| First Author | Ghimire K | Year | 2019 |
| Journal | FASEB J | Volume | 33 |
| Issue | 10 | Pages | 11528-11540 |
| PubMed ID | 31370677 | Mgi Jnum | J:290149 |
| Mgi Id | MGI:6435321 | Doi | 10.1096/fj.201900583R |
| Citation | Ghimire K, et al. (2019) Deficiency in SIRP-alpha cytoplasmic recruitment confers protection from acute kidney injury. FASEB J 33(10):11528-11540 |
| abstractText | 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 alpha (SIRP-alpha) is expressed on macrophages and limits inflammation and phagocytosis. SIRP-alpha 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-alpha signaling. Mice lacking SIRP-alpha cytoplasmic signaling (SIRP-alpha(mut)) and wild-type (WT) littermate controls underwent renal ischemia and reperfusion. Chimeric mice transplanted with WT or SIRP-alpha(mut) bone marrow were similarly challenged following engraftment. Molecular and immunohistochemical analysis of renal function, tissue damage, and key molecular targets was performed. SIRP-alpha(mut) 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-alpha(mut) occurred alongside down-regulation of CD47 and thrombospondin-1, which are known to exert SIRP-alpha crosstalk and also promote IR. In chimeric mice, lack of SIRP-alpha signaling conferred protection to IR regardless of the genotype of circulating cells. Renal tubular epithelial cells from SIRP-alpha(mut) mice produced fewer ROS and proinflammatory cytokines in vitro. These results identify parenchymal SIRP-alpha 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-alpha cytoplasmic recruitment confers protection from acute kidney injury. |
