Abstract: TH-PO638
HIF1α and Succinate Pathway: Role in Deceased Kidney Donors Inflammation
Session Information
- Transplantation: Basic
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Transplantation
- 2001 Transplantation: Basic
Author
- Vilardell, Jordi, Fundacio Puigvert, Barcelona, Catalunya, Spain
Background
The type of donor has an impact on the renal prognosis of the recipient. It has been observed that the decline of renal function is higher in deceased donor (DD). These could be related with the pre-implantation inflammation state of the donor and the development of fibrotic processes.
Own data indicate that complex succinate dehydrogenase (SDH) has a lower gene expression in DD kidneys and is associated with inflammatory markers, macrophages, and purinergic receptors and a worse renal function graft. The aim of this study is to determine that in renal DD, ischemia/hypoxia can increase renal succinate levels, inducing infiltration of inflammatory cells.
Methods
Pre-implantacional kidneys biopsies from 47 DD and 19 LD, were collected. 159 genes from these samples were analysed by qRT-PCR. Relative quantification of gene expression was performed with 3 internal controls. Genes with high positive correlation with HIF1α have been grouped in clusters using STRING database. Succinate levels were measured in serum from 27 renal DD and in 10 healthy volunteers with the EnzyChrom™ Succinate Assay Kit. All statistical data was analyzed using GraphPad Prism 5.
Results
To determine the hypoxia status of kidney donors, transcription levels of HIF1α and HIF2α were determined from renal tissue samples. A significant increase in HIF1α genic expression is observed in DD compared to LD (p<0.001). From the expression of the 159 genes analyzed, 24 of them are expressed exclusively in DD samples and have a high correlation with HIF1a (Rho > 0.5). These genes have been grouped in 3 different clusters: Transcription factors and metalloproteinases, ECM proteins and integrins and Inflammatory and Macrophages Markers. We also found reduced mRNA expression of all the SDH subunits (p<0.001) in DD samples. As a consequence, succinate cannot be converted to fumarate in concordance with the greater succinate levels (p=0.002) observed in sera of DD.
Conclusion
These results indicate that kidneys from DD undergo a greater hypoxia compared with LD, demonstrated by the increased transcription rate of HIF1α. Hypoxia not only increases HIF1α but also may affect the energetic metabolism of the cell, reducing the expression of SDH. As a consequence extracellular levels of succinate increase, maintaining HIF1α levels, that could take part in a sustained inflammatory/anti-inflammatory process in kidney from DD.
Funding
- Private Foundation Support