Mycophenolate mofetil prevents cerebrovascular injury in stroke-prone spontaneously hypertensive rats

Physiol Genomics. 2017 Mar 1;49(3):132-140. doi: 10.1152/physiolgenomics.00110.2016. Epub 2016 Dec 23.

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.

Keywords: SHRSP; immunosuppression; kidney; lymphocyte; stroke.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Pressure
  • Brain Edema / complications
  • Brain Edema / pathology
  • Brain Edema / physiopathology
  • Brain Injuries / etiology*
  • Brain Injuries / physiopathology
  • Brain Injuries / prevention & control*
  • Immunosuppression
  • Inflammation / pathology
  • Kidney / injuries
  • Kidney / pathology
  • Kidney / physiopathology
  • Mycophenolic Acid / pharmacology
  • Mycophenolic Acid / therapeutic use*
  • Rats, Inbred SHR
  • Stroke / complications*
  • Stroke / drug therapy*
  • Stroke / physiopathology
  • Survival Analysis

Substances

  • Mycophenolic Acid