Heterozygosity for Fibrinogen Results in Efficient Resolution of Kidney Ischemia Reperfusion Injury

Abstract

Fibrinogen (Fg) has been recognized to play a central role in coagulation, inflammation and tissue regeneration. Several studies have used Fg deficient mice (Fg-/-) in comparison with heterozygous mice (Fg+/-) to point the proinflammatory role of Fg in diverse pathological conditions and disease states. Although Fg+/- mice are considered 'normal', plasma Fg is reduced to ~75% of the normal circulating levels present in wild type mice (Fg+/+). We report that this reduction in Fg protein production in the Fg+/- mice is enough to protect them from kidney ischemia reperfusion injury (IRI) as assessed by tubular injury, kidney dysfunction, necrosis, apoptosis and inflammatory immune cell infiltration. Mechanistically, we observed binding of Fg to ICAM-1 in kidney tissues of Fg+/+ mice at 24 h following IRI as compared to a complete absence of binding observed in the Fg+/- and Fg-/- mice. Raf-1 and ERK were highly activated as evident by significantly higher phosphorylation in the Fg+/+ kidneys at 24 h following IRI as compared to Fg+/- and Fg-/- mice kidneys. On the other hand Cyclin D1 and pRb, indicating higher cell proliferation, were significantly increased in the Fg+/- and Fg-/- as compared to Fg+/+ kidneys. These data suggest that Fg heterozygosity allows maintenance of a critical balance of Fg that enables regression of initial injury and promotes faster resolution of kidney damage. © 2012 Ajay et al.