Affiliation:
1. Division of Nephrology Renmin Hospital of Wuhan University Wuhan China
2. Nephrology and Urology Research Institute of Wuhan University Wuhan China
3. Department of Nephrology The Central Hospital of Wuhan Wuhan China
4. Qianjiang Hospital Affiliated to Renmin Hospital of Wuhan University Qianjiang China
5. Qianjiang Clinical Medical College Health Science Center Yangtze University Qianjiang China
Abstract
AbstractDiabetic 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.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Hubei Province
Subject
Cell Biology,Molecular Medicine