The Mitochondria-Targeted Metabolic Tubular Injury in Diabetic Kidney Disease

• DOI: 10.33594/000000011
• Publication Date: 2019-02-27T09:54:25Z
• Authors: Hongfeng Huang; Yucheng Wang; Ying-ying Wang; Hong Jiang; Huajun Feng; Cuili Wang; Shi Feng; Alan J. Davidson; Xiujin Shen; Jianghua Chen; Meizhen Wang; Chunhua Weng; Sha Jia; Sudarshanee Geeki...; Lihui Qu; Xue Shao
• Keywords: Male; Membrane Potential, Mitochondrial; 0301 basic medicine; Physiology; QD415-436; Middle Aged; Biochemistry; DNA, Mitochondrial; Mitochondria; 3. Good health; 03 medical and health sciences; Cross-Sectional Studies; Kidney Tubules; QP1-981; Humans; Kidney Failure, Chronic; Metabolomics; Diabetic Nephropathies; Female

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) worldwide, and the importance of tubular injury has been highlighted in recent years. However, the underlying mechanisms and effective therapeutic targets are still unclear. In this study, we investigated mtDNA, mitochondrial dynamics, function and metabolic pathways to determine if mitochondrial damage plays a critical role in the development of tubular injury in DKD patients.A cross-sectional study was carried out among healthy controls (HCs, n = 65), diabetes patients without kidney disease (DCs, n = 48) and DKD patients (n = 60). Serum, peripheral blood mononuclear cells (PBMCs) and kidney biopsy specimens were obtained from participants. Metabolomics was employed to investigate cellular metabolism.DKD patients had decreased mtDNA copy numbers and increased mtDNA damage compared to DCs. Mitochondrial fragmentation was specifically presented in tubules, but not in podocytes of DKD patients. The accumulation of damaged mtDNA and fragmented mitochondria resulted in increased reactive oxygen species (ROS) generation, activation of apoptosis and loss of mitochondrial membrane potential (ΔΨm) in tubules and PBMCs. Furthermore, glycolysis and tricarboxylic acid (TCA) cycle was perturbed, and increased dihydroxyacetone phosphate (DHAP) and decreased succinyl-CoA synthetase (SCS) respectively in these two metabolic pathways were identified as potential biomarkers for tubular injury in DKD.Our study indicates that mitochondrial damage could be the hallmark of tubular injury in DKD patients, and this would provide a novel and attractive therapeutic target to improve this disease.