Renal
fibrosis and tubular apoptosis are common mechanisms of progressive
kidney disease. In vitro studies have implicated the
c-Jun amino-terminal kinase (JNK) pathway in these processes. Both of the major JNK
isoforms, JNK1 and JNK2, are expressed in the kidney, but their relative contribution to JNK signaling is unknown. This study investigated the role of JNK signaling in renal
fibrosis and tubular apoptosis in the unilateral
ureteral obstruction model using two different approaches: (1) Mice that were deficient in either JNK1 or JNK2 and (2) a specific inhibitor of all JNK
isoforms,
CC-401. Western blotting and immunostaining identified a marked increase in JNK signaling in the obstructed kidney, with substantial redundancy between JNK1 and JNK2
isoforms. Administration of
CC-401 blocked JNK signaling in the rat obstructed kidney and significantly inhibited renal
fibrosis in terms of interstitial myofibroblast accumulation and
collagen IV deposition. This effect was attributed to suppression of gene transcription for the profibrotic molecules
TGF-beta1 and
connective tissue growth factor.
CC-401 treatment also significantly reduced tubular apoptosis in the obstructed kidney. Genetic deletion of JNK1 or JNK2 did not protect mice from renal
fibrosis in the unilateral
ureteral obstruction model, but JNK1 deletion did result in a significant reduction in tubular cell apoptosis. In conclusion, this is the first study to demonstrate that JNK signaling plays a pathogenic role in renal
fibrosis and tubular apoptosis. Furthermore, JNK1 plays a nonredundant role in tubular cell apoptosis. These studies identify the JNK pathway as a potential therapeutic target in progressive
kidney disease.