Dihydroxyacetone phosphate accumulation leads to podocyte pyroptosis in diabetic kidney disease.

Autor: Zhang Z; Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.; Nephrology and Urology Research Institute of Wuhan University, Wuhan, China., Hu H; Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.; Nephrology and Urology Research Institute of Wuhan University, Wuhan, China., Luo Q; Department of Nephrology, The Central Hospital of Wuhan, Wuhan, China., Yang K; Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.; Nephrology and Urology Research Institute of Wuhan University, Wuhan, China., Zou Z; Qianjiang Hospital Affiliated to Renmin Hospital of Wuhan University, Qianjiang, China.; Qianjiang Clinical Medical College, Health Science Center, Yangtze University, Qianjiang, China., Shi M; Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.; Nephrology and Urology Research Institute of Wuhan University, Wuhan, China., Liang W; Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.; Nephrology and Urology Research Institute of Wuhan University, Wuhan, China.
Jazyk: angličtina
Zdroj: Journal of cellular and molecular medicine [J Cell Mol Med] 2024 Feb; Vol. 28 (3), pp. e18073. Date of Electronic Publication: 2023 Dec 08.
DOI: 10.1111/jcmm.18073
Abstrakt: Diabetic kidney disease (DKD) can lead to accumulation of glucose upstream metabolites due to dysfunctional glycolysis. But the effects of accumulated glycolysis metabolites on podocytes in DKD remain unknown. The present study examined the effect of dihydroxyacetone phosphate (DHAP) on high glucose induced podocyte pyroptosis. By metabolomics, levels of DHAP, GAP, glucose-6-phosphate and fructose 1, 6-bisphosphate were significantly increased in glomeruli of db/db mice. Furthermore, the expression of LDHA and PKM2 were decreased. mRNA sequencing showed upregulation of pyroptosis-related genes (Nlrp3, Casp1, etc.). Targeted metabolomics demonstrated higher level of DHAP in HG-treated podocytes. In vitro, ALDOB expression in HG-treated podocytes was significantly increased. siALDOB-transfected podocytes showed less DHAP level, mTORC1 activation, reactive oxygen species (ROS) production, and pyroptosis, while overexpression of ALDOB had opposite effects. Furthermore, GAP had no effect on mTORC1 activation, and mTORC1 inhibitor rapamycin alleviated ROS production and pyroptosis in HG-stimulated podocytes. Our findings demonstrate that DHAP represents a critical metabolic product for pyroptosis in HG-stimulated podocytes through regulation of mTORC1 pathway. In addition, the results provide evidence that podocyte injury in DKD may be treated by reducing DHAP.
(© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz: