Targeting apoptosis signal‐regulating kinase 1 in acute and chronic kidney disease
Greg H. Tesch, Y. Frank, David J. Nikolic‐Paterson
Abstract
Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase (MAP3K) family which acts as an upstream regulator for the activation of p38 MAPK and c-Jun N-terminal kinase (JNK). Experimental studies have demonstrated a pathogenic role for p38 MAPK and JNK activation in a number of kidney disease models; however, clinical studies targeting these kinases directly have been problematic due to their role in homeostatic functions. In comparison, ASK1 is activated in pathological states and is not essential for homeostatic functions, suggesting that ASK1 may be a safe and effective therapeutic target to inhibit p38 MAPK and JNK signaling in disease. Animal model studies using Ask1 gene deficient mice or a selective ASK1 inhibitor have demonstrated that ASK1 blockade is effective in a variety of acute and chronic kidney diseases; preventing cell injury, inflammation, fibrosis, albuminuria, and renal function impairment. Positive outcomes from these experimental studies have led to the current evaluation of an ASK1 inhibitor in patients with moderate to advanced diabetic kidney disease. This review summarizes the preclinical studies of ASK1 blockade in models of acute and chronic kidney injury and a clinical study examining ASK1 inhibitor treatment in diabetic kidney disease.