title: ASK1: a new therapeutic target for kidney disease.
abstract: Stress-induced activation of p38 MAPK and JNK signaling is a feature of both acute and chronic kidney disease and is associated with disease progression. Inhibitors of p38 MAPK or JNK activation provide protection against inflammation and fibrosis in animal models of kidney disease; however, clinical trials of p38 MAPK and JNK inhibitors in other diseases (rheumatoid arthritis and pulmonary fibrosis) have been disappointing. Apoptosis signal-regulating kinase 1 (ASK1) acts as an upstream regulator for the activation of p38 MAPK and JNK in kidney disease. Mice lacking the Ask1 gene are healthy with normal homeostatic functions and are protected from acute kidney injury induced by ischemia-reperfusion and from renal interstitial fibrosis induced by ureteric obstruction. Recent studies have shown that a selective ASK1 inhibitor substantially reduced renal p38 MAPK activation and halted the progression of nephropathy in diabetic mice, and this has led to a current clinical trial of an ASK1 inhibitor in patients with stage 3 or 4 diabetic kidney disease. This review explores the rationale for targeting ASK1 in kidney disease and the therapeutic potential of ASK1 inhibitors based on current experimental evidence.
authors.affiliation: Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia;, Monash Medical Centre, Clayton, Victoria, Australia; and Monash University Department of Medicine, Monash Medical Centre, 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 Medical Centre, Clayton, Victoria, Australia; and Monash University Department of Medicine, Monash Medical Centre, 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 Medical Centre, Clayton, Victoria, Australia; and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
mesh_terms: D000818:Animals; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy* / Q000235:genetics*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D048848:MAP Kinase Kinase Kinase 5 / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D048670:MAP Kinase Kinase 4
keywords: apoptosis signal-regulating kinase 1; c-Jun NH2-terminal kinase; diabetic nephropathy; glomerulosclerosis; mitogen-activated protein kinase; p38; renal injury