TY - JOUR

T1 - Selective Deletion of NBCe1 in Reactive Astrocytes Attenuates Ischemic Stroke Brain Damage

AU - Capuk, Okan

AU - Berthold, Elise

AU - Kaliyappan, Kathiravan

AU - Avunoori, Mansi

AU - Muduganti, Rajesh

AU - Krishna, Sanjana

AU - Metwally, Shamseldin

AU - McFarland, Mary

AU - Song, Shanshan

AU - Fiesler, Victoria

AU - Fischer, Sydney

AU - Foley, Lesley M.

AU - Hitchens, T. Kevin

AU - Waxman, Susannah

AU - Sigal, Ian A.

AU - Theparambil, Shefeeq M.

AU - Begum, Gulnaz

PY - 2025/8/5

Y1 - 2025/8/5

N2 - The electrogenic sodium bicarbonate transporter 1 (NBCe1/Slc4a4), predominantly expressed in astrocytes, is important for brain pH regulation and homeostasis. Increased NBCe1 expression in reactive astrocytes has been associated with neuronal degeneration in ischemic stroke. However, the effects of astrocytic NBCe1 inhibition in stroke remain contradictory, and the underlying mechanisms are unclear. Here, we show that wild‐type (WT) mice exhibited elevated NBCe1 expression in the peri‐lesional regions at 3 days post‐stroke. Astrocytic Nbce1 gene deletion in inducible Gfap‐CreERT2+/−; Nbce1f/f mice (Nbce1iΔAstro) resulted in a significant reduction in NBCe1 mRNA and protein expression in astrocytes. Compared to WT stroke mice, Nbce1iΔAstro mice displayed reduced infarct volume, decreased brain swelling, improved cerebral blood flow, and accelerated neurological function recovery in the 1–5‐day acute post‐stroke period. Moreover, Nbce1iΔAstro stroke mice exhibited decreased blood–brain barrier (BBB) permeability, accompanied by preserved perivascular AQP4 polarization, upregulation of Kir4.1 protein expression, and reduced astrocyte domain volume. Importantly, Nbce1iΔAstro stroke brains revealed an anti‐inflammatory cytokine profiling signature, marked by increased TIMP‐1 expression. Together, our findings suggest that astrocytic upregulation of pH regulatory protein NBCe1 after stroke contributes to increased BBB permeability, reactive astrogliosis, inflammation, and perivascular AQP4 dysregulation. Targeting astrocytic NBCe1 may represent a promising new therapeutic strategy to mitigate astroglial dysfunction in the post‐stroke brain.

AB - The electrogenic sodium bicarbonate transporter 1 (NBCe1/Slc4a4), predominantly expressed in astrocytes, is important for brain pH regulation and homeostasis. Increased NBCe1 expression in reactive astrocytes has been associated with neuronal degeneration in ischemic stroke. However, the effects of astrocytic NBCe1 inhibition in stroke remain contradictory, and the underlying mechanisms are unclear. Here, we show that wild‐type (WT) mice exhibited elevated NBCe1 expression in the peri‐lesional regions at 3 days post‐stroke. Astrocytic Nbce1 gene deletion in inducible Gfap‐CreERT2+/−; Nbce1f/f mice (Nbce1iΔAstro) resulted in a significant reduction in NBCe1 mRNA and protein expression in astrocytes. Compared to WT stroke mice, Nbce1iΔAstro mice displayed reduced infarct volume, decreased brain swelling, improved cerebral blood flow, and accelerated neurological function recovery in the 1–5‐day acute post‐stroke period. Moreover, Nbce1iΔAstro stroke mice exhibited decreased blood–brain barrier (BBB) permeability, accompanied by preserved perivascular AQP4 polarization, upregulation of Kir4.1 protein expression, and reduced astrocyte domain volume. Importantly, Nbce1iΔAstro stroke brains revealed an anti‐inflammatory cytokine profiling signature, marked by increased TIMP‐1 expression. Together, our findings suggest that astrocytic upregulation of pH regulatory protein NBCe1 after stroke contributes to increased BBB permeability, reactive astrogliosis, inflammation, and perivascular AQP4 dysregulation. Targeting astrocytic NBCe1 may represent a promising new therapeutic strategy to mitigate astroglial dysfunction in the post‐stroke brain.

KW - brain pH homeostasis

KW - ischemic stroke

KW - astrocytic end‐feet

KW - NBCe1

KW - AQP4

U2 - 10.1002/glia.70075

DO - 10.1002/glia.70075

M3 - Journal article

JO - Glia

JF - Glia

SN - 0894-1491

ER -