Background and purpose: Stroke-prone spontaneously hypertensive rats (SHR-A3) develop strokes and progressive kidney disease as a result of naturally occurring genetic variations. We recently identified genetic variants in immune signaling pathways that contribute to end-organ injury. The present study was designed to test the hypothesis that a dysregulated immune response promotes stroke susceptibility. Methods: 20-week old male SHR-A3 rats were salt loaded and treated with the immunosuppressant mycophenolate mofetil (MMF, 25 mg/kg/day, p.o.) (n=8) or vehicle (saline) (n=9) for 8 weeks. Blood pressure (BP) was measured weekly by telemetry. Results: Compared to vehicle-treated controls, MMF-treated SHR-A3 rats had improved survival and lower neurological deficit scores (1.44 vs 0.125; P<0.02). Gross morphology of the brain revealed cerebral edema in 8 of 9, and microbleeds and hemorrhages in 5 of 9 vehicle-treated rats. These lesions were absent in MMF-treated rats. Brain CD68 expression, indicating macrophage/microglial activation, was up-regulated in vehicle-treated rats with microbleeds and hemorrhages, but was undetectable in the brains of MMF-treated rats. MMF also prevented renal injury in SHR-A3 rats, evidenced by reduced proteinuria (albumin:creatinine) from 7.52 to 1.05 mg/mg (P<0.03) and lower tubulointerstitial injury scores (2.46 vs 1.43; P<0.01). Salt loading resulted in a progressive increase in BP, which was blunted in rats receiving MMF. Conclusions: Our findings provide evidence that abnormal immune activation predisposes to cerebrovascular and renal injury in stroke-prone SHR-A3 rats.
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