Abstract: FR-PO341
SrGAP3 Deficiency Mediates Podocyte Injury by Promoting Cdc42 and Rac1 Activity in Diabetic Nephropathy
Session Information
- Diabetic Kidney Disease: Basic - I
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Yang, Yan, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guang Zhou, Guangdong, China
- Zhang, Li, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guang Zhou, Guangdong, China
- Liang, Xinling, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guang Zhou, Guangdong, China
Background
Rho GTPase activity plays a key role in cytoskeletal rearrangement and apoptosis of podocytes in diabetic nephropathy (DN). However, the upstream regulatory mechanism directing Rho GTPases in podocytes of DN remains unclear. This study aimed to verify the expression of SrGAP3, a Rho GTPase activating protein, in kidney and its role and mechanism in podocyte injury of DN.
Methods
The level of SrGAP3 expression was analyzed using immunofluorescence in the glomerular podocytes of renal tissue from DN patients and diabetic mice with albuminuria. Albuminuria, podocyte injury and glomerular pathology were evaluated in SrGAP3 overexpression of type 2 diabetic db/db mice and STZ-induced type 1 diabetic mice. The expressions and activities of Cdc42 and Rac1 in the glomerular podocytes in vivo in diabetic mice and in vitro in podocytes exposed to either SrGAP3 knockdown or high glucose treated podocytes with SrGAP3 overexpression were detected by immunofluorescence, western blot and enzyme activity detection. Podocyte marker proteins, cytoskeleton, cell motility and apoptosis were observed in in vitro podocytes under different conditions.
Results
SrGAP3 was markedly reduced in glomerular podocytes from renal tissues of DN patients, db/db mice and STZ-induced diabetic mice with albuminuria.The albuminuria in db/db and STZ-induced diabetic mouse model was markedly attenuated after overexpression of SrGAP3 established by adeno-associated virus. This was accompanied by alleviation of basement membrane thickening, mesangial matrix expansion, and podocyte injury. The decreased expression of SrGAP3 in podocytes cultured with high glucose was upregulated after overexpression of SrGAP3, accompanied by restored decreased podocyte marker proteins, and improved actin cytoskeleton rearrangement, podocyte motility and apoptosis. Further studies found that increased activity of Cdc42 and Rac1 in podocytes in vivo and in vitro under the diabetic state were significantly inhibited after overexpression of SrGAP3.
Conclusion
SrGAP3 deficiency mediates podocyte injury of DN by promoting Cdc42 and Rac1 activation, which may provide a clinical therapeutic target for protecting podocyte injury of DN.
Funding
- Government Support – Non-U.S.