Succinate Receptor as an Emerging Target in Ischemic Stress

Renal ischemia/reperfusion (I/R) is the leading cause of acute kidney injury, and necessarily occurs during kidney transplantation or cardiovascular surgery. Renal ischemic preconditioning (RIP) includes the mechanical or pharmacological maneuvers aiming to reduce the ischemic insult. However, the current RIP methods fail to completely mitigate I/R injuries that still lead to well-established poor consequences for kidney function.
During ischemia, succinate concentration increases in intracellular and extracellular compartment. The intracellular effects of succinate during ischemia are well-studied, in contrast with its extracellular impact, notably mediated by its interaction with the Succinate Receptor (SUCNR1), highly expressed by macrophages.
SUCNR1 has recently emerged as an ischemic stress sensor, and we hypothesize that it may represent an innovative drug target in pharmacological RIP. Additionally, preliminary observations from our laboratory showed a significant decrease in kidney injuries following I/R in Sucnr1 knocked-out mice compared to wild-type.
Our research project plans to answer these outstanding questions :
1. What is the in vivo role of SUCNR1 during renal I/R, with a specific focus on the contribution of the SUCNR1 expressed by macrophages ?
2. What is the in vivo impact of the SUCNR1 pharmacological modulation on the RIP, and what are the mechanisms of action for various SUCNR1 ligands ?
Our experimental strategy consist in renal I/R model, applied both to (i) macrophages and proximal tubular cells, and (ii) transgenic mice lines (conditional Sucnr1-KO and Sucnr1 tagged with StayGold, a photostable and bright GFP). The impact of their exposition with SUCNR1 ligands will also be studied.