The role of renal 5-hydroxytryptamine synthesis and degradation in hyperglycemia-induced kidney injury
10.16438/j.0513-4870.2021-0152
- VernacularTitle:肾脏5-羟色胺合成和降解在高血糖诱导肾损伤时的作用研究
- Author:
Fan XU
1
;
Jing YANG
1
;
Jia-qi JIN
1
;
Yi ZHANG
1
;
Xiu-rui LIANG
1
;
Jing GUAN
1
;
Yu-xin ZHANG
1
;
Xue-chun SHAN
1
;
Rui ZHANG
1
;
Xi-tong ZHAO
2
;
Yu-xuan HAO
3
;
Ji-hua FU
1
Author Information
1. School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
2. School of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China
3. School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
- Publication Type:Research Article
- Keywords:
hyperglycemic kidney injury;
5-HT2A receptor;
5-HT synthesis;
5-HT degradation;
reactive oxygen species;
glomerular mesangial cell
- From:
Acta Pharmaceutica Sinica
2021;56(6):1612-1620
- CountryChina
- Language:Chinese
-
Abstract:
Hyperglycemic kidney injury (HKI) is a common complication of diabetic patients. We examined the relationship between HKI and the abnormal expression of 5-hydroxytryptamine (5-HT) system induced by hyperglycemia in type 2 diabetes mellitus (T2DM). In animal experiments, a T2DM model was established in mice by feeding a high-fat diet with intraperitoneal injection of streptozotocin. The mice were treated with the 5-HT2A receptor (5-HT2AR) antagonist sarpogrelate hydrochloride (SH) and 5-HT synthesis inhibitor carbidopa (CDP) (respectively or in combination). In cell culture experiments, human glomerular mesangial cells (HMC) were stimulated with D-glucose (D-Glu), and 5-HT2AR, 5-HT synthesis, and 5-HT degradation were inhibited by SH, CDP, or monoamine oxidase A (MAO-A) inhibitor clorgyline. Periodic acid-Schiff (PAS) staining and Masson staining, immunohistochemistry and Western blot, fluorescent probe, and enzyme linked immunosorbent assay (ELISA) and enzyme reagent were respectively used to detect histopathology, protein expression, intracellular reactive oxygen species (ROS), and biochemical indexes. The animal experiments were in accordance with the regulations of the Animal Ethics Committee of China Pharmaceutical University. The results showed that 5-HT2AR, 5-HT synthases, and MAO-A were expressed in glomerular basement membrane and kidney tubular epithelial cells of mouse kidney and HMC. The expression of these proteins was significantly up-regulated in T2DM mice or when HMC cells were exposed to high concentration of D-Glu. HKI, characterized by abnormal renal function, glomerular swelling, and glomerular basement membrane thickening and fibrosis, is closely associated with an increase in kidney 5-HT2AR, 5-HT synthesis, and 5-HT degradation. Among them, 5-HT2AR can mediate the expression of 5-HT synthases and MAO-A; MAO-A can catalyze the degradation of 5-HT to increase the production of mitochondrial ROS, leading to the phosphorylation of nuclear factor kappa B (NF-κB) with the production of inflammatory cytokines, and the up-regulation of matrix metalloproteinase-2 (MMP-2) and α-smooth muscle actin (α-SMA) with the production of collagens. SH and CDP can effectively treat HKI, and the combination of SH and CDP has a clear synergistic effect.
