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

Overview

Journal Physiol Genomics

Publisher American Physiological Society

Specialties Genetics
Molecular Biology

Date 2016 Dec 25

PMID 28011882

Citations 6

Authors

Isha S Dhande

Yaming Zhu

Michael C Braun

M John Hicks

Scott E Wenderfer

Peter A Doris

Affiliations

Soon will be listed here.

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) ( = 8) or vehicle (saline) ( = 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; < 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 ( < 0.03) and lower tubulointerstitial injury scores (2.46 vs. 1.43; < 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.

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