Loss of endogenous thymosin β(4) accelerates glomerular disease

Glomerular disease is characterized by morphologic changes in podocyte cells accompanied by inflammation and fibrosis. Thymosin β(4) regulates cell morphology, inflammation, and fibrosis in several organs and administration of exogenous thymosin β(4) improves animal models of unilateral ureteral obstruction and diabetic nephropathy. However, the role of endogenous thymosin β(4) in the kidney is unknown. We demonstrate that thymosin β(4) is expressed prominently in podocytes of developing and adult mouse glomeruli. Global loss of thymosin β(4) did not affect healthy glomeruli, but accelerated the severity of immune-mediated nephrotoxic nephritis with worse renal function, periglomerular inflammation, and fibrosis. Lack of thymosin β(4) in nephrotoxic nephritis led to the redistribution of podocytes from the glomerular tuft toward the Bowman capsule suggesting a role for thymosin β(4) in the migration of these cells. Thymosin β(4) knockdown in cultured podocytes also increased migration in a wound-healing assay, accompanied by F-actin rearrangement and increased RhoA activity. We propose that endogenous thymosin β(4) is a modifier of glomerular injury, likely having a protective role acting as a brake to slow disease progression.