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Growth arrest specific protein 6/Axl signaling in human inflammatory renal diseases
Anette Fiebeler1, Joon-Keun Park, Dominik N Muller
1Helios 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
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.
Conclusion:
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.
Insights
Growth arrest-specific gene 6 (Gas6) and its receptor Axl are involved in human kidney diseases. Their expression is increased in diseased kidneys and regulated by angiotensin II via NADPH oxidase, suggesting therapeutic potential.
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- Growth arrest-specific gene 6 (Gas6) and its receptor tyrosine kinase Axl are implicated in experimental nephritis.
- The Gas6/Axl signaling pathway's role in human renal diseases remains unclear.
Purpose of the Study:
- To investigate the involvement of the Gas6/Axl signaling pathway in human renal diseases.
- To determine if NADPH oxidase influences Gas6/Axl expression in vitro.
Main Methods:
- Comparative analysis of 26 human renal specimens (various nephritis types and normal controls).
- Immunofluorescence and Western blot to assess Gas6 and Axl expression.
- In vitro studies using cultured cells stimulated with angiotensin II and NADPH oxidase inhibitors/knockout models.
Main Results:
- Gas6 and Axl were minimally detected in normal kidneys but significantly upregulated in various human renal diseases.
- Angiotensin II stimulation increased Gas6 and Axl expression in cultured cells.
- NADPH oxidase activity, specifically the p22 phox and p47 phox subunits, was crucial for angiotensin II-induced Gas6 and Axl expression.
Conclusions:
- The Gas6/Axl signaling pathway is actively involved in human renal diseases.
- Angiotensin II-induced Gas6 and Axl expression is likely mediated by NADPH oxidase.
- Gas6 and Axl represent potential therapeutic targets for human renal diseases.
