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Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway
Minxia Zuo1,2, Cheng Meng1, Qian Song1
1NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital, And Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China.
Journal of Diabetes Research
|November 4, 2022
Summary
Diabetic ketosis, marked by high ketone levels, can injure kidney tubules. This injury, involving reduced albumin uptake, is linked to the AKT/DAB2/megalin pathway and improves when ketosis is controlled.
Area of Science:
- Nephrology
- Endocrinology
- Biochemistry
Background:
- Diabetic ketosis is associated with albuminuria, suggesting potential kidney damage.
- Previous research indicated acute hyperglycemia can cause nephrotoxic injury.
- The role of excessive ketone body levels in kidney injury and its mechanisms remained unclear.
Purpose of the Study:
- To investigate whether elevated ketone body levels cause kidney injury.
- To explore the underlying molecular mechanisms of ketone-induced kidney injury.
- To assess the impact of controlling diabetic ketosis on kidney markers.
Main Methods:
- Compared urinary biomarkers in type 2 diabetes patients with (DK) and without (NDK) ketosis, and healthy controls (NC).
- Treated human renal proximal tubule cells (HK-2) with beta-hydroxybutyric acid (BOHB), AKT pathway modulators, and DAB2 plasmids.
- Measured urinary albumin-to-creatinine ratio (ACR) and specific protein levels (TF, IgG, β2-MG, RBP, NAG, GAL).
Main Results:
- DK patients exhibited higher urinary levels of ACR and various proteins (TF, IgG, β2-MG, RBP, NAG, GAL) compared to NDK and NC groups.
- Controlling ketosis significantly reduced urinary microalbumin and protein levels in DK patients.
- In vitro, BOHB decreased albumin endocytosis and megalin expression in HK-2 cells, an effect modulated by AKT and DAB2.
Conclusions:
- Diabetic ketosis can lead to glomerular and tubular kidney injuries.
- These injuries show recovery after diabetic ketosis is managed.
- High BOHB concentrations inhibit the AKT/DAB2/megalin pathway, reducing megalin expression and albumin endocytosis in renal tubules.
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