high-fat diet (HFD) was established in wild type (C5aR+/+) and knockout (C5aR-/-) mice for 16 weeks. Mice fed with a normal diet (ND) were used as control. Serum biochemistry of glucose and lipid levels were measured. Kidney lipid accumulation and inflammation were assessed. Mitochondrial damage was determined by morphological changes and function analyses. Results: Both C5aR+/+ and C5aR-/- mice developed hyperglycemia after 16-weeks of HFD. A significant reduction in serum cholesterol and free fatty acid levels were observed in C5aR-/- mice but not wild type littermates. Lipid accumulation in the kidney detected by Oil Red O staining revealed fewer deposition of lipid droplets, along with significant reduction in triglyceride content in kidney tissues of C5aR-/- HFD mice vs C5aR+/+ animals. C5aR deficiency did not affect kidney cholesterol levels. Additionally, HFD-induced mTOR signaling was significantly inhibited in the kidney of C5aR-/- mice. HFD promoted kidney inflammation in C5aR+/+ mice with markedly increase in macrophage infiltration, which was decreased in C5aR-/- HFD mice. Finally, C5aR deficiency ameliorated HFD-induced mitochondrial fragmentation and swelling, and restored the mitochondrial markers of Opa1 and Tim23. Conclusion: C5aR deficiency reduces lipid accumulation and inflammation in the kidney induced by HFD, possibly via inhibition of mTOR signaling. Improvement in mitochondrial damage by blockade of C5aR signaling may also contribute to the regulation of lipid homeostasis in obesity-related kidney disease. Funding: Government Support – Non-U.S.