Loss of endogenous thymosin β₄ accelerates glomerular disease.

Abstract

Glomerular disease is characterized by morphologic changes in podocyte cells accompanied by inflammation and fibrosis. Thymosin β₄ regulates cell morphology, inflammation, and fibrosis in several organs and administration of exogenous thymosin β₄ improves animal models of unilateral ureteral obstruction and diabetic nephropathy. However, the role of endogenous thymosin β₄ in the kidney is unknown. We demonstrate that thymosin β₄ is expressed prominently in podocytes of developing and adult mouse glomeruli. Global loss of thymosin β₄ 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 β₄ in nephrotoxic nephritis led to the redistribution of podocytes from the glomerular tuft toward the Bowman capsule suggesting a role for thymosin β₄ in the migration of these cells. Thymosin β₄ 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 β₄ is a modifier of glomerular injury, likely having a protective role acting as a brake to slow disease progression.