Proximal Tubular Cell-Specific Ablation of Carnitine Acetyltransferase Causes Tubular Disease and Secondary Glomerulosclerosis.
Claudia KrugerTrang-Tiffany NguyenChelsea BreauxAlana GuilloryMargaret MangelliKevin T FridiantoJean-Paul KovalikDavid H BurkRobert C NolandRandall MynattKrisztian StadlerPublished in: Diabetes (2019)
Proximal tubular epithelial cells are highly energy demanding. Their energy need is covered mostly from mitochondrial fatty acid oxidation. Whether derailments in fatty acid metabolism and mitochondrial dysfunction are forerunners of tubular damage has been suggested but is not entirely clear. Here we modeled mitochondrial overload by creating mice lacking the enzyme carnitine acetyltransferase (CrAT) in the proximal tubules, thus limiting a primary mechanism to export carbons under conditions of substrate excess. Mice developed tubular disease and, interestingly, secondary glomerulosclerosis. This was accompanied by increased levels of apoptosis regulator and fibrosis markers, increased oxidative stress, and abnormal profiles of acylcarnitines and organic acids suggesting profound impairments in all major forms of nutrient metabolism. When mice with CrAT deletion were fed a high-fat diet, kidney disease was more severe and developed faster. Primary proximal tubular cells isolated from the knockout mice displayed energy deficit and impaired respiration before the onset of pathology, suggesting mitochondrial respiratory abnormalities as a potential underlying mechanism. Our findings support the hypothesis that derailments of mitochondrial energy metabolism may be causative to chronic kidney disease. Our results also suggest that tubular injury may be a primary event followed by secondary glomerulosclerosis, raising the possibility that focusing on normalizing tubular cell mitochondrial function and energy balance could be an important preventative strategy.
Keyphrases
- oxidative stress
- high glucose
- high fat diet
- fatty acid
- induced apoptosis
- chronic kidney disease
- insulin resistance
- single cell
- high fat diet induced
- cell cycle arrest
- dna damage
- adipose tissue
- cell death
- endothelial cells
- cell therapy
- stem cells
- autism spectrum disorder
- skeletal muscle
- signaling pathway
- hydrogen peroxide
- type diabetes
- wild type
- heat shock protein
- catheter ablation