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

Arch Biochem Biophys. 2020 Jul 30;688:108410. doi: 10.1016/j.abb.2020.108410. Epub 2020 May 21.

Abstract

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.

Keywords: Cold storage; Kidney transplantation; Mitochondria; NS11021; Oxidative stress; mitoBK channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cryopreservation
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Transplantation / adverse effects*
  • Large-Conductance Calcium-Activated Potassium Channels / agonists*
  • Large-Conductance Calcium-Activated Potassium Channels / metabolism
  • Male
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Rats
  • Tetrazoles / pharmacology*
  • Thiourea / analogs & derivatives*
  • Thiourea / pharmacology

Substances

  • 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-bromo-2-(1H-tetrazol-5-yl)phenyl)thiourea
  • Large-Conductance Calcium-Activated Potassium Channels
  • Tetrazoles
  • Thiourea