ASK1/p38 signaling in renal tubular epithelial cells promotes renal fibrosis in the mouse obstructed kidney

Abstract

Stress-activated kinases p38 MAPK and JNK promote renal fibrosis; however, how the pathways by which these kinases are activated in kidney disease remain poorly defined. Apoptosis signal-regulating kinase 1 (ASK1/MAPKKK5) is a member of the MAPKKK family that can induce activation of p38 and JNK. The present study examined whether ASK1 induces p38/JNK activation and renal fibrosis in unilateral ureteric obstruction (UUO) using wild-type (WT) and Ask1-deficient (Ask1(-/-)) mice. Basal p38 and JNK activation in WT kidneys was increased three- to fivefold in day 7 UUO mice in association with renal fibrosis. In contrast, there was no increase in p38 activation in Ask1(-/-) UUO mice, whereas JNK activation was only partially increased. The progressive increase in kidney collagen (hydroxyproline) content seen on days 7 and 12 of UUO in WT mice was significantly reduced in Ask1(-/-) UUO mice in association with reduced α-smooth muscle actin-positive myofibroblast accumulation. However, cultured WT and Ask1(-/-) renal fibroblasts showed equivalent proliferation and matrix production, indicating that ASK1 acts indirectly on fibroblasts. Tubular epithelial cells are the main site of p38 activation in the obstructed kidney. Angiotensin II and H₂O₂, but not IL-1 or lipopolysaccharide, induced p38 activation and upregulation of transforming growth factor-β₁, platelet-derived growth factor-B, and monocyte chemoattractant protein-1 production was suppressed in Ask1(-/-) tubular epithelial cells. In addition, macrophage accumulation was significantly inhibited in Ask1(-/-) UUO mice. In conclusion, ASK1 is an important upstream activator of p38 and JNK signaling in the obstructed kidney, and ASK1 is a potential therapeutic target in renal fibrosis.

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

“…Mice lacking the Ask1 gene (Ask1 2/2 including normal kidney structure and function, which contrasts with the fetal lethality of mice lacking the p38a/ Mapk14 gene (16,17). In addition, Ask1 2/2 mice show a dramatic inhibition of p38 MAPK activation and significant protection from kidney injury in models of acute tubular necrosis and renal interstitial fibrosis, providing results consistent with administration of p38 inhibitors (4,(18)(19)(20). Therefore, inhibition of ASK1/p38 signaling may have therapeutic potential for diabetic glomerulosclerosis.…”

“…This is consistent with a role for ASK1 in high glucose-induced p38 activation in cultured glomerular mesangial cells (36) and the various stresses present in diabetes (e.g., oxidative stress, endoplasmic reticular stress, hyperglycemia, and angiotensin II) that are known to activate ASK1/p38 signaling (37). However, activation of p38 MAPK signaling can operate independent of ASK1 in kidney cells as shown by the unaltered lipopolysaccharide and interleukin-1-induced p38 activation and biological responses seen in Ask1 2/2 tubular epithelial cells (4). Thus, ASK1 is a context-dependent regulator of p38 activation, which is particularly important in settings of oxidative stress owing to the regulation of ASK1 activation by antioxidant proteins such as thioredoxin.…”

“…Current therapies of controlling blood pressure and blood glucose levels have only a limited benefit in slowing progression to end-stage disease (1), indicating a major gap in our treatment options. The diabetic kidney is stressed by multiple factors including hyperglycemia, reactive oxygen species, advanced glycation end products, proinflammatory cytokines, and angiotensin II-all of which can induce signaling via the p38 mitogen-activated protein kinase (MAPK) (2)(3)(4)(5). Increased activation of p38 MAPK in glomeruli and the tubulointerstitial compartment has been described in animal models of diabetic nephropathy as well as in patients with diabetic nephropathy (6)(7)(8)(9).…”

Loureirin B Inhibits Hypertrophic Scar Formation via Inhibition of the TGF-β1-ERK/JNK Pathway

“…MAPKs can be activated in liver fibrosis, increasing Col1α2 transcription [23,24]. The MAPK pathway also plays a key role in myocardial fibrosis, lung fibrosis and renal fibrosis [25][26][27][28]. In normal skin, exogenous TGF-β1 can activate p38, which can combine with the Col1α2 promotor and increase the transcription of Col1α2.…”

Mitogen-Activated Protein Kinases and Hypoxic/Ischemic Nephropathy

“…On the other hand, p38 activation of proximal tubular epithelial cells by astrocyte elevated gene-1 plays an important role in TGF-β1-induced epithelial to mesenchymal transition, which is an important cellular event in organogenesis, cancer and renal tubulointerstitial fibrosis [96]. A member of the MAPKKK family, apoptosis signal-regulating kinase 1, can induce activation of p38 and JNK to promote renal fibrosis in an obstructed mouse kidney [97]. Xu et al showed that increasing the activation of the JNK and p38 pathways plays a prominent role in renal tubular cell apoptosis, which subsequently accelerates the progression of renal tubulointerstitial fibrosis.…”