The 6-hydroxychromanol derivative SUL-109 ameliorates renal injury after deep hypothermia and rewarming in rats

Pieter C Vogelaar, Maurits Roorda, Edwin L de Vrij, Martin C Houwertjes, Maaike Goris, Hjalmar Bouma, Adrianus C van der Graaf, Guido Krenning*, Robert H Henning

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

Background. Mitochondrial dysfunction plays an important role in kidney damage in various pathologies, including acute and chronic kidney injury and diabetic nephropathy. In addition to the well-studied ischaemia/reperfusion (I/R) injury, hypothermia/rewarming (H/R) also inflicts acute kidney injury. Substituted 6-hydroxychromanols are a novel class of mitochondrial medicines that ameliorate mitochondrial oxidative stress and protect the mitochondrial network. To identify a novel 6-hydroxychromanol that protects mitochondrial structure and function in the kidney during H/R, we screened multiple compounds in vitro and subsequently assessed the efficacy of the 6-hydroxychromanol derivatives SUL-109 and SUL-121 in vivo to protect against kidney injury after H/R in rats.

Methods. Human proximal tubule cell viability was assessed following exposure to H/R for 48/4 h in the presence of various 6-hydroxychromanols. Selected compounds (SUL-109, SUL-121) or vehicle were administered to ketamine-anaesthetized male Wistar rats (IV 135 mu g/kg/h) undergoing H/R at 15 degrees C for 3 h followed by rewarming and normothermia for 1 h. Metabolic parameters and body temperature were measured throughout. In addition, renal function, renal injury, histopathology and mitochondrial fitness were assessed.

Results. H/R injury in vitro lowered cell viability by 94 +/- 61%, which was counteracted dose-dependently by multiple 6-hydroxy-chomanols derivatives. In vivo, H/R in rats showed kidney injury molecule 1 expression in the kidney and tubular dilation, accompanied by double-strand DNA breaks and protein nitrosylation. SUL-109 and SUL-121 ameliorated tubular kidney damage, preserved mitochondrial mass and maintained cortical adenosine 50-triphosphate (ATP) levels, although SUL-121 did not reduce protein nitrosylation.

Conclusions. The substituted 6-hydroxychromanols SUL-109 and SUL-121 ameliorate kidney injury during in vivo H/R by preserving mitochondrial mass, function and ATP levels. In addition, both 6-hydroxychromanols limit DNA damage, but only SUL-109 also prevented protein nitrosylation in tubular cells. Therefore SUL-109 offers a promising therapeutic strategy to preserve kidney mitochondrial function.

Original languageEnglish
Pages (from-to)2128-2138
Number of pages11
JournalNephrology, Dialysis, Transplantation
Volume33
Issue number12
Early online date11-Apr-2018
DOIs
Publication statusPublished - Dec-2018

Keywords

  • 6-hydroxychromanol
  • hypothermia/rewarming
  • mitochondria
  • renal injury
  • tubular cells
  • ISCHEMIA-REPERFUSION INJURY
  • ACUTE KIDNEY INJURY
  • MITOCHONDRIAL-FUNCTION
  • ALPHA-TOCOPHEROL
  • TUBULAR CELLS
  • MECHANISMS
  • ANTIOXIDANTS
  • DYSFUNCTION
  • PREVENTION
  • MEMBRANES

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