Succinate receptor as an emerging pharmacological target in renal ischemic stress

Background
Succinate is an intermediate of the Krebs cycle that accumulates in Kssues during ischaemia or inflammaKon.
Besides its influence on cellular metabolism, the succinate acKvates a G-protein-coupled receptor (SUCNR1).
SUCNR1 is highly expressed by macrophages and modulates their polarisaKon : a high concentraKon of
succinate promotes an M1 (pro-inflammatory) phenotype, while a lower concentraKon promotes an M2 (anK-
inflammatory) phenotype. The succinate–SUCNR1 axis plays a key role in regulaKng renin, reKnal angiogenesis
and autoimmune arthriKs. In ischaemia/reperfusion (I/R) situaKons, SUCNR1 acKvaKon could be protecKve (as
promoKng neo-angiogenesis) or harmful (as causing an M1/M2 imbalance). The objecKve of this study is to
evaluate the impact of pharmacological inhibiKon of SUCNR1 by its inhibitor, the 4c, on macrophage
polarizaKon in I/R situaKons.
Methods
Murine model of lem renal I/R : 30-minute arterial clamping, right nephrectomy and 7-day reperfusion. Two
groups of 8 mice were disKnguished by the ligand injected intraperitoneally 1 hour before clamping : vehicle
versus 4c. The macrophage composiKon of the right kidneys (control) and lem kidneys (ischaemic) is studied by
flow cytometry.
Results
The iniKal results show that the ischaemic kidneys exhibit in comparaison to control kidneys a redistribuKon of
CD86+/CD206- (M1) and CD86-/CD206- (M0) renal macrophages towards CD86-/CD206+ (M2) and
CD86+/CD206+ macrophages, with no change in the total number of macrophages. Furthermore, compared to
the vehicle, administraKon of 4c accentuates the phenotypic redistribuKon in favour of M2 macrophages.
Conclusions
In our I/R model, renal macrophages switch to a M2 CD206+ phenotypes. AntagonisaKon of SUCNR1 by 4c
further reduces the M1 populaKon and favours the M2 subpopulaKon, suggesKng SUCNR1 as a therapeuKc
target to miKgate I/R-mediated kidney injuries.