A pathogenic role for JNK signaling in experimental anti-GBM glomerulonephritis

Kidney Int. 2007 Sep;72(6):698-708. doi: 10.1038/sj.ki.5002404. Epub 2007 Jun 27.


Activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway is involved in the immune response; however, little is known of its role in immune-induced renal injury. In this study, we examine JNK signaling in the rat anti-glomerular basement membrane (GBM) disease model using CC-401, a specific JNK inhibitor. Animals were given CC-401, vehicle alone or no treatment starting before anti-GBM serum injection and continued treatment until killing. In acute disease, CC-401 blocked JNK signaling and reduced proteinuria in the first 24 h. The transient neutrophil influx seen at 3 h of disease was not affected, however. Continued CC-401 treatment suppressed glomerular and tubulointerstitial damage usually seen at 14 days. The protective effect may be due to modulation of macrophage activation, as CC-401 had no effect upon glomerular macrophage infiltration at day 14 despite the suppression of glomerular lesions and a marked reduction in renal tumor necrosis factor-alpha and inducible nitric oxide synthase messenger RNA levels. Treatment with CC-401 had no apparent effect on T cell or humoral immune responses. These studies suggest that JNK signaling promotes renal injury in acute and progressive rat anti-GBM disease. JNK inhibitors may be a novel therapeutic approach for the treatment of human glomerulonephritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Anti-Glomerular Basement Membrane Disease / drug therapy*
  • Anti-Glomerular Basement Membrane Disease / immunology
  • Anti-Glomerular Basement Membrane Disease / metabolism*
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Enzyme Inhibitors / pharmacology*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / pathology
  • Macrophages / immunology
  • Neutrophils / immunology
  • Pyrazolones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology


  • CC 401
  • Enzyme Inhibitors
  • Pyrazolones
  • JNK Mitogen-Activated Protein Kinases