Year: 2019
Type: dissertation
Abstract: Thioredoxin-interacting protein (TXNIP) is markedly upregulated by high glucose (HG) and contributes to Diabetic Nephropathy (DN) development partly by inhibiting the endogenous antioxidant thioredoxin. We postulate that this contributes to the nitrosylation and oxidation of GAPDH, which has been found in neuronal cells to promote GAPDH-Siah1 binding and nuclear translocation, leading to apoptosis. The goal of this study was to determine if TXNIP regulates GAPDH-Siah1 signalling and if DN can be prevented by blocking this pathway. In vitro results show that HG caused significant nuclear localization of both GAPDH and Siah1 and upregulation of apoptotic markers in cultured wildtype mesangial cells (MCs), but not TXNIP-/- (KO) MCs. In vivo, deprenyl, an inhibitor of GAPDH-Siah1 binding, protected diabetic mice from developing various structural and functional markers of DN. These data suggest that the GAPDH-Siah1 pathway has a pathogenic role in DN and is downstream of TXNIP signalling.
Source: TSpace (University of Toronto)
Author: Hui Zhong
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3000593274