A Pathogenic Role for c-Jun Amino-Terminal Kinase Signaling in Renal Fibrosis and Tubular Cell Apoptosis

Abstract

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-␤1 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.

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

“…Genetic deletion of either Jnk1 or Jnk2 did not prevent the marked activation of JNK signaling seen in the obstructed kidney, or affect the development of renal fibrosis, demonstrating redundancy between the two JNK isoforms. However, tubular epithelial cell apoptosis was significantly reduced in Jnk1-/-mice, identifying a specific role for this isoform in one aspect of renal injury (19). The identification of both MKK3 and JNK1 in tubular apoptosis in the obstructed kidney is supported by studies in which stretch-induced apoptosis of cultured tubular cells is dependent upon p38 and JNK signaling (44).…”

“…The JNK signaling pathway also shows dramatic activation in tubular epithelial cells and myofibroblasts in the obstructed kidney (19). Administration of a JNK inhibitor was effective in preventing c-Jun phosphorylation and significantly reducing interstitial myofibroblast accumulation and collagen synthesis and deposition.…”

“…In addition, sodium reabsorption from tubules may also be affected by JNK activation through regulation of the synthesis of Na-K-ATPase γ-subunit (17,18). Administration of JNK inhibitor drugs to rats has shown no overall or renal toxicity (16,19), suggesting that JNK signaling is not critical for renal physiology -although this needs to be rigorously examined.…”

“…Administration of a JNK inhibitor was effective in preventing c-Jun phosphorylation and significantly reducing interstitial myofibroblast accumulation and collagen synthesis and deposition. In contrast to p38 blockade, inhibition of JNK signaling in the obstructed kidney caused a substantial reduction in TGF-β1 mRNA, indicating that JNK but not p38 signaling is required for upregulation of TGF-β1 expression (19,42). As both JNK1 and JNK2 isoforms are expressed in the kidney, interstitial fibrosis in Jnk1-/-and Jnk2-/-mice was examined in the obstructive kidney.…”

Emodin inhibits extracellular matrix synthesis by suppressing p38 and ERK1/2 pathways in TGF-β1-stimulated NRK-49F cells

“…Angiotensin II promotes ECM synthesis by activating the ERK and p38 pathways (12). ERK, p38 and JNK are also involved in the process of renal fibrosis in UUO rats (13)(14)(15). The activation of ERK and p38 induces the synthesis of TGF-β1 to form a vicious cycle aggravating renal fibrosis (16).…”