Abstract: PO0915
MTORC1/STAT1 Signaling Stimulates CFB Expression and Alternative Complement Pathway Activation to Induce Podocyte Dysfunction and Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic Mechanisms
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Lu, Qingmiao, Nanjing Medical University, Nanjing, Jiangsu, China
- Dai, Chunsunb, Nanjing Medical University, Nanjing, Jiangsu, China
Background
Alternative complement pathway activation has been reported in diabetic kidney disease (DKD). However, the role and mechanisms for regulating alternative complement pathway activation in podocyte dysfunction and DKD are not understood.
Methods
STZ-induced DKD mice, db/db mice, Podocyte-specific TSC1 deletion mice were used.
Results
The analysis of GSE30528 data and the immunohistochemical staining results showed that mTORC1 signaling, STAT1, complement factor B (CFB) and complement alternative pathway were activated in podocytes from patients and animal models with DKD. Knocking down CFB remarkably alleviated podocyte loss, glomerular basement membrane thickening, mesangial expansion, and proteinuria in DKD mice. In addition, ablation of Tsc1 in podocytes led to mTORC1 and STAT1 signaling activation, CFB induction, and alternative complement pathway activation in the glomeruli. In cultured podocytes, high glucose culture could activate mTORC1 signaling, stimulate STAT1 phosphorylation and upregulate CFB expression. Blockade of mTORC1 or STAT1 signaling could abolish high glucose upregulated CFB expression in podocytes.
Conclusion
This study uncovers that mTORC1/STAT1 activation in podocytes may promote DKD progression through activating complement alternative pathway.
Funding
- Government Support - Non-U.S.