Project 11: Role of the downstream mediator of glucocorticoids, annexin A1, in the repair process of acute kidney injury
In acute kidney injury (AKI), endothelial and epithelial cell damage is interrelated with perturbed local renal hemodynamics and release of pro-inflammatory mediators. In response to the latter, leukocytes migrate into the renal parenchyma and aggravate disease by the release of nitric oxide (NO), superoxide radicals (O2-), and prostaglandins causing oxidative/nitrosative stress and vasoconstriction and, thus, promote ongoing tissue hypoxia and acidosis. Endogenous inhibitors of these adverse effects include resolvins, protectin D1, lipoxin 4, and members of the annexin protein superfamily. Together, these inhibitors help resolve inflammation and restore renal function. The glucocorticoidinducible protein annexin A1 may be a key component herein, but the mechanisms of its protective effects remain to be elucidated. We hypothesize that annexin A1, together with its receptor, the formyl peptide receptor 2 (FPR2), form an intrarenal paracrine system that exerts renoprotective effects in the
setting of AKI, and may be targeted for organ-protective therapeutic strategies. To test this, AKI will be induced in rats and annexin A1-deficient mice. Inflammatory models (anti Thy-1 nephritis in rats, anti GBM nephritis in mice) and an ischemic approach (I/RI) will be chosen. Expression of annexin A1 and FPR2 will then be studied in a time- and cell-specific manner. Renal function, hemodynamics, and morphological alterations will be determined in parallel. In a therapeutic approach, we will compare the effects of glucocorticoids with those of full-length annexin A1 and its N-terminal fragment, AC2-26, in these models. To elucidate cellular mechanisms of annexin A1-mediated protective effects, we set out to study its role in the adaptation of cultured renal cells to hypoxia and acidosis. Taken together, these studies will advance our understanding of the recovery phase of AKI and the particular role of annexin A1. Ultimately we aim at developing novel, mechanism-based strategies for the preservation of renal function during AKI.
*Dr. Paliege left the institution in December 2016.