| First Author | Yang L | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 4 | Pages | 1620-36 |
| PubMed ID | 25751064 | Mgi Jnum | J:222096 |
| Mgi Id | MGI:5643968 | Doi | 10.1172/JCI75417 |
| Citation | Yang L, et al. (2015) KIM-1-mediated phagocytosis reduces acute injury to the kidney. J Clin Invest 125(4):1620-36 |
| abstractText | Kidney injury molecule 1 (KIM-1, also known as TIM-1) is markedly upregulated in the proximal tubule after injury and is maladaptive when chronically expressed. Here, we determined that early in the injury process, however, KIM-1 expression is antiinflammatory due to its mediation of phagocytic processes in tubule cells. Using various models of acute kidney injury (AKI) and mice expressing mutant forms of KIM-1, we demonstrated a mucin domain-dependent protective effect of epithelial KIM-1 expression that involves downregulation of innate immunity. Deletion of the mucin domain markedly impaired KIM-1-mediated phagocytic function, resulting in increased proinflammatory cytokine production, decreased antiinflammatory growth factor secretion by proximal epithelial cells, and a subsequent increase in tissue macrophages. Mice expressing KIM-1Deltamucin had greater functional impairment, inflammatory responses, and mortality in response to ischemia- and cisplatin-induced AKI. Compared with primary renal proximal tubule cells isolated from KIM-1Deltamucin mice, those from WT mice had reduced proinflammatory cytokine secretion and impaired macrophage activation. The antiinflammatory effect of KIM-1 expression was due to the interaction of KIM-1 with p85 and subsequent PI3K-dependent downmodulation of NF-kappaB. Hence, KIM-1-mediated epithelial cell phagocytosis of apoptotic cells protects the kidney after acute injury by downregulating innate immunity and inflammation. |
