title: Inhibition of the p38 MAPK pathway ameliorates renal fibrosis in an NPHP2 mouse model.
abstract: BACKGROUND
  Nephronophthisis (NPHP), the most frequent genetic cause of end-stage kidney disease in children and young adults, is characterized by a variable number of renal cysts associated with cortical tubular atrophy and interstitial fibrosis. The p38 mitogen-activated protein kinase (MAPK) pathway is an important intracellular signaling pathway involved in the production of profibrotic mediators. The relationship between p38 MAPK and renal fibrosis in NPHP2 is unknown.
  
  
  METHODS
  We administered a selective p38 MAPK inhibitor, FR167653, in a NPHP2 mouse model (inv/inv, invΔC mice) from 3 to 6 weeks old, and the kidneys were examined at 6 weeks of age. Phosphorylation of p38 MAPK (p-p38 MAPK) protein levels, the degree of renal fibrosis, messenger RNA (mRNA) levels for extracellular matrix genes and mRNA levels for transforming growth factor in the kidneys were studied. Effect of an extracellular signal-regulated protein kinase (ERK) kinase (MEK) inhibitor on renal fibrosis was also evaluated.
  
  
  RESULTS
  Expression of extracellular matrix genes and p-p38 MAPK were increased in the NPHP2 mouse model kidney. FR167653 successfully decreased p-p38 MAPK levels, the degree of fibrosis and extracellular matrix gene expressions. However, the FR167653 did not prevent cyst expansion, abnormal cell proliferation and acceleration of apoptosis and did not influence ERK activation. In contrast, MEK inhibition reduced both cyst expansion and fibrosis without affecting p38 MAPK activation.
  
  
  CONCLUSIONS
  These results suggest that inhibition of p38 MAPK reduced renal fibrosis but not cyst expansion, cell proliferation and apoptosis in NPHP2 model mice. Our results suggest that p38 MAPK and ERK signaling pathways independently affect renal fibrosis in inv mutant mice.
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sugiyama
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kohno
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D003560:Cysts / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control*; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C104334:FR 167653; D006131:Growth Inhibitors; C114503:INVS protein, human; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases