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Complement C5a Induces Renal Injury in Diabetic Kidney Disease by Disrupting Mitochondrial Metabolic Agility
- Source :
- Diabetes. 69:83-98
- Publication Year :
- 2019
- Publisher :
- American Diabetes Association, 2019.
-
Abstract
- The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD.
- Subjects :
- Male
0301 basic medicine
Endocrinology, Diabetes and Metabolism
Complement C5a
Mice, Transgenic
030209 endocrinology & metabolism
Inflammation
Pharmacology
Mitochondrion
Kidney
Diabetes Mellitus, Experimental
Rats, Sprague-Dawley
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Downregulation and upregulation
Diabetes mellitus
Internal Medicine
medicine
Cardiolipin
Animals
Humans
Diabetic Nephropathies
Respiratory function
Receptor, Anaphylatoxin C5a
Cells, Cultured
business.industry
medicine.disease
Fibrosis
Mitochondria
Rats
Mice, Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
chemistry
medicine.symptom
Energy Metabolism
business
Signal Transduction
Kidney disease
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 69
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....6e442c9d482a200f58a63e5d13ae4537