Growth arrest specific protein 6/Axl signaling in human inflammatory renal diseases.
BACKGROUND
Growth arrest-specific gene 6 (Gas6) and its binding partner, the receptor tyrosine kinase Axl, are important mediators in experimental nephritis. The authors tested whether the Gas6/Axl signaling pathway participates in human renal diseases.


METHODS
The authors compared 26 human renal specimens from patients with IgA nephritis, acute diffuse immune complex glomerulonephritis, acute lupus nephritis, antineutrophil cytoplasmic antibody--associated glomerulonephritis, acute transplant rejection, and normal renal tissue. Because reactive oxygen species are pivotal in inflammation, the authors tested whether the Axl/Gas6 expression is influenced by NADPH oxidase in vitro.


RESULTS
Gas6 and Axl immunofluorescence was barely detectable in normal kidney. However, in disease Axl was copiously expressed in the small vessel media, glomeruli, distal tubules, and collecting ducts. Similarly, Gas6 was upregulated in the small vessel intima and media, all segments of the renal tubules, the brush border, and glomeruli. Gas6 and Axl upregulation was a prominent but nonspecific finding in these renal diseases. Cultured rat vascular smooth muscle cells and immortalized human mesangial cells were stimulated with angiotensin (Ang) II (1 x 10(-7) mol/L) for 6 or 18 hours. Confocal microscopy and Western blot showed Ang II-dependent Gas6 and Axl expression. An antisense probe against the p22 phox unit of NADPH-oxidase suppressed Ang II-induced Gas6 and Axl expression. In addition, in p47 phox knockout cells Ang II-induced Gas6 and Axl expression were blocked.


CONCLUSIONS
GAS6/Axl signaling is involved in human renal disease. The Ang II-induced Gas6 and Axl expression may be dependent on NADPH-oxidase. Gas6 and Axl are important signaling molecules in human renal disease and may be potential therapeutic targets.
Fiebeler
Anette
A
Helios Klinikum-Berlin, Franz Volhard Clinic at the Max Delbrück Center, Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany. fiebeler@fvk-berlin.de
Park
Joon-Keun
JK
Muller
Dominik N
DN
Lindschau
Carsten
C
Mengel
Michael
M
Merkel
Saskia
S
Banas
Bernhard
B
Luft
Friedrich C
FC
Haller
Hermann
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D005260:Female; D005920:Glomerular Mesangium / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D019255:NADPH Oxidases / Q000494:pharmacology; D015513:Oncogene Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D000804:Angiotensin II; D036341:Intercellular Signaling Peptides and Proteins; D019255:NADPH Oxidases; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6