Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma.
OBJECTIVE
To determine if oral losartan treatment decreases the retinal ganglion cell (RGC) death caused by experimental intraocular pressure (IOP) elevation in mice.


METHODS
We produced IOP increase in CD1 mice and performed unilateral optic nerve crush. Mice received oral losartan, spironolactone, enalapril, or no drug to test effects of inhibiting angiotensin receptors. IOP was monitored by Tonolab, and blood pressure was monitored by tail cuff device. RGC loss was measured in masked axon counts and RGC bodies by β-tubulin labeling. Scleral changes that could modulate RGC injury were measured including axial length, scleral thickness, and retinal layer thicknesses, pressure-strain behavior in inflation testing, and study of angiotensin receptors and pathways by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry.


RESULTS
Losartan treatment prevented significant RGC loss (median loss = 2.5%, p = 0.13), while median loss with water, spironolactone, and enalapril treatments were 26%, 28% and 43%; p < 0.0001). The lower RGC loss with losartan was significantly less than the loss with spironolactone or enalapril (regression model p = 0.001; drug treatment group term p = 0.01). Both losartan and enalapril significantly lowered blood pressure (p< 0.001), but losartan was protective, while enalapril led to worse than water-treated RGC loss. RGC loss after crush injury was unaffected by losartan treatment (difference from control p = 0.9). Survival of RGC in cell culture was not prolonged by sartan treatment. Axonal transport blockade after 3 day IOP elevations was less in losartan-treated than in control glaucoma eyes (p = 0.007). Losartan inhibited effects of glaucoma, including reduction in extracellular signal-related kinase activity and modification of glaucoma-related changes in scleral thickness and creep under controlled IOP.


CONCLUSIONS
The neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes in the sclera expressed at the optic nerve head.
The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
Harry A
HA
Quigley
The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
Ian F
IF
Pitha
The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
Derek S
DS
Welsbie
The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
Cathy
C
Nguyen
The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
Matthew R
MR
Steinhart
Department of Mechanical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.
Thao D
TD
Nguyen
The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
Mary Ellen
ME
Pease
The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
Ericka N
EN
Oglesby
The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
Cynthia A
CA
Berlinicke
The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
Katherine L
KL
Mitchell
The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
Jessica
J
Kim
The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
Joan J
JJ
Jefferys
The Glaucoma Center of Excellence, Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
Elizabeth C
EC
Kimball
D000818:Animals; D004195:Disease Models, Animal; D005901:Glaucoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D019808:Losartan / Q000008:administration & dosage*; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage; D009898:Optic Disk / Q000187:drug effects / Q000473:pathology; D012160:Retina / Q000187:drug effects / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology; D012590:Sclera / Q000187:drug effects* / Q000473:pathology
D018696:Neuroprotective Agents; D019808:Losartan