The role of stress-activated protein kinase signaling in renal pathophysiology

Abstract

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.

APOL1 kidney disease risk variants cause cytotoxicity by depleting cellular potassium and inducing stress-activated protein kinases

“…In humans, the severity of glomerulosclerosis correlates with the number of phospho-p38 or phospho-JNK positive glomerular cells (41,42). In animal experimental models of glomerulopathies, activation of p38 MAPK or JNK is necessary for podocyte injury and proteinuria (40,43). Consistently, inhibition of these SAPKs prevents podocyte injury, suppresses proteinuria in animal models, and mitigates glomerulonephritis (41,(43)(44)(45)(46).…”

“…The SAPKs p38 and JNK are known to be activated in the context of glomerular and tubular injury (reviewed in ref. 40). In humans, the severity of glomerulosclerosis correlates with the number of phospho-p38 or phospho-JNK positive glomerular cells (41,42).…”

TGF-β1-activated kinase-1 regulates inflammation and fibrosis in the obstructed kidney

“…The stressactivated protein kinases, c-Jun NH 2 -terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), have been shown to play a functional role in these pathologic processes in vitro and in vivo (39). Drug-based inhibitor studies and the use of gene-deficient mice established that JNK and p38 MAPK pathways promote inflammation and fibrosis in animal models of glomerular and tubulointerstitial injury (6,9,10,17,20,32,36,37,41,56,57,59,66), while examination of biopsy tissues implicated JNK and p38 signaling in the development of inflammation and fibrosis in human kidney disease (1,6,20,52,58).…”

Diabetes-Induced Renal Injury in Rats Is Attenuated by Suramin

“…NF-B, STAT-3, and ERK1/2 has been established (Soldatos and Cooper, 2008;Kuhad and Chopra, 2009;Ma et al, 2009). Therefore, we tested the hypothesis that suramin might exert its anti-inflammatory effect by modulating these factors in STZ rats.…”