G H TESCH1,2, F Y MA1,2, S S BADAL3, J T LILES3, D J NIKOLIC-PATERSON1,2
1Nephrology Department, Monash Health, Clayton, Australia, 2Department of Medicine, Monash University, Clayton, Australia, 3Gilead Sciences, Foster City, USA
Aim: To assess whether ASK1 blockade inhibits the progression of experimental diabetic kidney disease by reducing stress-induced premature senescence (SIPS) and its consequences.
Background: The development of SIPS in kidney tubular epithelial cells (TEC) results in the release of stress-associated secretory proteins (SASPs), including proinflammatory and profibrotic factors which promote progression of kidney diseases. Activation of p38 MAPK is a key mechanism promoting SIPS. Therefore, we hypothesized that blockade of ASK1-p38 MAPK signalling would inhibit kidney diseases by reducing SIPS and SASPs.
Methods: Development of SIPS and production of SASPs were assessed in archived tissue from a model of progressive fibrotic kidney disease – streptozotocin (STZ)-induced diabetic kidney disease (DKD) in hypertensive endothelial nitric oxide synthase (Nos3) deficient mice. Mice with DKD were treated with an ASK1 inhibitor (GS-444217) as either an early intervention (2-8 weeks after STZ) or a late intervention (8-15 weeks after STZ).
Results: STZ-induced diabetes resulted in the development of senescent TEC in Nos3-/- mice. Treatment with GS-444217 blocked activation of the p38 MAPK pathway without affecting hyperglycaemia. This was associated with reduced levels of cellular senescence (Cdkn2A) and SASPs (CCL2, TNF-α, TGF-β1), which correlated with diminished levels of kidney fibrosis and renal function impairment. Therapeutic blockade of ASK1 was effective in reducing SIPS as both an early intervention (Cdkn2A ↓51%; P=0.0005) and as a late intervention (Cdkn2A ↓45%; P=0.02) in the DKD model.
Conclusion: Our data show that ASK1 inhibition reduces SIPS and SASPs independent of the underlying diabetic state. This may contribute to the overall benefit seen with ASK1 blockade in DKD. Further studies are warranted to explore this mechanism.
Associate Professor Greg Tesch is Head of Diabetes Research in the Nephrology Department at Monash Health. He has expertise in the study of inflammatory and fibrotic mechanisms in diabetic kidney disease. His research has led to the development and clinical trials of CCR2 antagonists and an ASK1 inhibitor for the treatment of diabetic kidney disease.