c-Jun NH2-terminal kinase is crucially involved in renal tubulo-interstitial inflammation.

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 tubulo-interstitial 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-1beta-, transforming growth factor-beta-, or bovine serum albumin-induced MCP-1 expression in a potent manner (up to 150-fold). In the rat I/R model, JNK activation was low in controls but induced in tubular cells from 30 min after I/R. The extent of JNK activation correlated with interstitial macrophage accumulation. Treatment with SP600125 (30 mg/kg/day i.p. for 4 days) reduced renal c-Jun activation; MCP-1, osteopontin, and vimentin expression; and interstitial macrophage and T-cell accumulation (all p < 0.05). In human renal disease, we also found induction of JNK activation, which correlated strongly with interstitial macrophage accumulation, tubulointerstitial fibrosis, and renal function loss. In conclusion, these data indicate that the JNK pathway plays an important role in renal inflammation, at least in part through induction of MCP-1 gene expression in tubular epithelial cells.