PROJECT SUMMARY Acute kidney injury (AKI) is a major complication for the critically ill and those undergoing cardiac surgery. Up to 24% of cardiac surgery and more than 57% of intensive care unit patients suffer AKI. ICU-AKI patients have a greatly increased odds of mortality (OR = 6.9 for stage 3 KDIGO Criteria). Additionally, patients who experience AKI requiring dialysis are at a 28-fold increased risk of developing chronic kidney disease (CKD). Despite these facts, there are no targeted therapies available for AKI beside treating the underlying cause. Oxidative stress-driven tubular cell death and acute inflammation, characterized by leukocytic infiltration, are major components of AKI pathogenesis. Heme oxygenase-1 (HO-1) degrades heme released from heme- proteins from dying cells and is induced as a protective response to oxidative stress that occurs in AKI. We previously demonstrated that the ability to induce HO-1 in myeloid cells is protective from damage, inflammation, and fibrosis secondary to AKI in the acute phase. While much is known about inflammation in AKI, the specific immune-mediated mechanisms that drive progressive kidney damage after AKI are unknown. MF mediate interstitial kidney fibrosis as well as immune complex deposition. The MF cellular origin (embryonic vs blood monocyte-derived) is an important determinant of function. Therefore, there is a crucial need to understand the origin and lineage relationships of kidney macrophages and their intersection with HO-1 expression in the AKI to CKD transition. Our central hypothesis is that deficiency of myeloid cell expression of HO-1 following AKI worsens early inflammatory tissue damage and delays injury resolution and tissue repair. Our objective is to elucidate the mechanisms by which myeloid cell HO-1 regulates the AKI to CKD transition. This is in line with the mission of the NIDDK, because it addresses important basic and translational aspects of the highly prevalent and detrimental AKI to CKD transition. As a result of the proposed studies, we expect to develop novel targets within the regulation of HO-1 expression or cell-based therapies for intervention in the AKI to CKD transition.