AMPK activation alleviates stroke severity in mice with chronic kidney disease
Résumé
Background and aims: Ischemic stroke is highly prevalent in patients with chronic kidney disease
(CKD) and has been associated with poor outcomes. In experimental studies, CKD mice display wider
and more inflammatory ischemic lesions as well as poorer functional outcomes than mice with normal
renal function. Our group recently showed that adenosine-monophosphate-activated protein kinase
(AMPK) activation is impaired within ischemic lesions of CKD mice. In rodents with normal renal
function, AMPK activation by metformin, an anti-diabetic drug, improved stroke outcomes. This work
aimed to investigate whether a 5-week pre-conditioning with metformin can restore AMPK activity and
improve functional recovery in mice with CKD.
Methods: . Eight-week old female C57BL/6J mice were assigned to CKD or SHAM groups. CKD was
induced through right kidney cortical electrocautery followed by left total nephrectomy. Mice received
metformin (200 mg/kg/day) or vehicle in drinking water. The treatment began 1 week after CKD
induction and was given for 5 weeks until stroke induction by transient middle cerebral artery occlusion (tMCAO).
Results: . Exposure to metformin rescued AMPK activation, decreased ischemic lesion size and
improved neurological score, grip strength and prehensile abilities in CKD mice. Ischemic hemisphere
of CKD mice exposed to metformin displayed decreased microglia/macrophages pro-inflammatory M1
signature genes’ expression (i.e. CD32, CD16, CD86, IL-1b and iNOS) as well as reduced activation of
the canonical NF-KB pathway.
Conclusions: . These data demonstrate that the AMPK could be a promising therapeutic target to
decrease brain inflammation and improve stroke recovery in CKD
