Journal
NEPHROLOGY DIALYSIS TRANSPLANTATION
Volume 33, Issue 12, Pages 2128-2138Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ndt/gfy080
Keywords
6-hydroxychromanol; hypothermia/rewarming; mitochondria; renal injury; tubular cells
Categories
Funding
- Innovative Action Program Groningen 2010-13 (IAG3)
- 'Samenwerkingsverband Noord Nederland (SNN)' EFRO Tender Valorization
- Groningen University Institute for Drug Exploration
- Netherlands Organization for Health Research and Development [916.11.022, 917.16.466]
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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.
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