A Mutant Fibrinogen that is Unable to Form Fibrin Can Improve Renal Phenotype in Mice with Sickle Cell Anemia

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Blair Hoeting
Md Nasimuzzaman

Abstract

By Blair Hoeting, Biological Sciences


Advisor: Md Nasimuzzaman



Presentation ID: 136


Abstract: Sickle cell anemia (SCA) causes nephropathy, including tubular pathology, manifests as urine concentrating defect and glomerulopathy, manifests as albuminuria that progresses to kidney failure. Besides clot formation, fibrin(ogen) is responsible for inflammation, tissue injury, and wound healing. However, the precise roles of soluble fibrinogen vs insoluble fibrin polymers in the disease processes were impossible to investigate until the generation of FibAEK mouse that bears a germ-line mutation in the fibrinogen Aα chain at the thrombin cleavage site. Thrombin cannot cleave and release fibrinopeptide-A from this mutant fibrinogen that fails to form fibrin polymer. However, the role of fibrinogen vs fibrin in kidney damage in SCA is not investigated. To determine if soluble fibrinogen (FibAEK) can prevent kidney damage in mice with SCA, we performed bone marrow transplantation (BMT) of Berkeley sickle mice into irradiated wild-type fibrinogen (FibWT) and FibAEK mice, and analyzed kidney functions and pathology. We found reduced albuminuria in SS FibAEK mice compared with SS FibWT mice at 12 months post-BMT. Kidney sections of SS FibAEK mice had reduced kidney fibrosis, ischemic lesions, and increased survival of podocytes in the glomeruli compared with SS FibWT mice. However, urine concentrating ability was not improved in SS FibAEK mice compared to SS FibWT mice. Therefore, FibAEK mutation offers protection from the development of glomerulopathology resulting in reduced albuminuria in mice with SCA but does not affect urine concentrating ability. FibAEK mutation may represent a novel therapeutic target to protect against kidney damage.

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New Frontiers