Deficiency in SIRP-α cytoplasmic recruitment confers protection from acute kidney injury

Abstract

Acute kidney injury (AKI) remains an important source of progressive chronic kidney injury. Loss of renal blood flow with subsequent restoration, termed ischemia reperfusion (IR), is a common cause of AKI. The cell surface receptor signal regulatory protein α (SIRP-α) is expressed on macrophages and limits inflammation and phagocytosis. SIRP-α has recently been found to have wider cell-based expression and play a role in renal IR. We have explored this in a genetic model of deficient SIRP-α signaling. Mice lacking SIRP-α cytoplasmic signaling (SIRP-αmut) and wild-type (WT) littermate controls underwent renal ischemia and reperfusion. Chimeric mice transplanted with WT or SIRP-αmut bone marrow were similarly challenged following engraftment. Molecular and immunohistochemical analysis of renal function, tissue damage, and key molecular targets was performed. SIRP-αmut mice were protected from renal IR compared with WT animals, demonstrating improved serum creatinine, less histologic damage, reduced proinflammatory cytokine production, and diminished production of reactive oxygen species (ROS). Resistance to renal IR in SIRP-αmut occurred alongside down-regulation of CD47 and thrombospondin-1, which are known to exert SIRP-α crosstalk and also promote IR. In chimeric mice, lack of SIRP-α signaling conferred protection to IR regardless of the genotype of circulating cells. Renal tubular epithelial cells from SIRP-αmut mice produced fewer ROS and proinflammatory cytokines in vitro. These results identify parenchymal SIRP-α as an independent driver of IR-mediated AKI and a potential therapeutic target.-Ghimire, K., Chiba, T., Minhas, N., Meijles, D. N., Lu, B., O'Connell, P., Rogers, N. M. Deficiency in SIRP-α cytoplasmic recruitment confers protection from acute kidney injury.