title: Mycophenolate mofetil prevents cerebrovascular injury in stroke-prone spontaneously hypertensive rats.
abstract: 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. We salt-loaded 20 wk old male SHR-A3 rats and treated them with the immunosuppressant mycophenolate mofetil (MMF, 25 mg/kg/day po) (n= 8) or vehicle (saline) (n= 9) for 8 wk. Blood pressure (BP) was measured weekly by telemetry. Compared with 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 upregulated 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. Our findings provide evidence that abnormal immune activation predisposes to cerebrovascular and renal injury in stroke-prone SHR-A3 rats.
authors.affiliation: Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas; and.
authors.forename: Isha S
authors.initials: IS
authors.lastname: Dhande
authors.affiliation: Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas; and.
authors.forename: Yaming
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Braun
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: M John
authors.initials: MJ
authors.lastname: Hicks
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Scott E
authors.identifier: 0000-0002-8991-8277
authors.initials: SE
authors.lastname: Wenderfer
authors.affiliation: Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas; and peter.a.doris@uth.tmc.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Doris
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001929:Brain Edema / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D009173:Mycophenolic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D011918:Rats, Inbred SHR; D020521:Stroke / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D016019:Survival Analysis
chemical_list: D009173:Mycophenolic Acid
keywords: SHRSP; immunosuppression; kidney; lymphocyte; stroke