The BK activator NS11021 partially protects rat kidneys from cold storage and transplantation-induced mitochondrial and renal injury

Kidneys from deceased donors used for transplantation are placed in cold storage (CS) solution during the search for a matched recipient. However, CS induces mitochondrial and cellular injury, which exacerbates renal graft dysfunction, highlighting the need for therapeutic interventions. Using an in...

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Veröffentlicht in:Archives of biochemistry and biophysics 2020-07, Vol.688, p.108410-108410, Article 108410
Hauptverfasser: Shrum, Stephen, Tobacyk, Julia, Lo, Sorena, Parajuli, Nirmala, MacMillan-Crow, Lee Ann
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Sprache:eng
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Zusammenfassung:Kidneys from deceased donors used for transplantation are placed in cold storage (CS) solution during the search for a matched recipient. However, CS induces mitochondrial and cellular injury, which exacerbates renal graft dysfunction, highlighting the need for therapeutic interventions. Using an in vitro model of renal CS, we recently reported that pharmacological activation of the mitochondrial BK channel (mitoBK) during CS protected against CS-induced mitochondrial injury and cell death. Here, we used an in vivo syngeneic rat model of renal CS (18 h) followed by transplantation (24 h reperfusion) (CS + Tx) to similarly evaluate whether addition of a mitoBK activator to the CS solution can alleviate CS + Tx-induced renal injury. Western blots detected the pore-forming α subunit of the BK channel in mitochondrial fractions from rat kidneys, and mitoBK protein level was reduced after CS + Tx compared to sham surgery. The addition of the BK activator NS11021 (3 μM) to the CS solution partially protected against CS + Tx-induced mitochondrial respiratory dysfunction, oxidative protein nitration, and cell death, but not acute renal dysfunction (SCr and BUN). In summary, the current preclinical study shows that pharmacologically targeting mitoBK channels during CS may be a promising therapeutic intervention to prevent CS + Tx-induced mitochondrial and renal injury. •Rat kidney mitochondria express the mitoBK channel, a novel therapeutic target.•Clinically relevant rat renal cold storage (CS) and transplantation model was used.•Treatment included adding mitoBK activator NS11021 to kidney in CS solution.•NS11021 mitigates CS-induced mitochondrial injury after renal transplantation.•NS11021 attenuates oxidative stress and cell death after renal transplantation.
ISSN:0003-9861
1096-0384
DOI:10.1016/j.abb.2020.108410