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Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway
- Source :
- Journal of Diabetes Research.
- Publication Year :
- 2022
- Publisher :
- Hindawi, 2022.
-
Abstract
- Aim. Patients with diabetic ketosis often exhibit albuminuria. We previously found that acute hyperglycaemia can cause nephrotoxic injury. Here, we explored whether an excessive ketone body level causes kidney injury and the potential underlying mechanism. Methods. Fifty-six type 2 diabetes without ketosis (NDK group), 81 type 2 diabetes with ketosis (DK group), and 38 healthy controls (NC group) were enrolled. Clinical data were collected before and after controlling diabetic ketosis. Beta-hydroxybutyric acid (BOHB), an AKT activator, an AKT inhibitor, or plasmids encoding DAB2 were transformed into human renal proximal tubule epithelial cells (HK-2 cells). Results. The urinary albumin-to-creatinine ratio (ACR), transferrin (TF), immunoglobulin G (IgG), Beta2-microglobulin (β2-MG), retinol-binding protein (RBP), N-acetyl-beta-glucosaminidase (NAG), and Beta-galactosidase (GAL) were higher in the DK than NC and NDK groups. The proportion of patients with an increased urinary level of TF, IgG, β2-MG, RBP, NAG, or GAL was higher in the DK group too. After controlling ketosis, urinary microalbumin, TF, IgG, β2-MG, and RBP decreased significantly. In HK-2 cells, albumin endocytosis and megalin expression decreased with increasing BOHB concentration. Compared with BOHB treatment, BOHB with AKT activator significantly increased the DAB2, megalin levels and albumin endocytosis; the AKT inhibitor treatment exhibited the opposite effects. Compared with BOHB treatment, megalin expression and albumin endocytosis were significantly increased after BOHB with DAB2 overexpression treatment. Conclusions. Patients with diabetic ketosis may suffer from glomerular and tubular injuries that recover after ketosis control. High concentrations of BOHB downregulate megalin expression by inhibiting the AKT/DAB2/megalin signalling pathway and albumin endocytosis in proximal renal tubules.
- Subjects :
- 3-Hydroxybutyric Acid
Article Subject
Endocrinology, Diabetes and Metabolism
Diabetic Ketoacidosis
Kidney Tubules, Proximal
Low Density Lipoprotein Receptor-Related Protein-2
Endocrinology
Diabetes Mellitus, Type 2
Albumins
Immunoglobulin G
Humans
Apoptosis Regulatory Proteins
Proto-Oncogene Proteins c-akt
Adaptor Proteins, Signal Transducing
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 23146745
- Database :
- OpenAIRE
- Journal :
- Journal of Diabetes Research
- Accession number :
- edsair.doi.dedup.....1c9e6d5c497fb257a358027b70b02d37
- Full Text :
- https://doi.org/10.1155/2022/3411123