ASK1 Inhibitor Halts Progression of Diabetic Nephropathy in Nos3-Deficient Mice

Diabetes. 2015 Nov;64(11):3903-13. doi: 10.2337/db15-0384. Epub 2015 Jul 15.


p38 mitogen-activated protein kinase (MAPK) signaling promotes diabetic kidney injury. Apoptosis signal-regulating kinase (ASK)1 is one of the upstream kinases in the p38 MAPK-signaling pathway, which is activated by inflammation and oxidative stress, suggesting a possible role for ASK1 in diabetic nephropathy. In this study, we examined whether a selective ASK1 inhibitor can prevent the induction and progression of diabetic nephropathy in mice. Diabetes was induced in hypertensive endothelial nitric oxide synthase (Nos3)-deficient mice by five low-dose streptozotocin (STZ) injections. Groups of diabetic Nos3(-/-) mice received ASK1 inhibitor (GS-444217 delivered in chow) as an early intervention (2-8 weeks after STZ) or late intervention (weeks 8-15 after STZ). Control diabetic and nondiabetic Nos3(-/-) mice received normal chow. Treatment with GS-444217 abrogated p38 MAPK activation in diabetic kidneys but had no effect upon hypertension in Nos3(-/-) mice. Early intervention with GS-444217 significantly inhibited diabetic glomerulosclerosis and reduced renal dysfunction but had no effect on the development of albuminuria. Late intervention with GS-444217 improved renal function and halted the progression of glomerulosclerosis, renal inflammation, and tubular injury despite having no effect on established albuminuria. In conclusion, this study identifies ASK1 as a new therapeutic target in diabetic nephropathy to reduce renal inflammation and fibrosis independent of blood pressure control.

Trial registration: NCT02177786.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology*
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Disease Progression
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • MAP Kinase Kinase Kinase 5 / antagonists & inhibitors*
  • Male
  • Mice
  • Mice, Knockout
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism*
  • Signal Transduction / drug effects


  • Enzyme Inhibitors
  • Nitric Oxide Synthase Type III
  • MAP Kinase Kinase Kinase 5

Associated data