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

Abstract

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.

• Authors: Greg H Tesch, Frank Y Ma, Yingjie Han, John T Liles, David G Breckenridge, David J Nikolic-Paterson
• Journal: Diabetes (Diabetes) Vol. 64 Issue 11 Pg. 3903-13 (Nov 2015) ISSN: 1939-327X [Electronic] United States
• PMID: 26180085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

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

Topics

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