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Abstract
Kidneys from deceased donors used for transplantation are placed in cold storage (CS) solution during the search for a matched recipient. However, CS causes mitochondrial injury, which may exacerbate renal graft dysfunction. Here, we explored whether adding NS11021, an activator of the mitochondrial big-conductance calcium-activated K+ (mitoBK) channel, to CS solution can mitigate CS-induced mitochondrial injury. We used normal rat kidney proximal tubular epithelial (NRK) cells as an in vitro model of renal cold storage (18 h) and rewarming (2 h) (CS + RW). Western blots detected the pore-forming α subunit of the BK channel in mitochondrial fractions from NRK cells. The fluorescent K+-binding probe, PBFI-AM, revealed that isolated mitochondria from NRK cells exhibited mitoBK-mediated K+ uptake, which was impaired ~70% in NRK cells subjected to CS + RW compared to control NRK cells maintained at 37 °C. Importantly, the addition of 1 μM NS11021 to CS solution prevented CS + RW-induced impairment of mitoBK-mediated K+ uptake. The NS11021–treated NRK cells also exhibited less cell death and mitochondrial injury after CS + RW, including mitigated mitochondrial respiratory dysfunction, depolarization, and superoxide production. In summary, these new data show for the first time that mitoBK channels may represent a therapeutic target to prevent renal CS-induced injury.
Highlights
Seventy percent of kidneys used for renal transplantation are provided by deceased donors and are routinely subjected to cold storage (CS) preservation prior to transplantation (2018 UNOS website data)
normal rat kidney proximal tubular epithelial (NRK) cells and to determine whether the expression level of the mitochondrial big-conductance calcium-activated K+ (mitoBK) channel is altered in NRK cells exposed to 18 h of CS followed by 2 h of rewarming (CS + RW)
Our findings clearly demonstrate that adding NS11021 to CS solution offers protection from CS + RW-induced injury to NRK mitochondria, a finding that we attribute to the activation of mitoBK channels, it should be noted that we detected the pore-forming BKα protein in NRK
Summary
Seventy percent of kidneys used for renal transplantation are provided by deceased donors and are routinely subjected to cold storage (CS) preservation prior to transplantation (2018 UNOS website data). CS causes renal injury, worsens renal dysfunction, and increases the chance of transplant failure 5-fold compared to transplanted kidneys that have not undergone CS [5,6,7]. Despite this evident problem, there is a lack of clinical interventions to protect donor kidneys from CS-induced damage. It is imperative to identify novel therapeutic targets to prevent CS-induced injury during renal transplantation
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