c-Jun NH₂-Terminal Kinase Is Crucially Involved in Renal Tubulo-Interstitial Inflammation

Abstract

Chronic inflammation is a major outcome determinant in several renal disorders. Induction of monocyte chemoattractant protein (MCP)-1 expression in tubular epithelial cells contributes importantly to the recruitment of inflammatory cells from the circulation toward the damaged tubulo-interstitium. Because the MCP-1 gene contains several c-Jun binding sites, we hypothesized that the c-Jun NH 2 -terminal kinase (JNK) pathway regulates MCP-1 expression and subsequently tubulointerstitial inflammation. This was investigated in cultured rat tubular epithelial cells (NRK-52E) and in the rat unilateral ischemia/reperfusion (I/R) model. In NRK-52E cells, the JNK inhibitor anthra(1,9-cd)pyrazol-6(2H)-one-1,9-pyrazoloanthrone (SP600125) reduced interleukin-1␤-, transforming growth factor-␤-, or bovine serum albumin-induced MCP-1

Capsaicin attenuates palmitate-induced expression of macrophage inflammatory protein 1 and interleukin 8 by increasing palmitate oxidation and reducing c-Jun activation in THP-1 (human acute monocytic leukemia cell) cells

“…The activation of JNK and p38 is stimulated by inflammatory responses. The JNK pathway plays an important role in renal inflammation through the induction of MCP-1 gene expression in tubular epithelial cells [34]. Our finding that palmitate activated JNK and c-Jun and induced MIP-1 expression in THP-1 macrophages agrees with an earlier report showing that adipocyte hypertrophy induced by palmitate loading caused oxidative stress, which activated JNK and IκB signaling and increased MCP-1 expression and secretion [33].…”

PTEN loss defines a TGF-β-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis

“…8E), but not TGF-␤, PDGF-B, or CTGF expression (not shown). Nevertheless, JNK inhibition ameliorated fibrosis after IRI (10,17,45). By itself, PTEN depletion likely cannot explain TIF and requires cooperation with other TGF-␤ intermediates.…”

“…Repair of kidney injury is associated with phlogistic and profibrotic signaling by c-Jun N-terminal kinase (JNK) (10,26,27,45) and JNK inhibition decreases TIF after ischemia (10,45). JNK and c-Jun were activated by 2 h of IRI (Fig.…”

“…Tubule defects that cause TIF after AKI include increased activity of transforming growth factor (TGF)-␤ (14, 37), Notch (3), c-Jun N-terminal kinase (JNK) (10,17,27,45), plateletderived growth factor (PDGF)-B (39), and connective tissue growth factor (CTGF) (45). These abnormalities may be interconnected; and TGF-␤ may be a proximal trigger.…”

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). Activation of the transcription factor, nuclear factor-B (NF-B), is another major proinflammatory signaling pathway, and this pathway is activated in human and experimental kidney disease with NF-B inhibitors being protective in animal models of glomerular disease (45,51,52,64,69).…”