Abstract P012: Mycophenolate Mofetil Prevents Cerebrovascular Injury in Stroke-prone Spontaneously Hypertensive Rats

Abstract

The stroke-prone spontaneously hypertensive rat strain (SHR-A3) develops hypertensive end-organ injury, including strokes and progressive kidney disease, as a result of naturally occurring genetic variations. Our recent work identifies genetic variants in immune signaling pathways that contribute to susceptibility to end organ injury. These variants are present in SHR-A3 animals, but absent in SHR lines that resist end organ injury. To test the hypothesis that a dysregulated immune response promotes stroke susceptibility, 20-week old male SHR-A3 rats were salt loaded (1% NaCl in drinking water) and treated daily with the immunosuppressant mycophenolate mofetil (MMF, 25 mg/kg/day, p.o.) (n=8) or vehicle (saline) (n=9) for 8 weeks. Blood pressure was measured weekly by telemetry for the duration of the study. Compared to untreated controls, MMF-treated SHR-A3 had improved survival and significantly lower neurological deficit scores (1.44 vs 0.125; p<0.02). Salt loading resulted in a progressive increase in blood pressure, which was prevented in rats receiving MMF. At the time of euthanasia, mean systolic BP in the untreated group was 243.0 ± 5.6 mmHg compared to 213.6 ± 7.1 mmHg (p<0.005) in the MMF-treated SHR-A3 group. Gross morphology of the brain revealed cerebrovascular lesions including cerebral edema in 90% (8 out of 9) and microbleeds and hemorrhages in about 50% (5 out of 9) of the untreated SHR-A3 rats. These lesions were absent in the MMF-treated cohort. The expression of CD68, a marker of activated microglia/macrophages, was up-regulated in the brain sections from vehicle-treated rats with microbleeds and hemorrhages, but was not detectable in the brains of rats receiving MMF. MMF also prevented renal injury in SHR-A3 rats, evidenced by reduced proteinuria (albumin to creatinine ratio) from 7.52 to 1.05 mg/mg (p<0.03) and lower tubulointerstitial injury scores (2.46 vs 1.43; p<0.01). Our findings provide evidence that suppression of immune activation prevents the occurrence of cerebrovascular and renal injury in salt-loaded SHR-A3 rats.