Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) is a leading cause of death in the U.S. With limited treatment options, the disease progresses to end‐stage renal disease (ESRD), which is also associated with significant morbidity and mortality. Better understanding of the mechanisms which underlie the progression of CKD is indispensable for developing novel treatments to slow or halt the progression of CKD. Towards this goal, we examined the role of mitochondrial function and metabolic reprogramming in renal tubules in the development and progression of CKD using the subtotal nephrectomy (STN) model of CKD.Weight and age‐matched male 129X1/SvJ mice underwent either sham or STN surgeries. Tubular mitochondrial respiration at 2 and 4 weeks post‐surgery were evaluated using a high‐throughput Seahorse XF Analyzer. Renal expression of genes regulating mitochondrial biogenesis, dynamics, and metabolism at 4 weeks post‐surgery were measured by real‐time PCR. The mitochondrial respiration were similar between sham and STN groups at 2 weeks post‐surgery. However, at 4 weeks post‐surgery, the basal, the ATP‐linked, and the maximum respiration were significantly reduced in the STN tubules compared with sham (Figure 1A). Reduction of renal oxidative respiration indicates an impairment of mitochondrial function in STN renal tubules. Interestingly, the expression level of glycolytic mRNA, including phosphofructokinase (PFK, a rate‐limiting enzyme of glycolysis), glycolytic pyruvate kinase (PKM), and Hexokinase‐1 (HK1) were all significantly increased (Figure 1B–D), while expressions of carnitine palmitoyltransferase I (CPT1, a rate limiting enzyme of lipid oxidation), and peroxisomal acyl‐coenzyme A oxidase 1 (acox 1) remained unchanged.In conclusion, we observed compromised mitochondrial function and metabolic switch from oxidative respiration to glycolysis at 4 weeks post‐STN. Additional studies to further delineate mitochondrial functional changes and switch in tubular metabolism are ongoing. Mitochondrial dysfunction and metabolic reprogramming may contribute to the development and/or progression of CKD. Therapeutic strategies which improve mitochondrial function and inhibit metabolic reprogramming pathway may serve as novel therapeutic targets in CKD treatment.Support or Funding InformationVA Merit Award BX002175 and NIH R01 DKDK107852This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.