title: 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.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia Monash University Department of Medicine, Clayton, Victoria, Australia greg.tesch@monash.edu.
authors.forename: Greg H
authors.initials: GH
authors.lastname: Tesch
authors.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia Monash University Department of Medicine, Clayton, Victoria, Australia.
authors.forename: Frank Y
authors.initials: FY
authors.lastname: Ma
authors.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia Monash University Department of Medicine, Clayton, Victoria, Australia.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Han
authors.affiliation: Gilead Sciences, Foster City, CA.
authors.forename: John T
authors.initials: JT
authors.lastname: Liles
authors.affiliation: Gilead Sciences, Foster City, CA.
authors.forename: David G
authors.initials: DG
authors.lastname: Breckenridge
authors.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia Monash University Department of Medicine, Clayton, Victoria, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D052250:Nitric Oxide Synthase Type III; D048848:MAP Kinase Kinase Kinase 5