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.

The novel intracellular protein CREG inhibits hepatic steatosis, obesity, and insulin resistance

“…(37) ASK1, a member of the MAPK kinase kinase (MAP3K) family, selectively activates JNK and promotes MKK4/7 phosphorylation. (38) Notably, recent studies have shown that ASK1 is responsive to nutrient apply and closely participated in inflammation, insulin resistance, and hepatic steatosis. Furthermore, using ASK1 binding signals such as TRAF1 may negatively regulate NAFLD.…”

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

“…For instance, IKK and TANK bind to the IRE1/TRAF2 complex and subsequently activate NF-κB signaling. Moreover, ASK1 kinase, a binding partner for TRAF2, exerts several contextdependent effects on inflammation, autophagy, and apoptosis [84]. ASK1 activates the expression of inflammatory genes through the JNK-AP-1 pathway ( Fig.…”

Molecular mechanisms of trauma-induced acute kidney injury: Inflammatory and metabolic insights from animal models

“…Opening of MPTP induces cell death through the release of cytochrome c and subsequent caspase activation [128]. Taken together, these studies identify mitochondria, apoptosis and MAPK and Akt pathways related pathways as potential novel targets for treating trauma-induced AKI [117].…”

“…This has also been shown in a murine burn model, where topical application of p38 inhibitors reduces epithelial apoptosis and systemic inflammation [115,116]. New upstream targets are being identified that may act on multiple MAPKs for even more pronounced pleiotropic effects [117].…”