Roles of PI3K and JAK pathways in viability of retinal ganglion cells after acute elevation of intraocular pressure in rats with different autoimmune backgrounds.
BACKGROUND
We recently showed that whereas inhibition of PI3K/akt or JAK/STAT pathway promoted retinal ganglion cell (RGC) survival after optic nerve (ON) injury in Fischer 344 (F344) rats, the same inhibition resulted in aggravated RGC loss after acute intraocular pressure (IOP) elevation in Sprague Dawley (SPD) rats. In addition, the responses of macrophages to ON injury and acute IOP elevation were different between F344 and Lewis rats, i.e., different autoimmune profiles. Using an acute IOP elevation paradigm in this study, we investigated 1) whether autoimmune background influences PI3K/akt and JAK/STAT functions by examining the effect of PI3K/akt and JAK/STAT pathway inhibition on RGC survival in F344 and Lewis rats, and 2) whether differential actions of macrophages occur in PI3K/akt and JAK/STAT pathways-dependent modulation of RGC survival. IOP elevation was performed at 110 mmHg for 2 hours. PI3K/akt and JAK/STAT pathway inhibitors were applied intravitreally to block their respective pathway signaling transduction. Because macrophage invasion was seen in the eye after the pathway inhibition, to examine the role of these pathways independent of macrophages, macrophages in the retina were removed by intravitreal application of clodronate liposomes. Viable RGCs were retrogradely labelled by FluoroGold 40 hours before animal sacrifice.


RESULTS
Similar to what was previously observed, significantly more RGCs were lost in Lewis than F344 rats 3 weeks after acute IOP elevation. As in SPD rats, inhibition of the PI3K/akt or JAK/STAT pathway increased the loss of RGCs in both F344 and Lewis rats. Removal of macrophages in the eye by clodronate liposomes reduced RGC loss due to pathway inhibition in both strains.


CONCLUSIONS
This study demonstrates that following acute IOP elevation 1) PI3K/akt and JAK/STAT pathways mediate RGC survival in both F344 and Lewis rats, 2) autoimmune responses do not influence the functions of these two pathways, and 3) PI3K/akt and JAK/STAT pathway inhibition-dependent activation of macrophages is detrimental to RGCs.
Huang
Yao
Y
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, PR China. huangyao78@163.com
Li
Zhiwei
Z
Wang
Ningli
N
van Rooijen
Nico
N
Cui
Qi
Q
D000208:Acute Disease; D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000502:physiology; D007429:Intraocular Pressure / Q000502:physiology*; D053612:Janus Kinases / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009798:Ocular Hypertension / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D012165:Retinal Ganglion Cells / Q000201:enzymology* / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology*; D013045:Species Specificity
D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases