Activin A Antagonism with Follistatin Reduces Kidney Fibrosis, Injury, and Cellular Senescence-Associated Inflammation in Murine Diabetic Kidney Disease.

Abstract

Background: Circulating activin A, an inflammatory mediator implicated in profibrotic kidney injury and cellular senescence-induced adipose tissue dysfunction, is increased in human diabetic kidney disease (DKD) and directly correlates with kidney dysfunction. We tested the hypothesis that activin A increases kidney injury, senescent cell abundance, and macrophage infiltration in DKD and antagonism through follistatin therapy diminishes these effects.

Methods: An accelerated nephropathy type 2 diabetes (db/db) mouse model was generated by implantation of angiotensin II-loaded osmotic minipumps resulting in increased albuminuria and glomerular and tubular injury. Kidney repair effects of follistatin (5µg intraperitoneal; two doses) were assessed through markers of kidney injury, fibrosis, inflammation, cellular senescence, and macrophage infiltration. In vitro studies examined anti-activin effects of follistatin on high glucose-exposed human monocytes, renal fibroblasts, and renal tubule epithelial cells.

Results: Activin A antagonism with follistatin reduced senescence (p19), pro-inflammatory (including senescence-associated secretory phenotype), and pro-fibrotic markers including activin A. Follistatin improved kidney morphology, restored podocyte markers (nephrin and Wilms tumor-1) and reduced kidney injury biomarkers, albuminuria and kidney fibrosis. Follistatin decreased kidney macrophage and leukocyte infiltration and AIM2 inflammasome activation. Follistatin appeared to suppress inflammation through the toll-like receptor-4 (TLR4)/nuclear factor-κB (NF-κB) pathway in vivo further supported in human macrophages in vitro. Additionally, follistatin reduced hyperglycemia-induced renal fibroblast activation and renal tubule epithelial cell senescence in vitro.

Conclusion: Activin A is a mediator of kidney injury through macrophage-associated inflammation in murine DKD. Follistatin acts through senomorphic activities which inhibit profibrotic, proinflammatory, and pro-senescence signaling by activin A. Hence, anti-activin targeting may aid in development of a promising, novel therapeutic for DKD.