The role of stress-activated protein kinase signaling in renal pathophysiology.
Two major stress-activated protein kinases are the p38 mitogen-activated protein kinase (MAPK) and the c-Jun amino terminal kinase (JNK). p38 and JNK are widely expressed in different cell types in various tissues and can be activated by a diverse range of stimuli. Signaling through p38 and JNK is critical for embryonic development. In adult kidney, p38 and JNK signaling is evident in a restricted pattern suggesting a normal physiological role. Marked activation of both p38 and JNK pathways occurs in human renal disease, including glomerulonephritis, diabetic nephropathy and acute renal failure. Administration of small molecule inhibitors of p38 and JNK has been shown to provide protection from renal injury in different types of experimental kidney disease through inhibition of renal inflammation, fibrosis, and apoptosis. In particular, a role for JNK signaling has been identified in macrophage activation resulting in up-regulation of pro-inflammatory mediators and the induction of renal injury. The ability to provide renal protection by blocking either p38 or JNK indicates a lack of redundancy for these two signaling pathways despite their activation by common stimuli. Therefore, the stress-activated protein kinases, p38 and JNK, are promising candidates for therapeutic intervention in human renal diseases.
Ma
F Y
FY
Department of Nephrology and Monash University Department of Medicine, Monash Medical Center, 246 Clayton Road, Clayton, Victoria, Australia.
Liu
J
J
Nikolic-Paterson
D J
DJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases