Retinoic acid metabolism blocking agents (RAMBAs) enhance repair after acute kidney injury (AKI)
AKI is a major public health concern. AKI’s severe implications for critically ill patients highlight the importance of investigating mechanisms for prevention and treatment. Previous studies have demonstrated a role for locally produced retinoic acid (RA) in the immune response to injury, specifically by reducing the initial inflammatory response and increasing the post-injury repair response in mice after AKI. RA coordinates this response via macrophage-dependent repair: M1 macrophages (injury response) are recruited into the kidney early after injury but are later replaced by M2 macrophages (repair response). The M1 response is suppressed by the exogenous RA agonist, ATRA, but it has no effect on M2 macrophages in the kidney after AKI. Since we have previously shown the M2 response is induced by local activation of RA signaling in the kidney, we hypothesize that enhancing local vs. systemic RA signaling using the RAMBA, Talarazole, will reduce injury and enhance recovery by increasing reparative M2 macrophages in the kidney after AKI. Two sub-aims will test this hypothesis.
Aim 1: Discovering the Effects of Modulating RA Signaling after AKI on Injury Response. We will compare the effects of ATRA and Talarazole treatment on the severity of injury and functional recovery in mice 3 days after ischemia-reperfusion induced AKI (IR-AKI). Aim 2: Discovering the Effects of Modulating RA Signaling after AKI on Macrophage Types. We will evaluate the effects of ATRA and Talarazole treatment on M1 and M2 macrophages in the kidneys of mice 3 days after IR-AKI.