Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway
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...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2022/3411123 |
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| _version_ | 1832551202090385408 |
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| author | Minxia Zuo Cheng Meng Qian Song Zhongai Gao Xiao Cui Jingyu Wang Yongmei Li Xiaochen Li Chunyan Shan Juhong Yang Baocheng Chang |
| author_facet | Minxia Zuo Cheng Meng Qian Song Zhongai Gao Xiao Cui Jingyu Wang Yongmei Li Xiaochen Li Chunyan Shan Juhong Yang Baocheng Chang |
| author_sort | Minxia Zuo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-910209e86a5a4bc79d386f51085d11d8 |
| institution | Kabale University |
| issn | 2314-6753 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-910209e86a5a4bc79d386f51085d11d82025-02-03T06:04:41ZengWileyJournal of Diabetes Research2314-67532022-01-01202210.1155/2022/3411123Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling PathwayMinxia Zuo0Cheng Meng1Qian Song2Zhongai Gao3Xiao Cui4Jingyu Wang5Yongmei Li6Xiaochen Li7Chunyan Shan8Juhong Yang9Baocheng Chang10NHC Key Laboratory of Hormones and DevelopmentNHC Key Laboratory of Hormones and DevelopmentNHC Key Laboratory of Hormones and DevelopmentNHC Key Laboratory of Hormones and DevelopmentDepartment of Respiratory and Infectious DiseasesNHC Key Laboratory of Hormones and DevelopmentNHC Key Laboratory of Hormones and DevelopmentNHC Key Laboratory of Hormones and DevelopmentNHC Key Laboratory of Hormones and DevelopmentNHC Key Laboratory of Hormones and DevelopmentNHC Key Laboratory of Hormones and DevelopmentAim. 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.http://dx.doi.org/10.1155/2022/3411123 |
| spellingShingle | Minxia Zuo Cheng Meng Qian Song Zhongai Gao Xiao Cui Jingyu Wang Yongmei Li Xiaochen Li Chunyan Shan Juhong Yang Baocheng Chang Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway Journal of Diabetes Research |
| title | Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway |
| title_full | Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway |
| title_fullStr | Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway |
| title_full_unstemmed | Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway |
| title_short | Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway |
| title_sort | beta hydroxybutyric acid inhibits renal tubular reabsorption via the akt dab2 megalin signalling pathway |
| url | http://dx.doi.org/10.1155/2022/3411123 |
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